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Krauklis SA, Towers AE, York JM, Baynard T, Gainey SJ, Freund GG, Steelman AJ. Mouse Testing Methods in Psychoneuroimmunology: Measuring Behavioral Responses. Methods Mol Biol 2025; 2868:163-203. [PMID: 39546231 DOI: 10.1007/978-1-0716-4200-9_10] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2024]
Abstract
The field of psychoneuroimmunology (PNI) aims to uncover the processes and consequences of nervous, immune, and endocrine system relationships. Behavior is a consequence of such interactions and manifests from a complex interweave of factors including immune-to-neural and neural-to-immune communication. Often the signaling molecules involved during a particular episode of neuroimmune activation are not known, but behavioral response provides evidence that bioactives such as neurotransmitters and cytokines are perturbed. Immunobehavioral phenotyping is a first-line approach when examining the neuroimmune system and its reaction to immune stimulation or suppression. Behavioral response is significantly more sensitive than direct measurement of a single specific bioactive and can quickly and efficiently rule in or out relevance of a particular immune challenge or therapeutic to neuroimmunity. Classically, immunobehavioral research was focused on sickness symptoms related to bacterial infection, but neuroimmune activation is now a recognized complication of diseases and disorders ranging from cancer to diabesity to Alzheimer's. Immunobehaviors include lethargy, loss of appetite, and disinterest in social activity/surrounding environment. In addition, neuroimmune activation can diminish physical activity, precipitate feelings of depression and anxiety, and impair cognitive and executive function. Provided is a detailed overview of behavioral tests frequently used to examine neuroimmune activation in mice with a special emphasis on pre-experimental conditions that can confound or prevent successful immunobehavioral experimentation.
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Affiliation(s)
- Steven A Krauklis
- Department of Animal Sciences, University of Illinois at Urbana-Champaign, Champaign, IL, USA
- Division of Nutritional Sciences, University of Illinois at Urbana-Champaign, Champaign, IL, USA
| | - Albert E Towers
- Division of Nutritional Sciences, University of Illinois at Urbana-Champaign, Champaign, IL, USA
| | - Jason M York
- Department of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, IL, USA
| | - Tracy Baynard
- Academic Affairs, University of Massachusetts-Boston, Boston, MA, USA
| | - Stephen J Gainey
- Department of Animal Sciences, University of Illinois at Urbana-Champaign, Champaign, IL, USA
| | - Gregory G Freund
- Department of Pathology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - Andrew J Steelman
- Department of Animal Sciences, University of Illinois at Urbana-Champaign, Champaign, IL, USA.
- Division of Nutritional Sciences, University of Illinois at Urbana-Champaign, Champaign, IL, USA.
- Neuroscience Program, University of Illinois at Urbana-Champaign, Champaign, IL, USA.
- Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Champaign, IL, USA.
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2
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Prasad J, Van Steenwinckel J, Gunn AJ, Bennet L, Korzeniewski SJ, Gressens P, Dean JM. Chronic Inflammation Offers Hints About Viable Therapeutic Targets for Preeclampsia and Potentially Related Offspring Sequelae. Int J Mol Sci 2024; 25:12999. [PMID: 39684715 PMCID: PMC11640791 DOI: 10.3390/ijms252312999] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2024] [Revised: 11/22/2024] [Accepted: 11/26/2024] [Indexed: 12/18/2024] Open
Abstract
The combination of hypertension with systemic inflammation during pregnancy is a hallmark of preeclampsia, but both processes also convey dynamic information about its antecedents and correlates (e.g., fetal growth restriction) and potentially related offspring sequelae. Causal inferences are further complicated by the increasingly frequent overlap of preeclampsia, fetal growth restriction, and multiple indicators of acute and chronic inflammation, with decreased gestational length and its correlates (e.g., social vulnerability). This complexity prompted our group to summarize information from mechanistic studies, integrated with key clinical evidence, to discuss the possibility that sustained or intermittent systemic inflammation-related phenomena offer hints about viable therapeutic targets, not only for the prevention of preeclampsia, but also the neurobehavioral and other developmental deficits that appear to be overrepresented in surviving offspring. Importantly, we feel that carefully designed hypothesis-driven observational studies are necessary if we are to translate the mechanistic evidence into child health benefits, namely because multiple pregnancy disorders might contribute to heightened risks of neuroinflammation, arrested brain development, or dysconnectivity in survivors who exhibit developmental problems later in life.
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Affiliation(s)
- Jaya Prasad
- Department of Physiology, Faculty of Medical and Health Sciences, University of Auckland, Auckland 1142, New Zealand; (J.P.); (A.J.G.); (L.B.); (J.M.D.)
| | | | - Alistair J. Gunn
- Department of Physiology, Faculty of Medical and Health Sciences, University of Auckland, Auckland 1142, New Zealand; (J.P.); (A.J.G.); (L.B.); (J.M.D.)
| | - Laura Bennet
- Department of Physiology, Faculty of Medical and Health Sciences, University of Auckland, Auckland 1142, New Zealand; (J.P.); (A.J.G.); (L.B.); (J.M.D.)
| | - Steven J. Korzeniewski
- C.S. Mott Center for Human Growth and Development, Department of Emergency Medicine, Wayne State University School of Medicine, Detroit, MI 48202, USA
| | - Pierre Gressens
- Inserm, Neurodiderot, Université de Paris, 75019 Paris, France;
- Centre for the Developing Brain, Division of Imaging Sciences and Department of Biomedical Engineering, King’s College London, King’s Health Partners, St. Thomas’ Hospital, London SE1 7EH, UK
| | - Justin M. Dean
- Department of Physiology, Faculty of Medical and Health Sciences, University of Auckland, Auckland 1142, New Zealand; (J.P.); (A.J.G.); (L.B.); (J.M.D.)
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Zhang Y, Wang Z, Xu F, Liu Z, Zhao Y, Yang LZ, Fang W. Progress of Astrocyte-Neuron Crosstalk in Central Nervous System Diseases. Neurochem Res 2024; 49:3187-3207. [PMID: 39292330 DOI: 10.1007/s11064-024-04241-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2024] [Revised: 08/08/2024] [Accepted: 09/04/2024] [Indexed: 09/19/2024]
Abstract
Neurons are the primary cells responsible for information processing in the central nervous system (CNS). However, they are vulnerable to damage and insult in a variety of neurological disorders. As the most abundant glial cells in the brain, astrocytes provide crucial support to neurons and participate in synapse formation, synaptic transmission, neurotransmitter recycling, regulation of metabolic processes, and the maintenance of the blood-brain barrier integrity. Though astrocytes play a significant role in the manifestation of injury and disease, they do not work in isolation. Cellular interactions between astrocytes and neurons are essential for maintaining the homeostasis of the CNS under both physiological and pathological conditions. In this review, we explore the diverse interactions between astrocytes and neurons under physiological conditions, including the exchange of neurotrophic factors, gliotransmitters, and energy substrates, and different CNS diseases such as Alzheimer's disease, Parkinson's disease, stroke, traumatic brain injury, and multiple sclerosis. This review sheds light on the contribution of astrocyte-neuron crosstalk to the progression of neurological diseases to provide potential therapeutic targets for the treatment of neurological diseases.
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Affiliation(s)
- Yi Zhang
- Department of Physiology, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Mailbox 207, Tongjiaxiang 24, Nanjing, 210009, P. R. China
| | - Ziyu Wang
- Department of Physiology, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Mailbox 207, Tongjiaxiang 24, Nanjing, 210009, P. R. China
| | - Fenglian Xu
- Department of Physiology, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Mailbox 207, Tongjiaxiang 24, Nanjing, 210009, P. R. China
| | - Zijun Liu
- Department of Physiology, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Mailbox 207, Tongjiaxiang 24, Nanjing, 210009, P. R. China
| | - Yu Zhao
- Department of Physiology, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Mailbox 207, Tongjiaxiang 24, Nanjing, 210009, P. R. China
| | - Lele Zixin Yang
- Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania, PA, 19107, USA
| | - Weirong Fang
- Department of Physiology, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Mailbox 207, Tongjiaxiang 24, Nanjing, 210009, P. R. China.
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4
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Wies Mancini VSB, Mattera VS, Pasquini JM, Pasquini LA, Correale JD. Microglia-derived extracellular vesicles in homeostasis and demyelination/remyelination processes. J Neurochem 2024; 168:3-25. [PMID: 38055776 DOI: 10.1111/jnc.16011] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2023] [Revised: 10/10/2023] [Accepted: 11/03/2023] [Indexed: 12/08/2023]
Abstract
Microglia (MG) play a crucial role as the predominant myeloid cells in the central nervous system and are commonly activated in multiple sclerosis. They perform essential functions under normal conditions, such as actively surveying the surrounding parenchyma, facilitating synaptic remodeling, engulfing dead cells and debris, and protecting the brain against infectious pathogens and harmful self-proteins. Extracellular vesicles (EVs) are diverse structures enclosed by a lipid bilayer that originate from intracellular endocytic trafficking or the plasma membrane. They are released by cells into the extracellular space and can be found in various bodily fluids. EVs have recently emerged as a communication mechanism between cells, enabling the transfer of functional proteins, lipids, different RNA species, and even fragments of DNA from donor cells. MG act as both source and recipient of EVs. Consequently, MG-derived EVs are involved in regulating synapse development and maintaining homeostasis. These EVs also directly influence astrocytes, significantly increasing the release of inflammatory cytokines like IL-1β, IL-6, and TNF-α, resulting in a robust inflammatory response. Furthermore, EVs derived from inflammatory MG have been found to inhibit remyelination, whereas Evs produced by pro-regenerative MG effectively promote myelin repair. This review aims to provide an overview of the current understanding of MG-derived Evs, their impact on neighboring cells, and the cellular microenvironment in normal conditions and pathological states, specifically focusing on demyelination and remyelination processes.
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Affiliation(s)
- V S B Wies Mancini
- Departamento de Química Biológica, Facultad de Farmacia y Bioquímica, Cátedra de Química Biológica Patológica, Universidad de Buenos Aires, Buenos Aires, Argentina
- Consejo Nacional de Investigaciones Científicas y Técnicas, Facultad de Farmacia y Bioquímica, Instituto de Química y Fisicoquímica Biológicas Prof. Dr. Alejandro C. Paladini, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - V S Mattera
- Departamento de Química Biológica, Facultad de Farmacia y Bioquímica, Cátedra de Química Biológica Patológica, Universidad de Buenos Aires, Buenos Aires, Argentina
- Consejo Nacional de Investigaciones Científicas y Técnicas, Facultad de Farmacia y Bioquímica, Instituto de Química y Fisicoquímica Biológicas Prof. Dr. Alejandro C. Paladini, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - J M Pasquini
- Departamento de Química Biológica, Facultad de Farmacia y Bioquímica, Cátedra de Química Biológica Patológica, Universidad de Buenos Aires, Buenos Aires, Argentina
- Consejo Nacional de Investigaciones Científicas y Técnicas, Facultad de Farmacia y Bioquímica, Instituto de Química y Fisicoquímica Biológicas Prof. Dr. Alejandro C. Paladini, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - L A Pasquini
- Departamento de Química Biológica, Facultad de Farmacia y Bioquímica, Cátedra de Química Biológica Patológica, Universidad de Buenos Aires, Buenos Aires, Argentina
- Consejo Nacional de Investigaciones Científicas y Técnicas, Facultad de Farmacia y Bioquímica, Instituto de Química y Fisicoquímica Biológicas Prof. Dr. Alejandro C. Paladini, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - J D Correale
- Departamento de Química Biológica, Facultad de Farmacia y Bioquímica, Cátedra de Química Biológica Patológica, Universidad de Buenos Aires, Buenos Aires, Argentina
- Departamento de Neurología, Fleni, Buenos Aires, Argentina
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Alam MZ. A review on plant-based remedies for the treatment of multiple sclerosis. ANNALES PHARMACEUTIQUES FRANÇAISES 2023; 81:775-789. [PMID: 36963654 DOI: 10.1016/j.pharma.2023.03.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2022] [Revised: 03/15/2023] [Accepted: 03/20/2023] [Indexed: 03/26/2023]
Abstract
Multiple sclerosis (MS) is a complex autoimmune disease of central nervous system, which is degenerative in nature usually appears between 20-40years of age. The exact cause of MS is still not clearly known. Loss of myelin sheath and axonal damage are the main features of MS that causes induction of inflammatory process and blocks free conduction of impulses. Till date FDA has approved 18 drugs to treat or modify MS symptoms. These medicines are disease-modifying in nature directed to prevent relapses or slow down the progression of disease. The use of the synthetic drug over an extended period causes undesirable effects that prompt us to look at Mother Nature. Complementary and alternative medicine involves the use of medicinal plants as an alternative to the existing modern medical treatment. However, modern drugs cannot be replaced completely with medicinal plants, but the two types of drugs can be used harmoniously with later one can be added as an adjuvant to the existing treatment. These medicinal plants have the potential to prevent progression and improve the symptoms of MS. Various plants such like Nigella sativa, ginger, saffron, pomegranate, curcumin, resveratrol, ginsenoside have been tested as therapeutics for many neurodegenerative diseases. The purpose of this write-up is to make information available about medicinal plants in their potential to treat or modify the symptoms of MS. Chronically ill patients tend to seek medicinal plants as they are easily available and there is a general perception about these medicines of having fewer undesirable effects.
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Affiliation(s)
- Mohammad Zubair Alam
- Pre-Clinical Research Unit, King Fahad Medical Research Center, King Abdulaziz University, Jeddah 21589, Saudi Arabia; Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah 21589, Saudi Arabia.
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Segklia K, Matsas R, Papastefanaki F. Brain Infection by Group B Streptococcus Induces Inflammation and Affects Neurogenesis in the Adult Mouse Hippocampus. Cells 2023; 12:1570. [PMID: 37371040 DOI: 10.3390/cells12121570] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2023] [Revised: 06/01/2023] [Accepted: 06/02/2023] [Indexed: 06/29/2023] Open
Abstract
Central nervous system infections caused by pathogens crossing the blood-brain barrier are extremely damaging and trigger cellular alterations and neuroinflammation. Bacterial brain infection, in particular, is a major cause of hippocampal neuronal degeneration. Hippocampal neurogenesis, a continuous multistep process occurring throughout life in the adult brain, could compensate for such neuronal loss. However, the high rates of cognitive and other sequelae from bacterial meningitis/encephalitis suggest that endogenous repair mechanisms might be severely affected. In the current study, we used Group B Streptococcus (GBS) strain NEM316, to establish an adult mouse model of brain infection and determine its impact on adult neurogenesis. Experimental encephalitis elicited neurological deficits and death, induced inflammation, and affected neurogenesis in the dentate gyrus of the adult hippocampus by suppressing the proliferation of progenitor cells and the generation of newborn neurons. These effects were specifically associated with hippocampal neurogenesis while subventricular zone neurogenesis was not affected. Overall, our data provide new insights regarding the effect of GBS infection on adult brain neurogenesis.
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Affiliation(s)
- Katerina Segklia
- Laboratory of Cellular and Molecular Neurobiology-Stem Cells, Neurobiology Department, Hellenic Pasteur Institute, 11521 Athens, Greece
| | - Rebecca Matsas
- Laboratory of Cellular and Molecular Neurobiology-Stem Cells, Neurobiology Department, Hellenic Pasteur Institute, 11521 Athens, Greece
| | - Florentia Papastefanaki
- Laboratory of Cellular and Molecular Neurobiology-Stem Cells, Neurobiology Department, Hellenic Pasteur Institute, 11521 Athens, Greece
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7
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Vesic K, Gavrilovic A, Mijailović NR, Borovcanin MM. Neuroimmune, clinical and treatment challenges in multiple sclerosis-related psychoses. World J Psychiatry 2023; 13:161-170. [PMID: 37123101 PMCID: PMC10130959 DOI: 10.5498/wjp.v13.i4.161] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2022] [Revised: 02/16/2023] [Accepted: 03/23/2023] [Indexed: 04/18/2023] Open
Abstract
In recent years, epidemiological and genetic studies have shown an association between autoimmune diseases and psychosis. The question arises whether patients with schizophrenia are more likely to develop multiple sclerosis (MS) later in life. It is well known that the immune system plays an important role in the etiopathogenesis of both disorders. Immune disturbances may be similar or very different in terms of different types of immune responses, disturbed myelination, and/or immunogenetic predispositions. A psychotic symptom may be a consequence of the MS diagnosis itself or a separate entity. In this review article, we discussed the timing of onset of psychotic symptoms and MS and whether the use of corticosteroids as therapy for acute relapses in MS is unfairly neglected in patients with psychiatric comorbidities. In addition, we discussed that the anti-inflammatory potential of antipsychotics could be useful and should be considered, especially in the treatment of psychosis that coexists with MS. Autoimmune disorders could precipitate psychotic symptoms, and in this context, autoimmune psychosis must be considered as a persistent symptomatology that requires continuous and specific treatment.
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Affiliation(s)
- Katarina Vesic
- Department of Neurology, University of Kragujevac, Faculty of Medical Sciences, Kragujevac 34000, Sumadija, Serbia
| | - Aleksandar Gavrilovic
- Department of Neurology, University of Kragujevac, Faculty of Medical Sciences, Kragujevac 34000, Sumadija, Serbia
| | - Nataša R Mijailović
- Department of Pharmacy, University of Kragujevac, Faculty of Medical Sciences, Kragujevac 34000, Sumadija, Serbia
| | - Milica M Borovcanin
- Department of Psychiatry, University of Kragujevac, Faculty of Medical Sciences, Kragujevac 34000, Sumadija, Serbia
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8
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Liu S, Lan XB, Tian MM, Zhu CH, Ma L, Yang JM, Du J, Zheng P, Yu JQ, Liu N. Targeting the chemokine ligand 2-chemokine receptor 2 axis provides the possibility of immunotherapy in chronic pain. Eur J Pharmacol 2023; 947:175646. [PMID: 36907261 DOI: 10.1016/j.ejphar.2023.175646] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Revised: 02/26/2023] [Accepted: 03/06/2023] [Indexed: 03/13/2023]
Abstract
Chronic pain affects patients' physical and psychological health and quality of life, entailing a tremendous public health challenge. Currently, drugs for chronic pain are usually associated with a large number of side effects and poor efficacy. Chemokines in the neuroimmune interface combine with their receptors to regulate inflammation or mediate neuroinflammation in the peripheral and central nervous system. Targeting chemokines and their receptor-mediated neuroinflammation is an effective means to treat chronic pain. In recent years, growing evidence has shown that the expression of chemokine ligand 2 (CCL2) and its main chemokine receptor 2 (CCR2) is involved in its occurrence, development and maintenance of chronic pain. This paper summarises the relationship between the chemokine system, CCL2/CCR2 axis, and chronic pain, and the CCL2/CCR2 axis changes under different chronic pain conditions. Targeting chemokine CCL2 and its chemokine receptor CCR2 through siRNA, blocking antibodies, or small molecule antagonists may provide new therapeutic possibilities for managing chronic pain.
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Affiliation(s)
- Shan Liu
- Department of Pharmacology, School of Pharmacy, Ningxia Medical University, 1160 Shengli Street, Yinchuan, 750004, China.
| | - Xiao-Bing Lan
- Department of Pharmacology, School of Pharmacy, Ningxia Medical University, 1160 Shengli Street, Yinchuan, 750004, China.
| | - Miao-Miao Tian
- Department of Pharmacology, School of Pharmacy, Ningxia Medical University, 1160 Shengli Street, Yinchuan, 750004, China.
| | - Chun-Hao Zhu
- Department of Pharmacology, School of Pharmacy, Ningxia Medical University, 1160 Shengli Street, Yinchuan, 750004, China.
| | - Lin Ma
- Department of Pharmacology, School of Pharmacy, Ningxia Medical University, 1160 Shengli Street, Yinchuan, 750004, China.
| | - Jia-Mei Yang
- Department of Pharmacology, School of Pharmacy, Ningxia Medical University, 1160 Shengli Street, Yinchuan, 750004, China.
| | - Juan Du
- Department of Pharmacology, School of Pharmacy, Ningxia Medical University, 1160 Shengli Street, Yinchuan, 750004, China.
| | - Ping Zheng
- Department of Pharmacology, School of Pharmacy, Ningxia Medical University, 1160 Shengli Street, Yinchuan, 750004, China.
| | - Jian-Qiang Yu
- Department of Pharmacology, School of Pharmacy, Ningxia Medical University, 1160 Shengli Street, Yinchuan, 750004, China; Ningxia Special Traditional Medicine Modern Engineering Research Center and Collaborative Innovation Center, Ningxia Medical University, 1160 Shengli Street, Yinchuan, 750004, China.
| | - Ning Liu
- Department of Pharmacology, School of Pharmacy, Ningxia Medical University, 1160 Shengli Street, Yinchuan, 750004, China; Ningxia Special Traditional Medicine Modern Engineering Research Center and Collaborative Innovation Center, Ningxia Medical University, 1160 Shengli Street, Yinchuan, 750004, China.
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9
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Locatelli G, Marques-Ferreira F, Katsoulas A, Kalaitzaki V, Krueger M, Ingold-Heppner B, Walthert S, Sankowski R, Prazeres da Costa O, Dolga A, Huber M, Gold M, Culmsee C, Waisman A, Bechmann I, Milchevskaya V, Prinz M, Tresch A, Becher B, Buch T. IGF1R expression by adult oligodendrocytes is not required in the steady-state but supports neuroinflammation. Glia 2023; 71:616-632. [PMID: 36394300 DOI: 10.1002/glia.24299] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2022] [Revised: 10/21/2022] [Accepted: 10/26/2022] [Indexed: 11/18/2022]
Abstract
In the central nervous system (CNS), insulin-like growth factor 1 (IGF-1) regulates myelination by oligodendrocyte (ODC) precursor cells and shows anti-apoptotic properties in neuronal cells in different in vitro and in vivo systems. Previous work also suggests that IGF-1 protects ODCs from cell death and enhances remyelination in models of toxin-induced and autoimmune demyelination. However, since evidence remains controversial, the therapeutic potential of IGF-1 in demyelinating CNS conditions is unclear. To finally shed light on the function of IGF1-signaling for ODCs, we deleted insulin-like growth factor 1 receptor (IGF1R) specifically in mature ODCs of the mouse. We found that ODC survival and myelin status were unaffected by the absence of IGF1R until 15 months of age, indicating that IGF-1 signaling does not play a major role in post-mitotic ODCs during homeostasis. Notably, the absence of IGF1R did neither affect ODC survival nor myelin status upon cuprizone intoxication or induction of experimental autoimmune encephalomyelitis (EAE), models for toxic and autoimmune demyelination, respectively. Surprisingly, however, the absence of IGF1R from ODCs protected against clinical neuroinflammation in the EAE model. Together, our data indicate that IGF-1 signaling is not required for the function and survival of mature ODCs in steady-state and disease.
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Affiliation(s)
- Giuseppe Locatelli
- Institute of Experimental Immunology, University of Zurich, Zurich.,Theodor Kocher Institute, University Bern, Bern, Switzerland
| | | | - Antonis Katsoulas
- Institute of Laboratory Animal Science, University of Zurich, Zurich
| | | | - Martin Krueger
- Institute of Anatomy, University of Leipzig, Leipzig, Germany
| | - Barbara Ingold-Heppner
- Institute of Pathology, Campus Mitte, Charité -Universitätsmedizin Berlin, Berlin, Germany
| | | | - Roman Sankowski
- Institute of Neuropathology, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Olivia Prazeres da Costa
- Institute for Medical Microbiology, Immunology and Hygiene, Technische Universität München, Munich, Germany
| | - Amalia Dolga
- Institute for Pharmacology and Clinical Pharmacy, Philipps-Universität Marburg, Marburg, Germany.,Groningen Research Institute of Pharmacy, Department of Molecular Pharmacology, Faculty of Science and Engineering, University of Groningen, Groningen, The Netherlands
| | - Magdalena Huber
- Institute for Medical Microbiology and Hospital Hygiene, Philipps University of Marburg, Marburg, Germany
| | - Maike Gold
- Department of Neurology, Philipps University of Marburg, Marburg, Germany
| | - Carsten Culmsee
- Institute for Pharmacology and Clinical Pharmacy, Philipps-Universität Marburg, Marburg, Germany
| | - Ari Waisman
- Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
| | - Ingo Bechmann
- Institute of Anatomy, University of Leipzig, Leipzig, Germany
| | - Vladislava Milchevskaya
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.,Institute of Medical Statistics and Computational Biology, Faculty of Medicine, University of Cologne, Cologne, Germany
| | - Marco Prinz
- Institute of Neuropathology, Faculty of Medicine, University of Freiburg, Freiburg, Germany.,Center for Basics in NeuroModulation (NeuroModulBasics), Faculty of Medicine, University of Freiburg, Freiburg, Germany.,Signalling Research Centres BIOSS and CIBSS, University of Freiburg, Freiburg, Germany
| | - Achim Tresch
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.,Institute of Medical Statistics and Computational Biology, Faculty of Medicine, University of Cologne, Cologne, Germany
| | - Burkhard Becher
- Institute of Experimental Immunology, University of Zurich, Zurich
| | - Thorsten Buch
- Institute of Experimental Immunology, University of Zurich, Zurich.,Institute of Laboratory Animal Science, University of Zurich, Zurich.,Institute for Medical Microbiology, Immunology and Hygiene, Technische Universität München, Munich, Germany
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10
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Wu K, Li R, Zhang Y, Liu Y, Wang M, Huang J, Zhu C, Zhang J, Yuan X, Liu Q. The discovery of a new type of innervation in lymphoid organs. Physiol Rep 2023; 11:e15604. [PMID: 36823776 PMCID: PMC9950540 DOI: 10.14814/phy2.15604] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2022] [Revised: 01/26/2023] [Accepted: 01/26/2023] [Indexed: 02/25/2023] Open
Abstract
It is well known that the main forms of innervation are synapses and free nerve endings, while other forms of innervation have not been reported. Here, we explore a new way of innervating lymphoid organs. Male Sprague-Dawley rats were used for studying the innervation of sympathetic nerve fibers in lymph nodes by means of anterograde tracking, immunoelectron microscopy, three-dimension reconstruction analysis, and immunofluorescence labeling. The results showed that the Fluoro-Ruby labeled nerve endings targeted only a group of cells in the lymph nodes and entered the cells through the plasma membrane. The electron microscopy showed that the biotinylated glucan amine reaction elements were distributed in the cytoplasm, and most of the biotinylated glucan amine active elements were concentrated on the microtubule and microfilament walls. Birbeck particles with rod-shaped and/or tennis racket like structures can be seen in the labeled cells at high magnification, and Birbeck particles contain biotinylated glucan amine-reactive elements. The immunofluoresence results showed that the Fluoro-Ruby-labeled nerve innervating cells expressed CD207 and CD1a protein. This result confirmed that the labeled cells were Langerhans cells. Our findings suggested that Langerhans cells might serve as a "bridge cell" for neuroimmune cross-talking in lymph organs, which play an important role in transmitting signals of the nervous system to immune system. This study also opened up a new way for further study of immune regulation mechanism.
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Affiliation(s)
- Kaiyun Wu
- Department of AnatomyMedical College of Soochow UniversitySuzhouChina
| | - Ruixi Li
- Department of Anatomy, Histology and EmbryologyShanghai Medical College of Fudan UniversityShanghaiChina
| | - Yanlin Zhang
- Department of NeurologySecond Affiliated Hospital of Soochow UniversitySuzhouChina
| | - YanMei Liu
- Department of AnatomyMedical College of Soochow UniversitySuzhouChina
| | - MinChen Wang
- Department of AnatomyMedical College of Soochow UniversitySuzhouChina
| | - Jinyu Huang
- Department of AnatomyMedical College of Soochow UniversitySuzhouChina
| | - Changlai Zhu
- Jiangsu Key Laboratory of NeuroregenerationNantong UniversityNantongChina
| | - Jianping Zhang
- Department of Anatomy, Histology and EmbryologyShanghai Medical College of Fudan UniversityShanghaiChina
| | - Xiangshan Yuan
- Department of Anatomy, Histology and EmbryologyShanghai Medical College of Fudan UniversityShanghaiChina
| | - Qingqing Liu
- Department of AnatomyMedical College of Soochow UniversitySuzhouChina
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11
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Lilienberg J, Apáti Á, Réthelyi JM, Homolya L. Microglia modulate proliferation, neurite generation and differentiation of human neural progenitor cells. Front Cell Dev Biol 2022; 10:997028. [PMID: 36313581 PMCID: PMC9606406 DOI: 10.3389/fcell.2022.997028] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2022] [Accepted: 09/16/2022] [Indexed: 10/10/2024] Open
Abstract
Microglia, the primary immune cells of the brain, significantly influence the fate of neurons after neural damage. Depending on the local environment, they exhibit a wide range of phenotypes, including patrolling (naïve), proinflammatory, and anti-inflammatory characteristics, which greatly affects neurotoxicity. Despite the fact that neural progenitor cells (NPCs) and hippocampal neurons represent cell populations, which play pivotal role in neural regeneration, interaction between microglia and these cell types is poorly studied. In the present work, we investigated how microglial cells affect the proliferation and neurite outgrowth of human stem cell-derived NPCs, and how microglia stimulation with proinflammatory or anti-inflammatory agents modulates this interaction. We found that naïve microglia slightly diminish NPC proliferation and have no effect on neurite outgrowth. In contrast, proinflammatory stimulated microglia promote both proliferation and neurite generation, whereas microglia stimulated with anti-inflammatory cytokines augment neurite outgrowth leaving NPC proliferation unaffected. We also studied how microglia influence neurite development and differentiation of hippocampal dentate gyrus granule cells differentiated from NPCs. We found that proinflammatory stimulated microglia inhibit axonal development but facilitate dendrite generation in these differentiating neurons. Our results elucidate a fine-tuned modulatory effect of microglial cells on cell types crucial for neural regeneration, opening perspectives for novel regenerative therapeutic interventions.
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Affiliation(s)
- Julianna Lilienberg
- Institute of Enzymology, Research Centre for Natural Sciences, Budapest, Hungary
- Doctoral School of Biology, Institute of Biology, ELTE Eötvös Loránd University, Budapest, Hungary
| | - Ágota Apáti
- Institute of Enzymology, Research Centre for Natural Sciences, Budapest, Hungary
| | - János M. Réthelyi
- Molecular Psychiatry and in vitro Disease Modelling Research Group, National Brain Research Project, Hungarian Academy of Sciences and Semmelweis University, Budapest, Hungary
- Department of Psychiatry and Psychotherapy, Semmelweis University, Budapest, Hungary
| | - László Homolya
- Institute of Enzymology, Research Centre for Natural Sciences, Budapest, Hungary
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12
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Clinical Investigation of French Maritime Pine Bark Extract on Attention-Deficit Hyperactivity Disorder as compared to Methylphenidate and Placebo: Part 2: Oxidative Stress and Immunological Modulation. J Funct Foods 2022. [DOI: 10.1016/j.jff.2022.105247] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
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13
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Mázala-de-Oliveira T, de Figueiredo CS, de Rezende Corrêa G, da Silva MS, Miranda RL, de Azevedo MA, Cossenza M, Dos Santos AA, Giestal-de-Araujo E. Ouabain-Na +/K +-ATPase Signaling Regulates Retinal Neuroinflammation and ROS Production Preventing Neuronal Death by an Autophagy-Dependent Mechanism Following Optic Nerve Axotomy In Vitro. Neurochem Res 2022; 47:723-738. [PMID: 34783975 DOI: 10.1007/s11064-021-03481-0] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Revised: 11/02/2021] [Accepted: 11/05/2021] [Indexed: 12/25/2022]
Abstract
Ouabain is a classic Na+K+ATPase ligand and it has been described to have neuroprotective effects on neurons and glial cells at nanomolar concentrations. In the present work, the neuroprotective and immunomodulatory potential of ouabain was evaluated in neonatal rat retinal cells using an optic nerve axotomy model in vitro. After axotomy, cultured retinal cells were treated with ouabain (3 nM) at different periods. The levels of important inflammatory receptors in the retina such as TNFR1/2, TLR4, and CD14 were analyzed. We observed that TNFR1, TLR4, and CD14 were decreased in all tested periods (15 min, 45 min, 24 h, and 48 h). On the other hand, TNFR2 was increased after 24 h, suggesting an anti-inflammatory potential for ouabain. Moreover, we showed that ouabain also decreased Iba-1 (microglial marker) density. Subsequently, analyses of retrograde labeling of retinal ganglion cells (RGC) were performed after 48 h and showed that ouabain-induced RGC survival depends on autophagy. Using an autophagy inhibitor (3-methyladenine), we observed a complete blockage of the ouabain effect. Western blot analyses showed that ouabain increases the levels of autophagy proteins (LC3 and Beclin-1) coupled to p-CREB transcription factor and leads to autophagosome formation. Additionally, we found that the ratio of cleaved/pro-caspase-3 did not change after ouabain treatment; however, p-JNK density was enhanced. Also, ouabain decreased reactive oxygen species production immediately after axotomy. Taken together, our results suggest that ouabain controls neuroinflammation in the retina following optic nerve axotomy and promotes RGC neuroprotection through activation of the autophagy pathway.
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Affiliation(s)
- Thalita Mázala-de-Oliveira
- Department of Neurobiology and Program of Neurosciences, Institute of Biology, Federal Fluminense University, Niterói, 24020-141, Brazil
- Souza Marques School of Medicine, Souza Marques Technical-Educational Foundation, Rio de Janeiro, 21310-310, Brazil
| | - Camila Saggioro de Figueiredo
- Department of Neurobiology and Program of Neurosciences, Institute of Biology, Federal Fluminense University, Niterói, 24020-141, Brazil
| | - Gustavo de Rezende Corrêa
- Department of Neurobiology and Program of Neurosciences, Institute of Biology, Federal Fluminense University, Niterói, 24020-141, Brazil
- Souza Marques School of Medicine, Souza Marques Technical-Educational Foundation, Rio de Janeiro, 21310-310, Brazil
| | - Mayra Santos da Silva
- Department of Neurobiology and Program of Neurosciences, Institute of Biology, Federal Fluminense University, Niterói, 24020-141, Brazil
- Souza Marques School of Medicine, Souza Marques Technical-Educational Foundation, Rio de Janeiro, 21310-310, Brazil
| | - Renan Lyra Miranda
- Department of Physiology and Pharmacology and Program of Neurosciences, Laboratory of Neurochemical I`nteractions & Laboratory of Molecular Pharmacology, Biomedical Institute, Federal Fluminense University, Niterói, 24020-141, Brazil
| | - Mariana Almeida de Azevedo
- Department of Neurobiology and Program of Neurosciences, Institute of Biology, Federal Fluminense University, Niterói, 24020-141, Brazil
| | - Marcelo Cossenza
- Department of Physiology and Pharmacology and Program of Neurosciences, Laboratory of Neurochemical I`nteractions & Laboratory of Molecular Pharmacology, Biomedical Institute, Federal Fluminense University, Niterói, 24020-141, Brazil
| | - Aline Araujo Dos Santos
- Department of Physiology and Pharmacology and Program of Neurosciences, Laboratory of Neurochemical I`nteractions & Laboratory of Molecular Pharmacology, Biomedical Institute, Federal Fluminense University, Niterói, 24020-141, Brazil
| | - Elizabeth Giestal-de-Araujo
- Department of Neurobiology and Program of Neurosciences, Institute of Biology, Federal Fluminense University, Niterói, 24020-141, Brazil.
- National Institute of Science and Technology on Neuroimmunomodulation - INCT-NIM, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, 21040-360, Brazil.
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14
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Kaur R, Arora N, Nair MG, Prasad A. The interplay of helminthic neuropeptides and proteases in parasite survival and host immunomodulation. Biochem Soc Trans 2022; 50:107-118. [PMID: 35076687 PMCID: PMC9042389 DOI: 10.1042/bst20210405] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Revised: 12/22/2021] [Accepted: 12/23/2021] [Indexed: 11/17/2022]
Abstract
Neuropeptides comprise a diverse and broad group of neurotransmitters in vertebrates and invertebrates, with critical roles in neuronal signal transduction. While their role in controlling learning and memory in the brains of mammals is known, their extra-synaptic function in infection and inflammation with effects on distinct tissues and immune cells is increasingly recognized. Helminth infections especially of the central nervous system (CNS), such as neurocysticercosis, induce neuropeptide production by both host and helminth, but their role in host-parasite interplay or host inflammatory response is unclear. Here, we review the neurobiology of helminths, and discuss recent studies on neuropeptide synthesis and function in the helminth as well as the host CNS and immune system. Neuropeptides are summarized according to structure and function, and we discuss the complex enzyme processing for mature neuropeptides, focusing on helminth enzymes as potential targets for novel anthelminthics. We next describe known immunomodulatory effects of mammalian neuropeptides discovered from mouse infection models and draw functional parallels with helminth neuropeptides. Last, we discuss the anti-microbial properties of neuropeptides, and how they may be involved in host-microbiota changes in helminth infection. Overall, a better understanding of the biology of helminth neuropeptides, and whether they affect infection outcomes could provide diagnostic and therapeutic opportunities for helminth infections.
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Affiliation(s)
- Rimanpreet Kaur
- School of Basic Sciences, Indian Institute of Technology Mandi, Mandi, Himachal Pradesh 175005, India
| | - Naina Arora
- School of Basic Sciences, Indian Institute of Technology Mandi, Mandi, Himachal Pradesh 175005, India
| | - Meera G. Nair
- Division of Biomedical Sciences, University of California Riverside, Riverside, CA 92521, U.S.A
| | - Amit Prasad
- School of Basic Sciences, Indian Institute of Technology Mandi, Mandi, Himachal Pradesh 175005, India
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15
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In Vitro Methodologies to Study the Role of Advanced Glycation End Products (AGEs) in Neurodegeneration. Nutrients 2022; 14:nu14020363. [PMID: 35057544 PMCID: PMC8777776 DOI: 10.3390/nu14020363] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Revised: 01/11/2022] [Accepted: 01/12/2022] [Indexed: 02/07/2023] Open
Abstract
Advanced glycation end products (AGEs) can be present in food or be endogenously produced in biological systems. Their formation has been associated with chronic neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, and amyotrophic lateral sclerosis. The implication of AGEs in neurodegeneration is related to their ability to bind to AGE-specific receptors and the ability of their precursors to induce the so-called “dicarbonyl stress”, resulting in cross-linking and protein damage. However, the mode of action underlying their role in neurodegeneration remains unclear. While some research has been carried out in observational clinical studies, further in vitro studies may help elucidate these underlying modes of action. This review presents and discusses in vitro methodologies used in research on the potential role of AGEs in neuroinflammation and neurodegeneration. The overview reveals the main concepts linking AGEs to neurodegeneration, the current findings, and the available and advisable in vitro models to study their role. Moreover, the major questions regarding the role of AGEs in neurodegenerative diseases and the challenges and discrepancies in the research field are discussed.
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16
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Zhang D, Zhao S, Zhang Z, Xu D, Lian D, Wu J, He D, Sun K, Li L. Regulation of the p75 neurotrophin receptor attenuates neuroinflammation and stimulates hippocampal neurogenesis in experimental Streptococcus pneumoniae meningitis. J Neuroinflammation 2021; 18:253. [PMID: 34727939 PMCID: PMC8561879 DOI: 10.1186/s12974-021-02294-w] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2021] [Accepted: 10/09/2021] [Indexed: 12/12/2022] Open
Abstract
Background Streptococcus pneumoniae meningitis is a destructive central nervous system (CNS) infection with acute and long-term neurological disorders. Previous studies suggest that p75NTR signaling influences cell survival, apoptosis, and proliferation in brain-injured conditions. However, the role of p75NTR signaling in regulating pneumococcal meningitis (PM)-induced neuroinflammation and altered neurogenesis remains largely to be elucidated. Methods p75NTR signaling activation in the pathological process of PM was assessed. During acute PM, a small-molecule p75NTR modulator LM11A-31 or vehicle was intranasally administered for 3 days prior to S. pneumoniae exposure. At 24 h post-infection, clinical severity, histopathology, astrocytes/microglia activation, neuronal apoptosis and necrosis, inflammation-related transcription factors and proinflammatory cytokines/mediators were evaluated. Additionally, p75NTR was knocked down by the adenovirus-mediated short-hairpin RNA (shRNA) to ascertain the role of p75NTR in PM. During long-term PM, the intranasal administration of LM11A-31 or vehicle was continued for 7 days after successfully establishing the PM model. Dynamic changes in inflammation and hippocampal neurogenesis were assessed. Results Our results revealed that both 24 h (acute) and 7, 14, 28 day (long-term) groups of infected rats showed increased p75NTR expression in the brain. During acute PM, modulation of p75NTR through pretreatment of PM model with LM11A-31 significantly alleviated S. pneumoniae-induced clinical severity, histopathological injury and the activation of astrocytes and microglia. LM11A-31 pretreatment also significantly ameliorated neuronal apoptosis and necrosis. Moreover, we found that blocking p75NTR with LM11A-31 decreased the expression of inflammation-related transcription factors (NF-κBp65, C/EBPβ) and proinflammatory cytokines/mediators (IL-1β, TNF-α, IL-6 and iNOS). Furthermore, p75NTR knockdown induced significant changes in histopathology and inflammation-related transcription factors expression. Importantly, long-term LM11A-31 treatment accelerated the resolution of PM-induced inflammation and significantly improved hippocampal neurogenesis. Conclusion Our findings suggest that the p75NTR signaling plays an essential role in the pathogenesis of PM. Targeting p75NTR has beneficial effects on PM rats by alleviating neuroinflammation and promoting hippocampal neurogenesis. Thus, the p75NTR signaling may be a potential therapeutic target to improve the outcome of PM. Supplementary Information The online version contains supplementary material available at 10.1186/s12974-021-02294-w.
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Affiliation(s)
- Dandan Zhang
- Department of Pediatric Neurology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Kongjiang Road 1665, Shanghai, 200092, China
| | - Shengnan Zhao
- Department of Pediatric Neurology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Kongjiang Road 1665, Shanghai, 200092, China
| | - Zhijie Zhang
- Department of Pediatric Neurology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Kongjiang Road 1665, Shanghai, 200092, China
| | - Danfeng Xu
- Department of Pediatric Neurology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Kongjiang Road 1665, Shanghai, 200092, China
| | - Di Lian
- Department of Pediatric Neurology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Kongjiang Road 1665, Shanghai, 200092, China
| | - Jing Wu
- Department of Pediatric Neurology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Kongjiang Road 1665, Shanghai, 200092, China
| | - Dake He
- Department of Pediatric Neurology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Kongjiang Road 1665, Shanghai, 200092, China
| | - Kun Sun
- Department of Pediatric Cardiology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Kongjiang Road 1665, Shanghai, 200092, China.
| | - Ling Li
- Department of Pediatric Neurology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Kongjiang Road 1665, Shanghai, 200092, China.
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17
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Al-Keilani MS, Almomani BA, Al-Sawalha NA, Al Qawasmeh M, Jaradat SA. Significance of serum VIP and PACAP in multiple sclerosis: an exploratory case-control study. Neurol Sci 2021; 43:2621-2630. [PMID: 34698942 DOI: 10.1007/s10072-021-05682-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Accepted: 10/18/2021] [Indexed: 10/20/2022]
Abstract
BACKGROUND Multiple sclerosis (MS) is a chronic inflammatory neurodegenerative disease of the central nervous system. Vasoactive and intestinal peptide (VIP) and pituitary adenylate cyclase-activating peptide (PACAP) are neuropeptides that play roles in anti-inflammation and neuroprotection in MS. In this study, we aimed to determine the serum levels of VIP and PACAP in MS patients versus healthy controls and to correlate them with demographics and clinical characteristics. METHODS Serum samples were collected from MS patients (n = 145) and healthy controls (n = 73) to measure serum levels VIP and PACAP. RESULTS VIP serum levels were lower in MS patients than healthy controls (p < 0.001). Serum PACAP levels were the same among the two groups. Gender-based analysis showed that VIP levels were lower in healthy females (1238.840 pg/ml) than healthy males (3300.105 pg/ml; p < 0.001), and PACAP serum levels were significantly lower in male MS patients (48,516.214 fg/ml) than female MS patients (62,466.400 fg/ml; p = 0.029). ROC curve suggested that serum VIP level can discriminate patients with MS from healthy controls. Relapsing-remitting MS, progressive-MS, and clinically isolated syndrome groups were different in age, MS disease duration, EDSS score, and VIP levels (p < 0.05). MS disease type and history of previous relapses in the preceding 24 months predicted serum VIP levels, while gender predicted PACAP levels. CONCLUSION VIP serum levels are decreased in MS patients and can be used to differentiate between MS patients and healthy controls. Further studies with larger sample sizes are required to investigate VIP as a marker to reflect MS disease progression.
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Affiliation(s)
- Maha S Al-Keilani
- College of Pharmacy, Department of Clinical Pharmacy, Jordan University of Science and Technology, P.O. Box 3030, Irbid, 22110, Jordan.
| | - Basima A Almomani
- College of Pharmacy, Department of Clinical Pharmacy, Jordan University of Science and Technology, P.O. Box 3030, Irbid, 22110, Jordan
| | - Nour A Al-Sawalha
- College of Pharmacy, Department of Clinical Pharmacy, Jordan University of Science and Technology, P.O. Box 3030, Irbid, 22110, Jordan
| | - Majdi Al Qawasmeh
- College of Medicine, Department of Neurology, Jordan University of Science and Technology, P.O. Box 3030, Irbid, 22110, Jordan
| | - Saied A Jaradat
- College of Science and Art, Department of Biotechnology and Genetic Engineering, Jordan University of Science and Technology, P.O. Box 3030, Irbid, 22110, Jordan
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18
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Brunialti E, Villa A, Mekhaeil M, Mornata F, Vegeto E, Maggi A, Di Monte DA, Ciana P. Inhibition of microglial β-glucocerebrosidase hampers the microglia-mediated antioxidant and protective response in neurons. J Neuroinflammation 2021; 18:220. [PMID: 34551802 PMCID: PMC8459568 DOI: 10.1186/s12974-021-02272-2] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Accepted: 08/23/2021] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND Homozygotic mutations in the GBA gene cause Gaucher's disease; moreover, both patients and heterozygotic carriers have been associated with 20- to 30-fold increased risk of developing Parkinson's disease. In homozygosis, these mutations impair the activity of β-glucocerebrosidase, the enzyme encoded by GBA, and generate a lysosomal disorder in macrophages, which changes morphology towards an engorged phenotype, considered the hallmark of Gaucher's disease. Notwithstanding the key role of macrophages in this disease, most of the effects in the brain have been attributed to the β-glucocerebrosidase deficit in neurons, while a microglial phenotype for these mutations has never been reported. METHODS We applied the bioluminescence imaging technology, immunohistochemistry and gene expression analysis to investigate the consequences of microglial β-glucocerebrosidase inhibition in the brain of reporter mice, in primary neuron/microglia cocultures and in cell lines. The use of primary cells from reporter mice allowed for the first time, to discriminate in cocultures neuronal from microglial responses consequent to the β-glucocerebrosidase inhibition; results were finally confirmed by pharmacological depletion of microglia from the brain of mice. RESULTS Our data demonstrate the existence of a novel neuroprotective mechanism mediated by a direct microglia-to-neuron contact supported by functional actin structures. This cellular contact stimulates the nuclear factor erythroid 2-related factor 2 activity in neurons, a key signal involved in drug detoxification, redox balance, metabolism, autophagy, lysosomal biogenesis, mitochondrial dysfunctions, and neuroinflammation. The central role played by microglia in this neuronal response in vivo was proven by depletion of the lineage in the brain of reporter mice. Pharmacological inhibition of microglial β-glucocerebrosidase was proven to induce morphological changes, to turn on an anti-inflammatory/repairing pathway, and to hinder the microglia ability to activate the nuclear factor erythroid 2-related factor 2 response, thus increasing the neuronal susceptibility to neurotoxins. CONCLUSION This mechanism provides a possible explanation for the increased risk of neurodegeneration observed in carriers of GBA mutations and suggest novel therapeutic strategies designed to revert the microglial phenotype associated with β-glucocerebrosidase inhibition, aimed at resetting the protective microglia-to-neuron communication.
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Affiliation(s)
| | - Alessandro Villa
- Department of Health Sciences, University of Milan, Milan, Italy.
| | | | - Federica Mornata
- Department of Pharmaceutical Sciences, University of Milan, Milan, Italy
| | - Elisabetta Vegeto
- Department of Pharmaceutical Sciences, University of Milan, Milan, Italy
| | - Adriana Maggi
- Department of Pharmaceutical Sciences, University of Milan, Milan, Italy
| | | | - Paolo Ciana
- Department of Health Sciences, University of Milan, Milan, Italy.
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Geng Y, Lu Z, Guan J, van Rooijen N, Zhi Y. Microglia/Macrophages and CD4 +CD25 + T Cells Enhance the Ability of Injury-Activated Lymphocytes to Reduce Traumatic Optic Neuropathy In Vitro. Front Immunol 2021; 12:687898. [PMID: 34484185 PMCID: PMC8414969 DOI: 10.3389/fimmu.2021.687898] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Accepted: 07/29/2021] [Indexed: 02/05/2023] Open
Abstract
Inflammation after acute CNS injury plays a dual role. The interplay between immune cells and inflammatory mediators is critical to the outcome of injured neurons. Microglia/macrophages are the first sensors and regulators of the immune response. We previously found that the enhancement of macrophages on neuron survival does not persist in thymectomized rats. How T lymphocytes and macrophages interact and benefit neuron survival is not fully elucidated. To this point, we introduce and characterize a cell-retina co-culture model that mimics the recruitment of peripheral lymphocytes at the injury site. Three-day post-optic nerve transection (ONT) in Fischer 344 rats, transected retinas were co-cultured with either peripheral lymph node-derived lymphocytes (injury-activated) or from intact rats as the control. The injury-activated lymphocytes preserved retinal ganglion cells (RGCs) and caused extensive retina microglial/macrophage infiltration. CD4+CD25+ T cells were upregulated in the injury-activated lymphocytes and increased RGC survival, suggesting that CD4+CD25+ T cells suppressed the cytotoxicity of control lymphocytes. When microglia/macrophages were depleted by clodronate, neuron loss was more extensive, the cytotoxicity of control lymphocytes on RGCs was alleviated, and the neuroprotective effect of injury-activated lymphocytes remain unchanged Cytokine detection showed an increase in IL-6 and TNF-α levels that were reduced with microglia/macrophage depletion. Our results suggest that microglial/macrophage infiltration into axotomized retinas promotes RGC survival by secreting cytokines to induce CD4+CD25+ T cells and suppress T cell-mediated RGC toxicity. These findings reveal a specific role for microglia/macrophage and CD4+CD25+ T cells in inflammation after CNS injury, thereby adding to the mechanistic basis for the development of microglial/macrophage modulation therapy for traumatic CNS injury.
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Affiliation(s)
- Yiqun Geng
- Laboratory of Molecular Pathology, Guangdong Provincial Key Laboratory of Infectious Diseases and Molecular Immunopathology, Shantou University Medical College, Shantou, China
- Joint Shantou International Eye Center of Shantou University and the Chinese University of Hong Kong, Shantou University Medical College, Shantou, China
| | - Zhihao Lu
- Joint Shantou International Eye Center of Shantou University and the Chinese University of Hong Kong, Shantou University Medical College, Shantou, China
| | - Jitian Guan
- Department of MRI, the Second Affiliated Hospital of Shantou University Medical College, Shantou, China
| | - Nico van Rooijen
- Department of Molecular Cell Biology, Vrije Universiteit Medical Center, Amsterdam, Netherlands
| | - Ye Zhi
- Department of Anatomy, Shantou University Medical College, Shantou, China
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20
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Al Mamun A, Ngwa C, Qi S, Honarpisheh P, Datar S, Sharmeen R, Xu Y, McCullough LD, Liu F. Neuronal CD200 Signaling Is Protective in the Acute Phase of Ischemic Stroke. Stroke 2021; 52:3362-3373. [PMID: 34353112 DOI: 10.1161/strokeaha.120.032374] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND AND PURPOSE CD200 (cluster of differentiation 200), a highly glycosylated protein primarily expressed on neurons in the central nervous system, binds with its receptor CD200R to form an endogenous inhibitory signal against immune responses. However, little is known about the effect of neuronal CD200 signaling in cerebral ischemia. The aim of this study was to investigate how neuronal CD200 signaling impacts poststroke inflammation and the ischemic injury. METHODS CD200 tma1lf/fl:Thy1CreER mice were treated with tamoxifen to induce conditional gene knockout (ICKO) of neuronal CD200. The mice were subjected to a 60-minute transient middle cerebral artery occlusion. Stroke outcomes, apoptotic cell death, immune cell infiltration, microglia activation, and other inflammatory profiles were evaluated at 3 and 7 days after stroke. RESULTS Infarct volumes were significantly larger, and behavioral deficits more severe in ICKO versus control mice at 3 days after middle cerebral artery occlusion. Terminal deoxynucleotidyl transferase dUTP nick end labeling assay also revealed a significant increase in apoptotic neuronal death in CD200 ICKO mice. An enhancement in lymphocytic infiltration and microglial proinflammatory responses were revealed by flow cytometry at 3 and 7 days after stroke in ICKO mice, accompanied by an increased microglial phagocytosis activity. Plasma proinflammatory cytokine (TNFα [tumor necrosis factor alpha] and IL [interleukin]-1β) levels significantly increased at 3 days, and IL-1β/IL-6 levels increased at 7 days in ICKO versus control animals. ICKO led to significantly lower baseline level of CD200 both in brain and plasma. CONCLUSIONS Neuronal CD200 inhibits proinflammatory responses and is protective against stroke injury.
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Affiliation(s)
- Abdullah Al Mamun
- Department of Neurology, The University of Texas Health Science Center at Houston, McGovern Medical School, Houston
| | - Conelius Ngwa
- Department of Neurology, The University of Texas Health Science Center at Houston, McGovern Medical School, Houston
| | - Shaohua Qi
- Department of Neurology, The University of Texas Health Science Center at Houston, McGovern Medical School, Houston
| | - Pedram Honarpisheh
- Department of Neurology, The University of Texas Health Science Center at Houston, McGovern Medical School, Houston
| | - Saumil Datar
- Department of Neurology, The University of Texas Health Science Center at Houston, McGovern Medical School, Houston
| | - Romana Sharmeen
- Department of Neurology, The University of Texas Health Science Center at Houston, McGovern Medical School, Houston
| | - Yan Xu
- Department of Neurology, The University of Texas Health Science Center at Houston, McGovern Medical School, Houston
| | - Louise D McCullough
- Department of Neurology, The University of Texas Health Science Center at Houston, McGovern Medical School, Houston
| | - Fudong Liu
- Department of Neurology, The University of Texas Health Science Center at Houston, McGovern Medical School, Houston
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21
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Epigenetics and Communication Mechanisms in Microglia Activation with a View on Technological Approaches. Biomolecules 2021; 11:biom11020306. [PMID: 33670563 PMCID: PMC7923060 DOI: 10.3390/biom11020306] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Revised: 02/12/2021] [Accepted: 02/14/2021] [Indexed: 12/13/2022] Open
Abstract
Microglial cells, the immune cells of the central nervous system (CNS), play a crucial role for the proper brain development and function and in CNS homeostasis. While in physiological conditions, microglia continuously check the state of brain parenchyma, in pathological conditions, microglia can show different activated phenotypes: In the early phases, microglia acquire the M2 phenotype, increasing phagocytosis and releasing neurotrophic and neuroprotective factors. In advanced phases, they acquire the M1 phenotype, becoming neurotoxic and contributing to neurodegeneration. Underlying this phenotypic change, there is a switch in the expression of specific microglial genes, in turn modulated by epigenetic changes, such as DNA methylation, histones post-translational modifications and activity of miRNAs. New roles are attributed to microglial cells, including specific communication with neurons, both through direct cell–cell contact and by release of many different molecules, either directly or indirectly, through extracellular vesicles. In this review, recent findings on the bidirectional interaction between neurons and microglia, in both physiological and pathological conditions, are highlighted, with a focus on the complex field of microglia immunomodulation through epigenetic mechanisms and/or released factors. In addition, advanced technologies used to study these mechanisms, such as microfluidic, 3D culture and in vivo imaging, are presented.
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Grigsby KB, Savarese AM, Metten P, Mason BJ, Blednov YA, Crabbe JC, Ozburn AR. Effects of Tacrolimus and Other Immune Targeting Compounds on Binge-Like Ethanol Drinking in High Drinking in the Dark Mice. Neurosci Insights 2020; 15:2633105520975412. [PMID: 33294845 PMCID: PMC7705291 DOI: 10.1177/2633105520975412] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2020] [Accepted: 11/02/2020] [Indexed: 12/20/2022] Open
Abstract
High Drinking in the Dark (HDID-1) mice represent a unique genetic risk model of binge-like drinking and a novel means of screening potential pharmacotherapies to treat alcohol use disorders (AUDs). We tested the effects of tacrolimus (0, 0.5, 1, and 2 mg/kg), sirolimus (0, 5, 10, and 20 mg/kg), palmitoylethanolamide (PEA; 0, 75, 150, and 225 mg/kg), and secukinumab (0, 5, 20, and 60 mg/kg) on binge-like ethanol intake (2-day, "Drinking in the Dark" [DID]) and blood alcohol levels (BALs) in HDID-1 mice. Tacrolimus reduced ethanol intake and BALs. Tacrolimus had no effect on water intake, but reduced saccharin intake. There was no effect of sirolimus, PEA, or secukinumab on ethanol intake or BALs. These results compare and contrast with previous work addressing these compounds or their targeted mechanisms of action on ethanol drinking, highlighting the importance of screening a wide range of models and genotypes to inform the role of neuroimmune signaling in AUDs.
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Affiliation(s)
- Kolter B Grigsby
- Portland Alcohol Research Center,
Department of Behavioral Neuroscience at Oregon Health and Science University and VA
Portland Health Care System, Portland, OR, USA
| | - Antonia M Savarese
- Portland Alcohol Research Center,
Department of Behavioral Neuroscience at Oregon Health and Science University and VA
Portland Health Care System, Portland, OR, USA
| | - Pamela Metten
- Portland Alcohol Research Center,
Department of Behavioral Neuroscience at Oregon Health and Science University and VA
Portland Health Care System, Portland, OR, USA
| | - Barbara J Mason
- Department of Molecular Medicine, The
Scripps Research Institute, La Jolla, CA, USA
| | - Yuri A Blednov
- Waggoner Center for Alcoholism and
Addiction Research, University of Texas at Austin, Austin, TX, USA
| | - John C Crabbe
- Portland Alcohol Research Center,
Department of Behavioral Neuroscience at Oregon Health and Science University and VA
Portland Health Care System, Portland, OR, USA
| | - Angela R Ozburn
- Portland Alcohol Research Center,
Department of Behavioral Neuroscience at Oregon Health and Science University and VA
Portland Health Care System, Portland, OR, USA
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23
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Purinergic signaling orchestrating neuron-glia communication. Pharmacol Res 2020; 162:105253. [PMID: 33080321 DOI: 10.1016/j.phrs.2020.105253] [Citation(s) in RCA: 61] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/06/2020] [Revised: 09/29/2020] [Accepted: 10/09/2020] [Indexed: 12/12/2022]
Abstract
This review discusses the evidence supporting a role for ATP signaling (operated by P2X and P2Y receptors) and adenosine signaling (mainly operated by A1 and A2A receptors) in the crosstalk between neurons, astrocytes, microglia and oligodendrocytes. An initial emphasis will be given to the cooperation between adenosine receptors to sharpen information salience encoding across synapses. The interplay between ATP and adenosine signaling in the communication between astrocytes and neurons will then be presented in context of the integrative properties of the astrocytic syncytium, allowing to implement heterosynaptic depression processes in neuronal networks. The process of microglia 'activation' and its control by astrocytes and neurons will then be analyzed under the perspective of an interplay between different P2 receptors and adenosine A2A receptors. In spite of these indications of a prominent role of purinergic signaling in the bidirectional communication between neurons and glia, its therapeutical exploitation still awaits obtaining an integrated view of the spatio-temporal action of ATP signaling and adenosine signaling, clearly distinguishing the involvement of both purinergic signaling systems in the regulation of physiological processes and in the control of pathogenic-like responses upon brain dysfunction or damage.
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24
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Ashitha SNM, Ramachandra NB. Integrated Functional Analysis Implicates Syndromic and Rare Copy Number Variation Genes as Prominent Molecular Players in Pathogenesis of Autism Spectrum Disorders. Neuroscience 2020; 438:25-40. [DOI: 10.1016/j.neuroscience.2020.04.051] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2019] [Revised: 04/28/2020] [Accepted: 04/29/2020] [Indexed: 01/05/2023]
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25
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Tanaka M, Yamasaki T, Hasebe R, Suzuki A, Horiuchi M. Enhanced phosphorylation of PERK in primary cultured neurons as an autonomous neuronal response to prion infection. PLoS One 2020; 15:e0234147. [PMID: 32479530 PMCID: PMC7263615 DOI: 10.1371/journal.pone.0234147] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2020] [Accepted: 05/19/2020] [Indexed: 01/29/2023] Open
Abstract
Conversion of cellular prion protein (PrPC) into the pathogenic isoform of prion protein (PrPSc) in neurons is one of the key pathophysiological events in prion diseases. However, the molecular mechanism of neurodegeneration in prion diseases has yet to be fully elucidated because of a lack of suitable experimental models for analyzing neuron-autonomous responses to prion infection. In the present study, we used neuron-enriched primary cultures of cortical and thalamic mouse neurons to analyze autonomous neuronal responses to prion infection. PrPSc levels in neurons increased over the time after prion infection; however, no obvious neuronal losses or neurite alterations were observed. Interestingly, a finer analysis of individual neurons co-stained with PrPSc and phosphorylated protein kinase RNA-activated-like endoplasmic reticulum (ER) kinase (p-PERK), the early cellular response of the PERK-eukaryotic initiation factor 2 (eIF2α) pathway, demonstrated a positive correlation between the number of PrPSc granular stains and p-PERK granular stains, in cortical neurons at 21 dpi. Although the phosphorylation of PERK was enhanced in prion-infected cortical neurons, there was no sign of subsequent translational repression of synaptic protein synthesis or activations of downstream unfolded protein response (UPR) in the PERK-eIF2α pathway. These results suggest that PrPSc production in neurons induces ER stress in a neuron-autonomous manner; however, it does not fully activate UPR in prion-infected neurons. Our findings provide insights into the autonomous neuronal responses to prion propagation and the involvement of neuron-non-autonomous factor(s) in the mechanisms of neurodegeneration in prion diseases.
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Affiliation(s)
- Misaki Tanaka
- Laboratory of Veterinary Hygiene, Faculty of Veterinary Medicine, Hokkaido University, Sapporo, Japan
| | - Takeshi Yamasaki
- Laboratory of Veterinary Hygiene, Faculty of Veterinary Medicine, Hokkaido University, Sapporo, Japan
| | - Rie Hasebe
- Laboratory of Veterinary Hygiene, Faculty of Veterinary Medicine, Hokkaido University, Sapporo, Japan
| | - Akio Suzuki
- Laboratory of Veterinary Hygiene, Faculty of Veterinary Medicine, Hokkaido University, Sapporo, Japan
| | - Motohiro Horiuchi
- Laboratory of Veterinary Hygiene, Faculty of Veterinary Medicine, Hokkaido University, Sapporo, Japan
- Global Station for Zoonosis Control, Global Institute for Collaborative Research and Education, Hokkaido University, Sapporo, Japan
- * E-mail:
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26
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Pavón-Fuentes N, Marín-Prida J, Llópiz-Arzuaga A, Falcón-Cama V, Campos-Mojena R, Cervantes-Llanos M, Piniella-Matamoros B, Pentón-Arias E, Pentón-Rol G. Phycocyanobilin reduces brain injury after endothelin-1- induced focal cerebral ischaemia. Clin Exp Pharmacol Physiol 2019; 47:383-392. [PMID: 31732975 DOI: 10.1111/1440-1681.13214] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2019] [Revised: 09/27/2019] [Accepted: 11/12/2019] [Indexed: 12/11/2022]
Abstract
Pharmacological therapies for interrupting biochemical events of the ischaemic cascade and protecting against stroke in humans are as yet unavailable. Up to now, the neuroprotective activity in cerebral ischaemia of phycocyanobilin (PCB), a tetrapyrrolic natural antioxidant, has not been fully examined. Here, we evaluated if PCB protects PC12 neuronal cells against oxygen and glucose deprivation plus reperfusion, and its protective effects in a rat model of endothelin-1-induced focal brain ischaemia. PCB was purified from the cyanobacteria Spirulina platensis and characterized by spectrophotometric, liquid and gas chromatography and mass spectrometry techniques. In Wistar rats, PCB at 50, 100 and 200 μg/kg or phosphate-buffered saline (vehicle) was administered intraperitoneally at equal subdoses in a therapeutic schedule (30 minutes, 1, 3 and 6 hours after the surgery). Brain expression of myelin basic protein (MBP) and the enzyme CNPase was determined by immunoelectron microscopy. PCB was obtained with high purity (>95%) and the absence of solvent contaminants and was able to ameliorate PC12 cell ischaemic injury. PCB treatment significantly decreased brain infarct volume, limited the exploratory behaviour impairment and preserved viable cortical neurons in ischaemic rats in a dose-dependent manner, compared to the vehicle group. Furthermore, PCB at high doses restored the MBP and CNPase expression levels in ischaemic rats. An improved PCB purification method from its natural source is reported, obtaining PCB that is suitable for pharmacological trials showing neuroprotective effects against experimental ischaemic stroke. Therefore, PCB could be a therapeutic pharmacological alternative for ischaemic stroke patients.
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Affiliation(s)
| | - Javier Marín-Prida
- Centre for Research and Biological Evaluations (CEIEB), Institute of Pharmacy and Food, University of Havana, Havana, Cuba
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27
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Zhang SZ, Wang QQ, Yang QQ, Gu HY, Yin YQ, Li YD, Hou JC, Chen R, Sun QQ, Sun YF, Hu G, Zhou JW. NG2 glia regulate brain innate immunity via TGF-β2/TGFBR2 axis. BMC Med 2019; 17:204. [PMID: 31727112 PMCID: PMC6857135 DOI: 10.1186/s12916-019-1439-x] [Citation(s) in RCA: 91] [Impact Index Per Article: 15.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2019] [Accepted: 10/01/2019] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Brain innate immunity is vital for maintaining normal brain functions. Immune homeostatic imbalances play pivotal roles in the pathogenesis of neurological diseases including Parkinson's disease (PD). However, the molecular and cellular mechanisms underlying the regulation of brain innate immunity and their significance in PD pathogenesis are still largely unknown. METHODS Cre-inducible diphtheria toxin receptor (iDTR) and diphtheria toxin-mediated cell ablation was performed to investigate the impact of neuron-glial antigen 2 (NG2) glia on the brain innate immunity. RNA sequencing analysis was carried out to identify differentially expressed genes in mouse brain with ablated NG2 glia and lipopolysaccharide (LPS) challenge. Neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice were used to evaluate neuroinflammatory response in the presence or absence of NG2 glia. The survival of dopaminergic neurons or glial cell activation was evaluated by immunohistochemistry. Co-cultures of NG2 glia and microglia were used to examine the influence of NG2 glia to microglial activation. RESULTS We show that NG2 glia are required for the maintenance of immune homeostasis in the brain via transforming growth factor-β2 (TGF-β2)-TGF-β type II receptor (TGFBR2)-CX3C chemokine receptor 1 (CX3CR1) signaling, which suppresses the activation of microglia. We demonstrate that mice with ablated NG2 glia display a profound downregulation of the expression of microglia-specific signature genes and remarkable inflammatory response in the brain following exposure to endotoxin lipopolysaccharides. Gain- or loss-of-function studies show that NG2 glia-derived TGF-β2 and its receptor TGFBR2 in microglia are key regulators of the CX3CR1-modulated immune response. Furthermore, deficiency of NG2 glia contributes to neuroinflammation and nigral dopaminergic neuron loss in MPTP-induced mouse PD model. CONCLUSIONS These findings suggest that NG2 glia play a critical role in modulation of neuroinflammation and provide a compelling rationale for the development of new therapeutics for neurological disorders.
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Affiliation(s)
- Shu-Zhen Zhang
- Institute of Neuroscience, State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai, 200031, China
| | - Qin-Qin Wang
- Institute of Neuroscience, State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai, 200031, China.,School of Future Technology, University of Chinese Academy of Sciences, Beijing, 100049, China.,Neurobiology Key Laboratory, Jining Medical University, Jining, 272067, Shandong, China
| | - Qiao-Qiao Yang
- Institute of Neuroscience, State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai, 200031, China
| | - Huan-Yu Gu
- Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, Nanjing, 210029, Jiangsu, China
| | - Yan-Qing Yin
- Institute of Neuroscience, State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai, 200031, China
| | - Yan-Dong Li
- Institute of Neuroscience, State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai, 200031, China
| | - Jin-Can Hou
- Institute of Neuroscience, State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai, 200031, China
| | - Rong Chen
- Institute of Neuroscience, State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai, 200031, China.,School of Future Technology, University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Qing-Qing Sun
- Institute of Neuroscience, State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai, 200031, China.,School of Future Technology, University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Ying-Feng Sun
- Center for Brain Disorders Research, Center of Parkinson's Disease, Beijing Institute for Brain Disorders, Capital Medical University, Beijing, 100053, China
| | - Gang Hu
- Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, Nanjing, 210029, Jiangsu, China
| | - Jia-Wei Zhou
- Institute of Neuroscience, State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai, 200031, China. .,School of Future Technology, University of Chinese Academy of Sciences, Beijing, 100049, China. .,Co-innovation Center of Neuroregeneration, School of Medicine, Nantong University, Nantong, 226001, Jiangsu, China. .,Shanghai Center for Brain Science and Brain-Inspired Intelligence Technology, Shanghai, 201210, China.
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28
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Gibson D, Mehler PS. Anorexia Nervosa and the Immune System-A Narrative Review. J Clin Med 2019; 8:jcm8111915. [PMID: 31717370 PMCID: PMC6912362 DOI: 10.3390/jcm8111915] [Citation(s) in RCA: 58] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2019] [Revised: 10/24/2019] [Accepted: 11/04/2019] [Indexed: 12/13/2022] Open
Abstract
The pathogenesis of an increasing number of chronic diseases is being attributed to effects of the immune system. However, its role in the development and maintenance of anorexia nervosa is seemingly under-appreciated. Yet, in examining the available research on the immune system and genetic studies in anorexia nervosa, one becomes increasingly suspicious of the immune system’s potential role in the pathophysiology of anorexia nervosa. Specifically, research is suggestive of increased levels of various pro-inflammatory cytokines as well as the spontaneous production of tumor necrosis factor in anorexia nervosa; genetic studies further support a dysregulated immune system in this disorder. Potential contributors to this dysregulated immune system are discussed including increased oxidative stress, chronic physiological/psychological stress, changes in the intestinal microbiota, and an abnormal bone marrow microenvironment, all of which are present in anorexia nervosa.
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Affiliation(s)
- Dennis Gibson
- Assistant Medical Director, ACUTE Center for Eating Disorders @ Denver Health; Assistant Professor of Medicine, University of Colorado School of Medicine; 777 Bannock St., Denver, CO 80204, USA
- Correspondence: ; Tel.: +303-602-5067; Fax: +303-602-3811
| | - Philip S Mehler
- President, Eating Recovery Center; Founder and Executive Medical Director, ACUTE Center for Eating Disorders @ Denver Health; Glassman Professor of Medicine, University of Colorado School of Medicine; 7351 E Lowry Blvd, Suite 200, Denver, CO 80230, USA;
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29
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Hahn N, Büschgens L, Schwedhelm-Domeyer N, Bank S, Geurten BRH, Neugebauer P, Massih B, Göpfert MC, Heinrich R. The Orphan Cytokine Receptor CRLF3 Emerged With the Origin of the Nervous System and Is a Neuroprotective Erythropoietin Receptor in Locusts. Front Mol Neurosci 2019; 12:251. [PMID: 31680856 PMCID: PMC6797617 DOI: 10.3389/fnmol.2019.00251] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2019] [Accepted: 09/27/2019] [Indexed: 12/19/2022] Open
Abstract
The orphan cytokine receptor-like factor 3 (CRLF3) was identified as a neuroprotective erythropoietin receptor in locust neurons and emerged with the evolution of the eumetazoan nervous system. Human CRLF3 belongs to class I helical cytokine receptors that mediate pleiotropic cellular reactions to injury and diverse physiological challenges. It is expressed in various tissues including the central nervous system but its ligand remains unidentified. A CRLF3 ortholog in the holometabolous beetle Tribolium castaneum was recently shown to induce anti-apoptotic mechanisms upon stimulation with human recombinant erythropoietin. To test the hypothesis that CRLF3 represents an ancient cell-protective receptor for erythropoietin-like cytokines, we investigated its presence across metazoan species. Furthermore, we examined CRLF3 expression and function in the hemimetabolous insect Locusta migratoria. Phylogenetic analysis of CRLF3 sequences indicated that CRLF3 is absent in Porifera, Placozoa and Ctenophora, all lacking the traditional nervous system. However, it is present in all major eumetazoan groups ranging from cnidarians over protostomians to mammals. The CRLF3 sequence is highly conserved and abundant amongst vertebrates. In contrast, relatively few invertebrates express CRLF3 and these sequences show greater variability, suggesting frequent loss due to low functional importance. In L. migratoria, we identified the transcript Lm-crlf3 by RACE-PCR and detected its expression in locust brain, skeletal muscle and hemocytes. These findings correspond to the ubiquitous expression of crlf3 in mammalian tissues. We demonstrate that the sole addition of double-stranded RNA to the culture medium (called soaking RNA interference) specifically interferes with protein expression in locust primary brain cell cultures. This technique was used to knock down Lm-crlf3 expression and to abolish its physiological function. We confirmed that recombinant human erythropoietin rescues locust brain neurons from hypoxia-induced apoptosis and showed that this neuroprotective effect is absent after knocking down Lm-crlf3. Our results affirm the erythropoietin-induced neuroprotective function of CRLF3 in a second insect species from a different taxonomic group. They suggest that the phylogenetically conserved CRLF3 receptor may function as a cell protective receptor for erythropoietin or a structurally related cytokine also in other animals including vertebrate and mammalian species.
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Affiliation(s)
- Nina Hahn
- Department of Cellular Neurobiology, Institute for Zoology and Anthropology, Georg-August University of Göttingen, Göttingen, Germany
| | - Luca Büschgens
- Department of Cellular Neurobiology, Institute for Zoology and Anthropology, Georg-August University of Göttingen, Göttingen, Germany
| | - Nicola Schwedhelm-Domeyer
- Department of Cellular Neurobiology, Institute for Zoology and Anthropology, Georg-August University of Göttingen, Göttingen, Germany
| | - Sarah Bank
- Department of Animal Evolution and Biodiversity, Institute for Zoology & Anthropology, Georg-August University of Göttingen, Göttingen, Germany
| | - Bart R. H. Geurten
- Department of Cellular Neurobiology, Institute for Zoology and Anthropology, Georg-August University of Göttingen, Göttingen, Germany
| | - Pia Neugebauer
- Department of Cellular Neurobiology, Institute for Zoology and Anthropology, Georg-August University of Göttingen, Göttingen, Germany
| | - Bita Massih
- Department of Cellular Neurobiology, Institute for Zoology and Anthropology, Georg-August University of Göttingen, Göttingen, Germany
| | - Martin C. Göpfert
- Department of Cellular Neurobiology, Institute for Zoology and Anthropology, Georg-August University of Göttingen, Göttingen, Germany
| | - Ralf Heinrich
- Department of Cellular Neurobiology, Institute for Zoology and Anthropology, Georg-August University of Göttingen, Göttingen, Germany
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Liu W, Kämpfe Nordström C, Danckwardt-Lillieström N, Rask-Andersen H. Human Inner Ear Immune Activity: A Super-Resolution Immunohistochemistry Study. Front Neurol 2019; 10:728. [PMID: 31354608 PMCID: PMC6635812 DOI: 10.3389/fneur.2019.00728] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2019] [Accepted: 06/19/2019] [Indexed: 12/20/2022] Open
Abstract
Background: Like the brain, the human inner ear was long thought to be devoid of immune activity. Only the endolymphatic sac (ES) was known to be endowed with white blood cells that could process antigens and serve as an immunologic defense organ for the entire inner ear. Unexpectedly, the cochlear and vestibular organs, including the eighth cranial nerve, were recently shown to contain macrophages whose functions and implication in ear disease are somewhat undefined. Here, we review recent inner ear findings in man and extend the analyses to the vestibular nerve using super-resolution structured illumination microscopy (SR-SIM). Materials and Methods: Human ESs and cochleae were collected during surgery to treat patients with vestibular schwannoma and life-threatening petro-clival meningioma compressing the brainstem. The ESs and cochleae were placed in fixative, decalcified, and rapidly frozen and cryostat sectioned. Antibodies against ionized calcium-binding adaptor molecule 1-expressing cells (IBA1 cells), laminin β2 and type IV collagen TUJ1, cytokine fractalkine (CX3CL1), toll-like receptor 4 (TLR4), CD68, CD11b, CD4, CD8, the major histocompatibility complex type II (MHCII), and the microglial marker TEME119 were used. Results: IBA1-positive cells were present in the ESs, the cochlea, central and peripheral axons of the cochlear nerve, and the vestibular nerve trunk. IBA1 cells were found in the cochlear lateral wall, spiral limbus, and spiral ganglion. Notable variants of IBA1 cells adhered to neurons with “synapse-like” specializations and cytoplasmic projections. Slender IBA1 cells occasionally protracted into the basal lamina of the Schwann cells and had intimate contact with surrounding axons. Discussion: The human eighth nerve may be under the control of a well-developed macrophage cell system. A small number of CD4+ and CD8+ cells were found in the ES and occasionally in the cochlea, mostly located in the peripheral region of Rosenthal's canal. A neuro-immunologic axis may exist in the human inner ear that could play a role in the protection of the auditory nerve. The implication of the macrophage system during disease, surgical interventions, and cell-based transplantation should be further explored.
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Affiliation(s)
- Wei Liu
- Section of Otolaryngology, Department of Surgical Sciences, Uppsala University Hospital, Uppsala, Sweden
| | - Charlotta Kämpfe Nordström
- Section of Otolaryngology, Department of Surgical Sciences, Uppsala University Hospital, Uppsala, Sweden
| | | | - Helge Rask-Andersen
- Section of Otolaryngology, Department of Surgical Sciences, Uppsala University Hospital, Uppsala, Sweden
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31
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Cell Clearing Systems Bridging Neuro-Immunity and Synaptic Plasticity. Int J Mol Sci 2019; 20:ijms20092197. [PMID: 31060234 PMCID: PMC6538995 DOI: 10.3390/ijms20092197] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2019] [Revised: 04/29/2019] [Accepted: 04/30/2019] [Indexed: 02/06/2023] Open
Abstract
In recent years, functional interconnections emerged between synaptic transmission, inflammatory/immune mediators, and central nervous system (CNS) (patho)-physiology. Such interconnections rose up to a level that involves synaptic plasticity, both concerning its molecular mechanisms and the clinical outcomes related to its behavioral abnormalities. Within this context, synaptic plasticity, apart from being modulated by classic CNS molecules, is strongly affected by the immune system, and vice versa. This is not surprising, given the common molecular pathways that operate at the cross-road between the CNS and immune system. When searching for a common pathway bridging neuro-immune and synaptic dysregulations, the two major cell-clearing cell clearing systems, namely the ubiquitin proteasome system (UPS) and autophagy, take center stage. In fact, just like is happening for the turnover of key proteins involved in neurotransmitter release, antigen processing within both peripheral and CNS-resident antigen presenting cells is carried out by UPS and autophagy. Recent evidence unravelling the functional cross-talk between the cell-clearing pathways challenged the traditional concept of autophagy and UPS as independent systems. In fact, autophagy and UPS are simultaneously affected in a variety of CNS disorders where synaptic and inflammatory/immune alterations concur. In this review, we discuss the role of autophagy and UPS in bridging synaptic plasticity with neuro-immunity, while posing a special emphasis on their interactions, which may be key to defining the role of immunity in synaptic plasticity in health and disease.
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Oxidative stress and immune aberrancies in attention-deficit/hyperactivity disorder (ADHD): a case-control comparison. Eur Child Adolesc Psychiatry 2019; 28:719-729. [PMID: 30350094 DOI: 10.1007/s00787-018-1239-4] [Citation(s) in RCA: 44] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2018] [Accepted: 10/13/2018] [Indexed: 02/02/2023]
Abstract
The objective of this study is to compare oxidative stress and immune biomarkers between attention-deficit/hyperactivity disorder (ADHD) patients and controls without ADHD. A case-control comparison between 57 paediatric (6-12 years) untreated ADHD patients from the Antwerp University Hospital and 69 controls without ADHD from random schools in Flanders, Belgium, was conducted. Erythrocyte glutathione (GSH) and plasma lipid-soluble antioxidants (retinol, α-tocopherol, γ-tocopherol, retinyl palmitate, β-carotene, and co-enzyme Q10) were determined by HPLC with electrochemical detection, plasma malondialdehyde (MDA) by HPLC with fluorescence detection, plasma cytokines (interleukin (IL)-1β, IL-5, IL-6, IL-8, IL-10, tumour necrosis factor (TNF) and interferon (INF)-γ) and immunoglobulins (IgE, IgG and IgM) by flow cytometry and urinary 8-hydroxy-2'deoxyguanosine (8-OHdG) levels by ELISA assay. Dietary habits were determined by a food frequency questionnaire. Plasma MDA levels were on average 0.031 µM higher in patients than in controls (p < 0.05), and a trend for higher urinary 8-OHdG was observed. Erythrocyte GSH and plasma retinyl palmitate levels, as well as IgG and IgE levels, were higher in patients than in controls as well (on average 93.707 µg/ml, 0.006 µg/ml, 301.555 µg/ml and 125.004 µg/ml, resp., p < 0.05). Finally, a trend for lower plasma IL-5 levels was observed. After Bonferroni correction for multiple testing, the difference in GSH levels remained statistically significant (nominally significant for retinyl palmitate), while significance was lost for MDA, IgG and IgE levels. Dietary habits do not appear to cause the observed differences. These results point at the potential involvement of slight oxidative stress and immune disturbances in ADHD.
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Limanaqi F, Biagioni F, Gaglione A, Busceti CL, Fornai F. A Sentinel in the Crosstalk Between the Nervous and Immune System: The (Immuno)-Proteasome. Front Immunol 2019; 10:628. [PMID: 30984192 PMCID: PMC6450179 DOI: 10.3389/fimmu.2019.00628] [Citation(s) in RCA: 46] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2019] [Accepted: 03/08/2019] [Indexed: 12/20/2022] Open
Abstract
The wealth of recent evidence about a bi-directional communication between nerve- and immune- cells revolutionized the traditional concept about the brain as an “immune-privileged” organ while opening novel avenues in the pathophysiology of CNS disorders. In fact, altered communication between the immune and nervous system is emerging as a common hallmark in neuro-developmental, neurodegenerative, and neuro-immunological diseases. At molecular level, the ubiquitin proteasome machinery operates as a sentinel at the crossroad between the immune system and brain. In fact, the standard proteasome and its alternative/inducible counterpart, the immunoproteasome, operate dynamically and coordinately in both nerve- and immune- cells to modulate neurotransmission, oxidative/inflammatory stress response, and immunity. When dysregulations of the proteasome system occur, altered amounts of standard- vs. immune-proteasome subtypes translate into altered communication between neurons, glia, and immune cells. This contributes to neuro-inflammatory pathology in a variety of neurological disorders encompassing Parkinson's, Alzheimer's, and Huntingtin's diseases, brain trauma, epilepsy, and Multiple Sclerosis. In the present review, we analyze those proteasome-dependent molecular interactions which sustain communication between neurons, glia, and brain circulating T-lymphocytes both in baseline and pathological conditions. The evidence here discussed converges in that upregulation of immunoproteasome to the detriment of the standard proteasome, is commonly implicated in the inflammatory- and immune- biology of neurodegeneration. These concepts may foster additional studies investigating the role of immunoproteasome as a potential target in neurodegenerative and neuro-immunological disorders.
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Affiliation(s)
- Fiona Limanaqi
- Human Anatomy, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy
| | | | | | | | - Francesco Fornai
- Human Anatomy, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy.,I.R.C.C.S Neuromed, Pozzilli, Italy
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Yong HYF, Rawji KS, Ghorbani S, Xue M, Yong VW. The benefits of neuroinflammation for the repair of the injured central nervous system. Cell Mol Immunol 2019; 16:540-546. [PMID: 30874626 DOI: 10.1038/s41423-019-0223-3] [Citation(s) in RCA: 132] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2019] [Revised: 02/28/2019] [Accepted: 03/01/2019] [Indexed: 02/07/2023] Open
Abstract
Inflammation of the nervous system (neuroinflammation) is now recognized as a hallmark of virtually all neurological disorders. In neuroinflammatory conditions such as multiple sclerosis, there is prominent infiltration and a long-lasting representation of various leukocyte subsets in the central nervous system (CNS) parenchyma. Even in classic neurodegenerative disorders, where such immense inflammatory infiltrates are absent, there is still evidence of activated CNS-intrinsic microglia. The consequences of excessive and uncontrolled neuroinflammation are injury and death to neural elements, which manifest as a heterogeneous set of neurological symptoms. However, it is now readily acknowledged, due to instructive studies from the peripheral nervous system and a large body of CNS literature, that aspects of the neuroinflammatory response can be beneficial for CNS outcomes. The recognized benefits of inflammation to the CNS include the preservation of CNS constituents (neuroprotection), the proliferation and maturation of various neural precursor populations, axonal regeneration, and the reformation of myelin on denuded axons. Herein, we highlight the benefits of neuroinflammation in fostering CNS recovery after neural injury using examples from multiple sclerosis, traumatic spinal cord injury, stroke, and Alzheimer's disease. We focus on CNS regenerative responses, such as neurogenesis, axonal regeneration, and remyelination, and discuss the mechanisms by which neuroinflammation is pro-regenerative for the CNS. Finally, we highlight treatment strategies that harness the benefits of neuroinflammation for CNS regenerative responses.
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Affiliation(s)
| | | | | | - Mengzhou Xue
- The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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Lin W, Hsuan YCY, Lin MT, Kuo TW, Lin CH, Su YC, Niu KC, Chang CP, Lin HJ. Human Umbilical Cord Mesenchymal Stem Cells Preserve Adult Newborn Neurons and Reduce Neurological Injury after Cerebral Ischemia by Reducing the Number of Hypertrophic Microglia/Macrophages. Cell Transplant 2018; 26:1798-1810. [PMID: 29338384 PMCID: PMC5784525 DOI: 10.1177/0963689717728936] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
Microglia are the first source of a neuroinflammatory cascade, which seems to be involved in every phase of stroke-related neuronal damage. Two weeks after transient middle cerebral artery occlusion (MCAO), vehicle-treated rats displayed higher numbers of total ionized calcium-binding adaptor molecule 1 (Iba-1)-positive cells, greater cell body areas of Iba-1-positive cells, and higher numbers of hypertrophic Iba-1-positive cells (with a cell body area over 80 μm2) in the ipsilateral ischemic brain regions including the frontal cortex, striatum, and parietal cortex. In addition, MCAO decreased the number of migrating neuroblasts (or DCX- and 5-ethynyl-2′-deoxyuridine-positive cells) in the cortex, subventricular zone, and hippocampus of the ischemic brain, followed by neurological injury (including brain infarct and neurological deficits). Intravenous administration of human umbilical cord–derived mesenchymal stem cells (hUC-MSCs; 1 × 106 or 4 × 106) at 24 h after MCAO reduced neurological injury, decreased the number of hypertrophic microglia/macrophages, and increased the number of newborn neurons in rat brains. Thus, the accumulation of hypertrophic microglia/macrophages seems to be detrimental to neurogenesis after stroke. Treatment with hUC-MSCs preserved adult newborn neurons and reduced functional impairment after transient cerebral ischemia by reducing the number of hypertrophic microglia/macrophages.
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Affiliation(s)
- Willie Lin
- 1 Meridigen Biotech Co., Ltd., Neihu, Taipei City, Taiwan
| | | | - Mao-Tsun Lin
- 2 Department of Medical Research, Chi Mei Medical Center, Tainan City, Taiwan
| | - Ting-Wei Kuo
- 3 Department of Biotechnology, Southern Taiwan University of Science and Technology, Tainan City, Taiwan
| | | | - Yu-Chin Su
- 1 Meridigen Biotech Co., Ltd., Neihu, Taipei City, Taiwan
| | - Ko-Chi Niu
- 4 Department of Hyperbaric Oxygen, Chi Mei Medical Center, Tainan City, Taiwan
| | - Ching-Ping Chang
- 2 Department of Medical Research, Chi Mei Medical Center, Tainan City, Taiwan.,3 Department of Biotechnology, Southern Taiwan University of Science and Technology, Tainan City, Taiwan.,5 The Ph.D. Program for Neural Regenerative Medicine, Taipei Medical University, Taipei City, Taiwan
| | - Hung-Jung Lin
- 3 Department of Biotechnology, Southern Taiwan University of Science and Technology, Tainan City, Taiwan.,6 Department of Emergency Medicine, Chi Mei Medical Center, Tainan City, Taiwan
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Szepesi Z, Manouchehrian O, Bachiller S, Deierborg T. Bidirectional Microglia-Neuron Communication in Health and Disease. Front Cell Neurosci 2018; 12:323. [PMID: 30319362 PMCID: PMC6170615 DOI: 10.3389/fncel.2018.00323] [Citation(s) in RCA: 307] [Impact Index Per Article: 43.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2018] [Accepted: 09/06/2018] [Indexed: 12/12/2022] Open
Abstract
Microglia are ramified cells that exhibit highly motile processes, which continuously survey the brain parenchyma and react to any insult to the CNS homeostasis. Although microglia have long been recognized as a crucial player in generating and maintaining inflammatory responses in the CNS, now it has become clear, that their function are much more diverse, particularly in the healthy brain. The innate immune response and phagocytosis represent only a little segment of microglia functional repertoire that also includes maintenance of biochemical homeostasis, neuronal circuit maturation during development and experience-dependent remodeling of neuronal circuits in the adult brain. Being equipped by numerous receptors and cell surface molecules microglia can perform bidirectional interactions with other cell types in the CNS. There is accumulating evidence showing that neurons inform microglia about their status and thus are capable of controlling microglial activation and motility while microglia also modulate neuronal activities. This review addresses the topic: how microglia communicate with other cell types in the brain, including fractalkine signaling, secreted soluble factors and extracellular vesicles. We summarize the current state of knowledge of physiological role and function of microglia during brain development and in the mature brain and further highlight microglial contribution to brain pathologies such as Alzheimer’s and Parkinson’s disease, brain ischemia, traumatic brain injury, brain tumor as well as neuropsychiatric diseases (depression, bipolar disorder, and schizophrenia).
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Affiliation(s)
- Zsuzsanna Szepesi
- Experimental Neuroinflammation Laboratory, Department of Experimental Medical Science, Lund University, Lund, Sweden
| | - Oscar Manouchehrian
- Experimental Neuroinflammation Laboratory, Department of Experimental Medical Science, Lund University, Lund, Sweden
| | - Sara Bachiller
- Experimental Neuroinflammation Laboratory, Department of Experimental Medical Science, Lund University, Lund, Sweden
| | - Tomas Deierborg
- Experimental Neuroinflammation Laboratory, Department of Experimental Medical Science, Lund University, Lund, Sweden
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Abstract
This paper discusses the current evidence from animal and human studies for a central role of inflammation in schizophrenia. In animal models, pre- or perinatal elicitation of the immune response may increase immune reactivity throughout life, and similar findings have been described in humans. Levels of pro-inflammatory markers, such as cytokines, have been found to be increased in the blood and cerebrospinal fluid of patients with schizophrenia. Numerous epidemiological and clinical studies have provided evidence that various infectious agents are risk factors for schizophrenia and other psychoses. For example, a large-scale epidemiological study performed in Denmark clearly showed that severe infections and autoimmune disorders are such risk factors. The vulnerability-stress-inflammation model may help to explain the role of inflammation in schizophrenia because stress can increase pro-inflammatory cytokines and may even contribute to a chronic pro-inflammatory state. Schizophrenia is characterized by risk genes that promote inflammation and by environmental stress factors and alterations of the immune system. Typical alterations of dopaminergic, serotonergic, noradrenergic, and glutamatergic neurotransmission described in schizophrenia have also been found in low-level neuroinflammation and consequently may be key factors in the generation of schizophrenia symptoms. Further support for the relevance of a low-level neuroinflammatory process in schizophrenia is provided by the loss of central nervous system volume and microglial activation demonstrated in neuroimaging studies. Last but not least, the benefit of anti-inflammatory medications found in some studies and the intrinsic anti-inflammatory and immunomodulatory effects of antipsychotics provide further support for the role of inflammation in this debilitating disease.
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Affiliation(s)
- Norbert Müller
- Department of Psychiatry and Psychotherapy Ludwig Maximilian University and Marion von Tessin Memory Center, Munich, Germany
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Disdier C, Chen X, Kim JE, Threlkeld SW, Stonestreet BS. Anti-Cytokine Therapy to Attenuate Ischemic-Reperfusion Associated Brain Injury in the Perinatal Period. Brain Sci 2018; 8:E101. [PMID: 29875342 PMCID: PMC6025309 DOI: 10.3390/brainsci8060101] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2018] [Revised: 05/31/2018] [Accepted: 06/05/2018] [Indexed: 12/26/2022] Open
Abstract
Perinatal brain injury is a major cause of morbidity and long-standing disability in newborns. Hypothermia is the only therapy approved to attenuate brain injury in the newborn. However, this treatment is unfortunately only partially neuroprotective and can only be used to treat hypoxic-ischemic encephalopathy in full term infants. Therefore, there is an urgent need for adjunctive therapeutic strategies. Post-ischemic neuro-inflammation is a crucial contributor to the evolution of brain injury in neonates and constitutes a promising therapeutic target. Recently, we demonstrated encouraging neuroprotective capacities of anti-cytokine monoclonal antibodies (mAbs) in an ischemic-reperfusion (I/R) model of brain injury in the ovine fetus. The purpose of this review is to summarize the current knowledge regarding the inflammatory response in the perinatal sheep brain after I/R injury and to review our recent findings regarding the beneficial effects of treatment with anti-cytokine mAbs.
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Affiliation(s)
- Clémence Disdier
- Department of Pediatrics, Women & Infants Hospital of Rhode Island, The Alpert Medical School of Brown University, Providence, RI 02905, USA.
| | - Xiaodi Chen
- Department of Pediatrics, Women & Infants Hospital of Rhode Island, The Alpert Medical School of Brown University, Providence, RI 02905, USA.
| | - Jeong-Eun Kim
- Department of Pediatrics, Women & Infants Hospital of Rhode Island, The Alpert Medical School of Brown University, Providence, RI 02905, USA.
| | | | - Barbara S Stonestreet
- Department of Pediatrics, Women & Infants Hospital of Rhode Island, The Alpert Medical School of Brown University, Providence, RI 02905, USA.
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Pringproa K, Srivorakul S, Tantilertcharoen R, Thanawongnuwech R. Restricted Infection and Cytokine Expression in Primary Murine Astrocytes Induced by the H5N1 Influenza Virus. NEUROCHEM J+ 2018. [DOI: 10.1134/s1819712418010129] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
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Abstract
The field of psychoneuroimmunology (PNI) aims to uncover the processes and consequences of nervous, immune, and endocrine system relationships. Behavior is a consequence of such interactions and manifests from a complex interweave of factors including immune-to-neural and neural-to-immune communication. Often the signaling molecules involved during a particular episode of neuroimmune activation are not known but behavioral response provides evidence that bioactives such as neurotransmitters and cytokines are perturbed. Immunobehavioral phenotyping is a first-line approach when examining the neuroimmune system and its reaction to immune stimulation or suppression. Behavioral response is significantly more sensitive than direct measurement of a single specific bioactive and can quickly and efficiently rule in or out relevance of a particular immune challenge or therapeutic to neuroimmunity. Classically, immunobehavioral research was focused on sickness symptoms related to bacterial infection but neuroimmune activation is now a recognized complication of diseases and disorders ranging from cancer to diabesity to Alzheimer's. Immunobehaviors include lethargy, loss of appetite, and disinterest in social activity/surrounding environment. In addition, neuroimmune activation can diminish physical activity, precipitate feelings of depression and anxiety, and impair cognitive and executive function. Provided is a detailed overview of behavioral tests frequently used to examine neuroimmune activation in mice with a special emphasis on pre-experimental conditions that can confound or prevent successful immunobehavioral experimentation.
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Bajnok A, Berta L, Orbán C, Veres G, Zádori D, Barta H, Méder Ü, Vécsei L, Tulassay T, Szabó M, Toldi G. Distinct cytokine patterns may regulate the severity of neonatal asphyxia-an observational study. J Neuroinflammation 2017; 14:244. [PMID: 29233180 PMCID: PMC5727967 DOI: 10.1186/s12974-017-1023-2] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2017] [Accepted: 12/05/2017] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Neuroinflammation and a systemic inflammatory reaction are important features of perinatal asphyxia. Neuroinflammation may have dual aspects being a hindrance, but also a significant help in the recovery of the CNS. We aimed to assess intracellular cytokine levels of T-lymphocytes and plasma cytokine levels in moderate and severe asphyxia in order to identify players of the inflammatory response that may influence patient outcome. METHODS We analyzed the data of 28 term neonates requiring moderate systemic hypothermia in a single-center observational study. Blood samples were collected between 3 and 6 h of life, at 24 h, 72 h, 1 week, and 1 month of life. Neonates were divided into a moderate (n = 17) and a severe (n = 11) group based on neuroradiological and amplitude-integrated EEG characteristics. Peripheral blood mononuclear cells were assessed with flow cytometry. Cytokine plasma levels were measured using Bioplex immunoassays. Components of the kynurenine pathway were assessed by high-performance liquid chromatography. RESULTS The prevalence and extravasation of IL-1b + CD4 cells were higher in severe than in moderate asphyxia at 6 h. Based on Receiver operator curve analysis, the assessment of the prevalence of CD4+ IL-1β+ and CD4+ IL-1β+ CD49d+ cells at 6 h appears to be able to predict the severity of the insult at an early stage in asphyxia. Intracellular levels of TNF-α in CD4 cells were increased at all time points compared to 6 h in both groups. At 1 month, intracellular levels of TNF-α were higher in the severe group. Plasma IL-6 levels were higher at 1 week in the severe group and decreased by 1 month in the moderate group. Intracellular levels of IL-6 peaked at 24 h in both groups. Intracellular TGF-β levels were increased from 24 h onwards in the moderate group. CONCLUSIONS IL-1β and IL-6 appear to play a key role in the early events of the inflammatory response, while TNF-α seems to be responsible for prolonged neuroinflammation, potentially contributing to a worse outcome. The assessment of the prevalence of CD4+ IL-1β+ and CD4+ IL-1β+ CD49d+ cells at 6 h appears to be able to predict the severity of the insult at an early stage in asphyxia.
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Affiliation(s)
- Anna Bajnok
- First Department of Obstetrics and Gynecology, Semmelweis University, Baross str. 27, Budapest, H-1088, Hungary.,First Department of Pediatrics, Semmelweis University, Bókay János str. 53-54, Budapest, H-1083, Hungary
| | - László Berta
- First Department of Pediatrics, Semmelweis University, Bókay János str. 53-54, Budapest, H-1083, Hungary
| | - Csaba Orbán
- First Department of Pediatrics, Semmelweis University, Bókay János str. 53-54, Budapest, H-1083, Hungary
| | - Gábor Veres
- Department of Neurology, Albert Szent-Györgyi Clinical Centre, Faculty of Medicine, University of Szeged, Semmelweis str. 6, 5th floor, Szeged, H-6725, Hungary.,MTA-SZTE Neuroscience Research Group, Szeged, Hungary
| | - Dénes Zádori
- Department of Neurology, Albert Szent-Györgyi Clinical Centre, Faculty of Medicine, University of Szeged, Semmelweis str. 6, 5th floor, Szeged, H-6725, Hungary
| | - Hajnalka Barta
- First Department of Pediatrics, Semmelweis University, Bókay János str. 53-54, Budapest, H-1083, Hungary
| | - Ünőke Méder
- First Department of Pediatrics, Semmelweis University, Bókay János str. 53-54, Budapest, H-1083, Hungary
| | - László Vécsei
- Department of Neurology, Albert Szent-Györgyi Clinical Centre, Faculty of Medicine, University of Szeged, Semmelweis str. 6, 5th floor, Szeged, H-6725, Hungary.,MTA-SZTE Neuroscience Research Group, Szeged, Hungary
| | - Tivadar Tulassay
- First Department of Pediatrics, Semmelweis University, Bókay János str. 53-54, Budapest, H-1083, Hungary.,MTA-SE Pediatrics and Nephrology Research Group, Budapest, Hungary
| | - Miklós Szabó
- First Department of Pediatrics, Semmelweis University, Bókay János str. 53-54, Budapest, H-1083, Hungary.,MTA-SE Pediatrics and Nephrology Research Group, Budapest, Hungary
| | - Gergely Toldi
- First Department of Obstetrics and Gynecology, Semmelweis University, Baross str. 27, Budapest, H-1088, Hungary. .,First Department of Pediatrics, Semmelweis University, Bókay János str. 53-54, Budapest, H-1083, Hungary. .,Birmingham Women's and Children's Hospital, Neonatal Unit, Birmingham, UK.
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Tian L, Hui CW, Bisht K, Tan Y, Sharma K, Chen S, Zhang X, Tremblay ME. Microglia under psychosocial stressors along the aging trajectory: Consequences on neuronal circuits, behavior, and brain diseases. Prog Neuropsychopharmacol Biol Psychiatry 2017; 79:27-39. [PMID: 28095309 DOI: 10.1016/j.pnpbp.2017.01.007] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2016] [Revised: 12/30/2016] [Accepted: 01/13/2017] [Indexed: 12/18/2022]
Abstract
Mounting evidence indicates the importance of microglia for proper brain development and function, as well as in complex stress-related neuropsychiatric disorders and cognitive decline along the aging trajectory. Considering that microglia are resident immune cells of the brain, a homeostatic maintenance of their effector functions that impact neuronal circuitry, such as phagocytosis and secretion of inflammatory factors, is critical to prevent the onset and progression of these pathological conditions. However, the molecular mechanisms by which microglial functions can be properly regulated under healthy and pathological conditions are still largely unknown. We aim to summarize recent progress regarding the effects of psychosocial stress and oxidative stress on microglial phenotypes, leading to neuroinflammation and impaired microglia-synapse interactions, notably through our own studies of inbred mouse strains, and most importantly, to discuss about promising therapeutic strategies that take advantage of microglial functions to tackle such brain disorders in the context of adult psychosocial stress or aging-induced oxidative stress.
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Affiliation(s)
- Li Tian
- Neuroscience Center, University of Helsinki, Viikinkaari 4, Helsinki FIN-00014, Finland; Psychiatry Research Center, Beijing Huilongguan Hospital, Peking University, Beijing, China.
| | - Chin Wai Hui
- Axe Neurosciences, Centre de recherche du CHU de Québec, Québec, Canada
| | - Kanchan Bisht
- Axe Neurosciences, Centre de recherche du CHU de Québec, Québec, Canada
| | - Yunlong Tan
- Psychiatry Research Center, Beijing Huilongguan Hospital, Peking University, Beijing, China
| | - Kaushik Sharma
- Axe Neurosciences, Centre de recherche du CHU de Québec, Québec, Canada
| | - Song Chen
- Psychiatry Research Center, Beijing Huilongguan Hospital, Peking University, Beijing, China; Beijing Key Laboratory of Mental Disorders and Center of Schizophrenia, Beijing Institute for Brain Disorders, Beijing Anding Hospital, Capital Medical University, China
| | - Xiangyang Zhang
- Psychiatry Research Center, Beijing Huilongguan Hospital, Peking University, Beijing, China; Department of Psychiatry and Behavioral Sciences, The University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Marie-Eve Tremblay
- Axe Neurosciences, Centre de recherche du CHU de Québec, Québec, Canada.
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Bellaver B, Souza DG, Souza DO, Quincozes-Santos A. Hippocampal Astrocyte Cultures from Adult and Aged Rats Reproduce Changes in Glial Functionality Observed in the Aging Brain. Mol Neurobiol 2017; 54:2969-2985. [PMID: 27026184 DOI: 10.1007/s12035-016-9880-8] [Citation(s) in RCA: 94] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2016] [Accepted: 03/21/2016] [Indexed: 10/22/2022]
Abstract
Astrocytes are dynamic cells that maintain brain homeostasis, regulate neurotransmitter systems, and process synaptic information, energy metabolism, antioxidant defenses, and inflammatory response. Aging is a biological process that is closely associated with hippocampal astrocyte dysfunction. In this sense, we demonstrated that hippocampal astrocytes from adult and aged Wistar rats reproduce the glial functionality alterations observed in aging by evaluating several senescence, glutamatergic, oxidative and inflammatory parameters commonly associated with the aging process. Here, we show that the p21 senescence-associated gene and classical astrocyte markers, such as glial fibrillary acidic protein (GFAP), vimentin, and actin, changed their expressions in adult and aged astrocytes. Age-dependent changes were also observed in glutamate transporters (glutamate aspartate transporter (GLAST) and glutamate transporter-1 (GLT-1)) and glutamine synthetase immunolabeling and activity. Additionally, according to in vivo aging, astrocytes from adult and aged rats showed an increase in oxidative/nitrosative stress with mitochondrial dysfunction, an increase in RNA oxidation, NADPH oxidase (NOX) activity, superoxide levels, and inducible nitric oxide synthase (iNOS) expression levels. Changes in antioxidant defenses were also observed. Hippocampal astrocytes also displayed age-dependent inflammatory response with augmentation of proinflammatory cytokine levels, such as TNF-α, IL-1β, IL-6, IL-18, and messenger RNA (mRNA) levels of cyclo-oxygenase 2 (COX-2). Furthermore, these cells secrete neurotrophic factors, including glia-derived neurotrophic factor (GDNF), brain-derived neurotrophic factor (BDNF), S100 calcium-binding protein B (S100B) protein, and transforming growth factor-β (TGF-β), which changed in an age-dependent manner. Classical signaling pathways associated with aging, such as nuclear factor erythroid-derived 2-like 2 (Nrf2), nuclear factor kappa B (NFκB), heme oxygenase-1 (HO-1), and p38 mitogen-activated protein kinase (MAPK), were also changed in adult and aged astrocytes and are probably related to the changes observed in senescence marker, glutamatergic metabolism, mitochondrial dysfunction, oxidative/nitrosative stress, antioxidant defenses, inflammatory response, and trophic factors release. Together, our results reinforce the role of hippocampal astrocytes as a target for understanding the mechanisms involved in aging and provide an innovative tool for studies of astrocyte roles in physiological and pathological aging brain.
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Affiliation(s)
- Bruna Bellaver
- Departamento de Bioquímica, Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2600 - Anexo, Bairro Santa Cecília, Porto Alegre, Rio Grande do Sul, 90035-003, Brazil
| | - Débora Guerini Souza
- Departamento de Bioquímica, Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2600 - Anexo, Bairro Santa Cecília, Porto Alegre, Rio Grande do Sul, 90035-003, Brazil
| | - Diogo Onofre Souza
- Departamento de Bioquímica, Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2600 - Anexo, Bairro Santa Cecília, Porto Alegre, Rio Grande do Sul, 90035-003, Brazil
| | - André Quincozes-Santos
- Departamento de Bioquímica, Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2600 - Anexo, Bairro Santa Cecília, Porto Alegre, Rio Grande do Sul, 90035-003, Brazil.
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Law HCH, Szeto SSW, Quan Q, Zhao Y, Zhang Z, Krakovska O, Lui LT, Zheng C, Lee SMY, Siu KWM, Wang Y, Chu IK. Characterization of the Molecular Mechanisms Underlying the Chronic Phase of Stroke in a Cynomolgus Monkey Model of Induced Cerebral Ischemia. J Proteome Res 2017; 16:1150-1166. [PMID: 28102082 DOI: 10.1021/acs.jproteome.6b00651] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Stroke is one of the main causes of mortality and long-term disability worldwide. The pathophysiological mechanisms underlying this disease are not well understood, particularly in the chronic phase after the initial ischemic episode. In this study, a Macaca fascicularis stroke model consisting of two sample groups, as determined by MRI-quantified infarct volumes as a measure of the stroke severity 28 days after the ischemic episode, was evaluated using qualitative and quantitative proteomics analyses. By using multiple online multidimensional liquid chromatography platforms, 8790 nonredundant proteins were identified that condensed to 5223 protein groups at 1% global false discovery rate (FDR). After the application of a conservative criterion (5% local FDR), 4906 protein groups were identified from the analysis of cerebral cortex. Of the 2068 quantified proteins, differential proteomic analyses revealed that 31 and 23 were dysregulated in the elevated- and low-infarct-volume groups, respectively. Neurogenesis, synaptogenesis, and inflammation featured prominently as the cellular processes associated with these dysregulated proteins. Protein interaction network analysis revealed that the dysregulated proteins for inflammation and neurogenesis were highly connected, suggesting potential cross-talk between these processes in modulating the cytoskeletal structure and dynamics in the chronic phase poststroke. Elucidating the long-term consequences of brain tissue injuries from a cellular prospective, as well as the molecular mechanisms that are involved, would provide a basis for the development of new potentially neurorestorative therapies.
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Affiliation(s)
- Henry C H Law
- Department of Chemistry, The University of Hong Kong , Hong Kong, China
| | - Samuel S W Szeto
- Department of Chemistry, The University of Hong Kong , Hong Kong, China
| | - Quan Quan
- Department of Chemistry, The University of Hong Kong , Hong Kong, China
| | - Yun Zhao
- Department of Chemistry, The University of Hong Kong , Hong Kong, China
| | - Zaijun Zhang
- Institute of New Drug Research and Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine, College of Pharmacy, Jinan University , Guangzhou 510632, China
| | - Olga Krakovska
- Department of Chemistry and Centre for Research in Mass Spectrometry, York University , Toronto, Ontario M3J 1P3, Canada
| | - Leong Ting Lui
- Department of Chemistry, The University of Hong Kong , Hong Kong, China
| | - Chengyou Zheng
- Institute of New Drug Research and Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine, College of Pharmacy, Jinan University , Guangzhou 510632, China
| | - Simon M-Y Lee
- State Key Laboratory of Quality Research in Chinese Medicine and Institute of Chinese Medical Sciences, University of Macau , Avenue Padre Tomás Pereira S.J., Taipa, Macau 999078, China
| | - K W Michael Siu
- Department of Chemistry and Centre for Research in Mass Spectrometry, York University , Toronto, Ontario M3J 1P3, Canada.,Department of Chemistry and Biochemistry, University of Windsor , Windsor, Ontario N9B 3P4, Canada
| | - Yuqiang Wang
- Institute of New Drug Research and Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine, College of Pharmacy, Jinan University , Guangzhou 510632, China
| | - Ivan K Chu
- Department of Chemistry, The University of Hong Kong , Hong Kong, China
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CD4 and CD8 T cells mediate distinct lethal meningoencephalitis in mice challenged with Tacaribe arenavirus. Cell Mol Immunol 2016; 14:90-107. [PMID: 27569560 PMCID: PMC5214944 DOI: 10.1038/cmi.2016.41] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2016] [Revised: 06/15/2016] [Accepted: 06/17/2016] [Indexed: 01/25/2023] Open
Abstract
Neonates are at increased risk of viral encephalopathies that can result in neurological dysfunction, seizures, permanent disability and even death. The neurological damage results from the combined effect of the virus and the immune response it elicits, thus finding tools to facilitate viral clearance from central nervous system (CNS) while minimizing neuron damage remains a critical challenge. Neonatal mice inoculated intraperitoneally with Tacaribe virus (TCRV) develop seizures, hindlimb paralysis and death within 15 days of inoculation. TCRV localizes to the CNS within days of challenge, primarily infecting astrocytes in the cerebellum and brain stem. We show that infection leads to inflammation, T cell and monocyte infiltration into the cerebellar parenchyma, apoptosis of astrocytes, neuronal degeneration and loss of Purkinje cells. Infiltrating antigen-specific T cells fail to clear the virus but drive the disease, as T-cell-deficient CD3ɛ KO mice survive TCRV infection with minimal inflammation or clinical manifestations despite no difference in CNS viral loads in comparison with T-cell sufficient mice. CD8+ T cells drive the pathology, which even in the absence of CD4+ T-cell help, infiltrate the parenchyma and mediate the apoptotic loss of cerebellar astrocytes, neurodegeneration and loss of Purkinje cells resulting in loss of balance, paralysis and death. CD4+ T cells are also pathogenic inducing gliosis and inflammation in the cerebellum and cerebrum that are associated with wasting and death several weeks after CD4+ T-cell transfer. These data demonstrate distinct pathogenic effects of CD4+ and CD8+ T cells and identify them as possible therapeutic targets.
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Frau L, Simola N, Porceddu PF, Morelli M. Effect of crowding, temperature and age on glia activation and dopaminergic neurotoxicity induced by MDMA in the mouse brain. Neurotoxicology 2016; 56:127-138. [PMID: 27451954 DOI: 10.1016/j.neuro.2016.07.008] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2016] [Revised: 07/15/2016] [Accepted: 07/20/2016] [Indexed: 12/13/2022]
Abstract
3,4-methylenedyoxymethamphetamine (MDMA or "ecstasy"), a recreational drug of abuse, can induce glia activation and dopaminergic neurotoxicity. Since MDMA is often consumed in crowded environments featuring high temperatures, we studied how these factors influenced glia activation and dopaminergic neurotoxicity induced by MDMA. C57BL/6J adolescent (4 weeks old) and adult (12 weeks old) mice received MDMA (4×20mg/kg) in different conditions: 1) while kept 1, 5, or 10×cage at room temperature (21°C); 2) while kept 5×cage at either room (21°C) or high (27°C) temperature. After the last MDMA administration, immunohistochemistry was performed in the caudate-putamen for CD11b and GFAP, to mark microglia and astroglia, and in the substantia nigra pars compacta for tyrosine hydroxylase, to mark dopaminergic neurons. MDMA induced glia activation and dopaminergic neurotoxicity, compared with vehicle administration. Crowding (5 or 10 mice×cage) amplified MDMA-induced glia activation (in adult and adolescent mice) and dopaminergic neurotoxicity (in adolescent mice). Conversely, exposure to a high environmental temperature (27°C) potentiated MDMA-induced glia activation in adult and adolescent mice kept 5×cage, but not dopaminergic neurotoxicity. Crowding and exposure to a high environmental temperature amplified MDMA-induced hyperthermia, and a positive correlation between body temperature and activation of either microglia or astroglia was found in adult and adolescent mice. These results provide further evidence that the administration setting influences the noxious effects of MDMA in the mouse brain. However, while crowding amplifies both glia activation and dopaminergic neurotoxicity, a high environmental temperature exacerbates glia activation only.
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Affiliation(s)
- Lucia Frau
- Department of Biomedical Sciences, Section of Neuropsychopharmacology, University of Cagliari, Via Ospedale 72, 09124, Cagliari, Italy.
| | - Nicola Simola
- Department of Biomedical Sciences, Section of Neuropsychopharmacology, University of Cagliari, Via Ospedale 72, 09124, Cagliari, Italy.
| | - Pier Francesca Porceddu
- Department of Biomedical Sciences, Section of Neuropsychopharmacology, University of Cagliari, Via Ospedale 72, 09124, Cagliari, Italy.
| | - Micaela Morelli
- Department of Biomedical Sciences, Section of Neuropsychopharmacology, University of Cagliari, Via Ospedale 72, 09124, Cagliari, Italy; CNR, Institute of Neuroscience, Cagliari, Italy.
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Metformin Prevented Dopaminergic Neurotoxicity Induced by 3,4-Methylenedioxymethamphetamine Administration. Neurotox Res 2016; 30:101-9. [DOI: 10.1007/s12640-016-9633-5] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2015] [Revised: 05/19/2016] [Accepted: 05/21/2016] [Indexed: 01/31/2023]
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Muraleedharan CK, McClellan SA, Barrett RP, Li C, Montenegro D, Carion T, Berger E, Hazlett LD, Xu S. Inactivation of the miR-183/96/182 Cluster Decreases the Severity of Pseudomonas aeruginosa-Induced Keratitis. Invest Ophthalmol Vis Sci 2016; 57:1506-17. [PMID: 27035623 PMCID: PMC4819431 DOI: 10.1167/iovs.16-19134] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2016] [Accepted: 02/20/2016] [Indexed: 12/19/2022] Open
Abstract
PURPOSE The microRNA-183/96/182 cluster (miR-183/96/182) plays important roles in sensory organs. Because the cornea is replete with sensory innervation, we hypothesized that miR-183/96/182 modulates the corneal response to bacterial infection through regulation of neuroimmune interactions. METHODS Eight-week-old miR-183/96/182 knockout (ko) mice and their wild-type littermates (wt) were used. The central cornea of anesthetized mice was scarred and infected with Pseudomonas aeruginosa (PA), strain 19660. Corneal disease was graded at 1, 3, and 5 days postinfection (dpi). Corneal RNA was harvested for quantitative RT-PCR. Polymorphonuclear neutrophils (PMN) were enumerated by myeloperoxidase assays; the number of viable bacteria was determined by plate counts, and ELISA assays were performed to determine cytokine protein levels. A macrophage (Mϕ) cell line and elicited peritoneal PMN were used for in vitro functional assays. RESULTS MicroRNA-183/96/182 is expressed in the cornea, and in Mϕ and PMN of both mice and humans. Inactivation of miR-183/96/182 resulted in decreased corneal nerve density compared with wt mice. Overexpression of miR-183/96/182 in Mϕ decreased, whereas knockdown or inactivation of miR-183/96/182 in Mϕ and PMN increased their capacity for phagocytosis and intracellular killing of PA. In PA-infected corneas, ko mice showed decreased proinflammatory neuropeptides such as substance P and chemoattractant molecules, MIP-2, MCP1, and ICAM1; decreased number of PMN at 1 and 5 dpi; increased viable bacterial load at 1 dpi, but decreased at 5 dpi; and markedly decreased corneal disease. CONCLUSIONS MicroRNA-183/96/182 modulates the corneal response to bacterial infection through its regulation of corneal innervation and innate immunity.
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Affiliation(s)
- Chithra K. Muraleedharan
- Department of Ophthalmology, Kresge Eye Institute, Wayne State University, School of Medicine, Detroit, Michigan, United States
- Department of Anatomy and Cell Biology, Wayne State University, School of Medicine, Detroit, Michigan, United States
| | - Sharon A. McClellan
- Department of Anatomy and Cell Biology, Wayne State University, School of Medicine, Detroit, Michigan, United States
| | - Ronald P. Barrett
- Department of Anatomy and Cell Biology, Wayne State University, School of Medicine, Detroit, Michigan, United States
| | - Cui Li
- Department of Anatomy and Cell Biology, Wayne State University, School of Medicine, Detroit, Michigan, United States
| | - Daniel Montenegro
- Department of Ophthalmology, Kresge Eye Institute, Wayne State University, School of Medicine, Detroit, Michigan, United States
| | - Thomas Carion
- Department of Anatomy and Cell Biology, Wayne State University, School of Medicine, Detroit, Michigan, United States
| | - Elizabeth Berger
- Department of Ophthalmology, Kresge Eye Institute, Wayne State University, School of Medicine, Detroit, Michigan, United States
- Department of Anatomy and Cell Biology, Wayne State University, School of Medicine, Detroit, Michigan, United States
| | - Linda D. Hazlett
- Department of Ophthalmology, Kresge Eye Institute, Wayne State University, School of Medicine, Detroit, Michigan, United States
- Department of Anatomy and Cell Biology, Wayne State University, School of Medicine, Detroit, Michigan, United States
| | - Shunbin Xu
- Department of Ophthalmology, Kresge Eye Institute, Wayne State University, School of Medicine, Detroit, Michigan, United States
- Department of Anatomy and Cell Biology, Wayne State University, School of Medicine, Detroit, Michigan, United States
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Makar TK, Nimmagadda VK, Singh IS, Lam K, Mubariz F, Judge SI, Trisler D, Bever CT. TrkB agonist, 7,8-dihydroxyflavone, reduces the clinical and pathological severity of a murine model of multiple sclerosis. J Neuroimmunol 2016; 292:9-20. [DOI: 10.1016/j.jneuroim.2016.01.002] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2015] [Revised: 12/23/2015] [Accepted: 01/04/2016] [Indexed: 01/05/2023]
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Frau L, Costa G, Porceddu PF, Khairnar A, Castelli MP, Ennas MG, Madeddu C, Wardas J, Morelli M. Influence of caffeine on 3,4-methylenedioxymethamphetamine-induced dopaminergic neuron degeneration and neuroinflammation is age-dependent. J Neurochem 2015; 136:148-62. [DOI: 10.1111/jnc.13377] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2015] [Revised: 09/02/2015] [Accepted: 09/03/2015] [Indexed: 02/03/2023]
Affiliation(s)
- Lucia Frau
- Department of Biomedical Sciences; Section of Neuropsychopharmacology; University of Cagliari; Cagliari Italy
| | - Giulia Costa
- Department of Biomedical Sciences; Section of Neuropsychopharmacology; University of Cagliari; Cagliari Italy
| | - Pier Francesca Porceddu
- Department of Biomedical Sciences; Section of Neuropsychopharmacology; University of Cagliari; Cagliari Italy
| | - Amit Khairnar
- Applied Neuroscience Research Group; CEITEC - Central European Institute of Technology; Masaryk University; Brno Czech Republic
| | - Maria Paola Castelli
- Department of Biomedical Sciences; Section of Neuroscience and Clinical Pharmacology; University of Cagliari; Monserrato (CA) Italy
| | - Maria Grazia Ennas
- Department of Biomedical Sciences; Section of Neuroscience and Clinical Pharmacology; University of Cagliari; Monserrato (CA) Italy
| | - Camilla Madeddu
- Department of Biomedical Sciences; Section of Neuroscience and Clinical Pharmacology; University of Cagliari; Monserrato (CA) Italy
| | - Jadwiga Wardas
- Department of Neuropsychopharmacology; Institute of Pharmacology; Polish Academy of Sciences; Krakow Poland
| | - Micaela Morelli
- Department of Biomedical Sciences; Section of Neuropsychopharmacology; University of Cagliari; Cagliari Italy
- CNR; Institute of Neuroscience; Cagliari Italy
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