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Pordel S, McCloskey AP, Almahmeed W, Sahebkar A. The protective effects of statins in traumatic brain injury. Pharmacol Rep 2024; 76:235-250. [PMID: 38448729 DOI: 10.1007/s43440-024-00582-9] [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: 11/28/2023] [Revised: 02/28/2024] [Accepted: 02/29/2024] [Indexed: 03/08/2024]
Abstract
Traumatic brain injury (TBI), often referred to as the "silent epidemic", is the most common cause of mortality and morbidity worldwide among all trauma-related injuries. It is associated with considerable personal, medical, and economic consequences. Although remarkable advances in therapeutic approaches have been made, current treatments and clinical management for TBI recovery still remain to be improved. One of the factors that may contribute to this gap is that existing therapies target only a single event or pathology. However, brain injury after TBI involves various pathological mechanisms, including inflammation, oxidative stress, blood-brain barrier (BBB) disruption, ionic disturbance, excitotoxicity, mitochondrial dysfunction, neuronal necrosis, and apoptosis. Statins have several beneficial pleiotropic effects (anti-excitotoxicity, anti-inflammatory, anti-oxidant, anti-thrombotic, immunomodulatory activity, endothelial and vasoactive properties) in addition to promoting angiogenesis, neurogenesis, and synaptogenesis in TBI. Supposedly, using agents such as statins that target numerous and diverse pathological mechanisms, may be more effective than a single-target approach in TBI management. The current review was undertaken to investigate and summarize the protective mechanisms of statins against TBI. The limitations of conducted studies and directions for future research on this potential therapeutic application of statins are also discussed.
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Affiliation(s)
- Safoora Pordel
- Department of Immunology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Alice P McCloskey
- School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Liverpool, UK
| | - Wael Almahmeed
- Heart and Vascular Institute, Cleveland Clinic Abu Dhabi, Abu Dhabi, United Arab Emirates
| | - Amirhossein Sahebkar
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
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Alruwaili M, Al-kuraishy HM, Alexiou A, Papadakis M, ALRashdi BM, Elhussieny O, Saad HM, Batiha GES. Pathogenic Role of Fibrinogen in the Neuropathology of Multiple Sclerosis: A Tale of Sorrows and Fears. Neurochem Res 2023; 48:3255-3269. [PMID: 37442896 PMCID: PMC10514123 DOI: 10.1007/s11064-023-03981-1] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Revised: 06/20/2023] [Accepted: 06/29/2023] [Indexed: 07/15/2023]
Abstract
Multiple sclerosis (MS) is an autoimmune demyelinating neurodegenerative disease of the central nervous system (CNS) due to injury of the myelin sheath by immune cells. The clotting factor fibrinogen is involved in the pathogenesis of MS by triggering microglia and the progress of neuroinflammation. Fibrinogen level is correlated with MS severity; consequently, inhibition of the fibrinogen cascade may reduce MS neuropathology. Thus, this review aimed to clarify the potential role of fibrinogen in the pathogenesis of MS and how targeting of fibrinogen affects MS neuropathology. Accumulation of fibrinogen in the CNS may occur independently or due to disruption of blood-brain barrier (BBB) integrity in MS. Fibrinogen acts as transduction and increases microglia activation which induces the progression of inflammation, oxidative stress, and neuronal injury. Besides, brain fibrinogen impairs the remyelination process by inhibiting the differentiation of oligodendrocyte precursor cells. These findings proposed that fibrinogen is associated with MS neuropathology through interruption of BBB integrity, induction of neuroinflammation, and demyelination with inhibition of the remyelination process by suppressing oligodendrocytes. Therefore, targeting of fibrinogen and/or CD11b/CD18 receptors by metformin and statins might decrease MS neuropathology. In conclusion, inhibiting the expression of CD11b/CD18 receptors by metformin and statins may decrease the pro-inflammatory effect of fibrinogen on microglia which is involved in the progression of MS.
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Affiliation(s)
- Mubarak Alruwaili
- Department of Internal Medicine, College of Medicine, Jouf University, Sakaka, Saudi Arabia
| | - Hayder M. Al-kuraishy
- Department of Pharmacology, Toxicology and Medicine, Medical Faculty, College of Medicine, Al-Mustansiriyah University, P.O. Box 14132, Baghdad, Iraq
| | - Athanasios Alexiou
- Department of Science and Engineering, Novel Global Community Educational Foundation, Hebersham, NSW 2770 Australia
- AFNP Med, 1030 Vienna, Austria
| | - Marios Papadakis
- Department of Surgery II, University Hospital Witten-Herdecke, University of Witten-Herdecke, Heusnerstrasse 40, 42283 Wuppertal, Germany
| | - Barakat M. ALRashdi
- Biology Department, College of Science, Jouf University, Sakaka, 41412 Saudi Arabia
| | - Omnya Elhussieny
- Department of Histology and Cytology, Faculty of Veterinary Medicine, Matrouh University, Marsa Matruh, 51744 Egypt
| | - Hebatallah M. Saad
- Department of Pathology, Faculty of Veterinary Medicine, Matrouh University, Marsa Matruh, 51744 Egypt
| | - Gaber El-Saber Batiha
- Department of Pharmacology and Therapeutics, Faculty of Veterinary Medicine, Damanhour University, Damanhour, 22511 Egypt
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Al-Kuraishy HM, Al-Gareeb AI, Saad HM, Batiha GES. The potential therapeutic effect of statins in multiple sclerosis: beneficial or detrimental effects. Inflammopharmacology 2023; 31:1671-1682. [PMID: 37160526 DOI: 10.1007/s10787-023-01240-x] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2023] [Accepted: 04/21/2023] [Indexed: 05/11/2023]
Abstract
Multiple sclerosis (MS) is a chronic progressive disabling disease of the central nervous system (CNS) characterized by demyelination and neuronal injury. Dyslipidemia is observed as one of the imperative risk factors involved in MS neuropathology. Also, chronic inflammation in MS predisposes to the progress of dyslipidemia. Therefore, treatment of dyslipidemia in MS by statins may attenuate dyslipidemia-induced MS and avert MS-induced metabolic changes. Therefore, the present review aimed to elucidate the possible effects of statins on the pathogenesis and outcomes of MS. Statins adversely affect the cognitive function in MS by decreasing brain cholesterol CoQ10, which is necessary for the regulation of neuronal mitochondrial function. However, statins could be beneficial in MS by shifting the immune response from pro-inflammatory Th17 to an anti-inflammatory regulatory T cell (Treg). The protective effect of statins against MS is related to anti-inflammatory and immunomodulatory effects with modulation of fibrinogen and growth factors. In conclusion, the effects of statins on MS neuropathology seem to be conflicting, as statins seem to be protective in the acute phase of MS through anti-inflammatory and antioxidant effects. However, statins lead to detrimental effects in the chronic phase of MS by reducing brain cholesterol and inhibiting the remyelination process.
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Affiliation(s)
- Hayder M Al-Kuraishy
- Professor in Department of Clinical Pharmacology and Therapeutic Medicine, College of Medicine, ALmustansiriyiah University, M. B. Ch. B, FRCP, Box 14132, Baghdad, Iraq
| | - Ali I Al-Gareeb
- Professor in Department of Clinical Pharmacology and Therapeutic Medicine, College of Medicine, ALmustansiriyiah University, M. B. Ch. B, FRCP, Box 14132, Baghdad, Iraq
| | - Hebatallah M Saad
- Department of Pathology, Faculty of Veterinary Medicine, Matrouh University, Marsa Matrouh, 51744, Egypt.
| | - Gaber El-Saber Batiha
- Department of Pharmacology and Therapeutics, Faculty of Veterinary Medicine, Damanhour University, Damanhour, 22511, AlBeheira, Egypt.
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Caffes N, Hendricks K, Bradley JS, Twenhafel NA, Simard JM. Anthrax Meningoencephalitis and Intracranial Hemorrhage. Clin Infect Dis 2022; 75:S451-S458. [PMID: 36251558 PMCID: PMC9649421 DOI: 10.1093/cid/ciac521] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022] Open
Abstract
The neurological sequelae of Bacillus anthracis infection include a rapidly progressive fulminant meningoencephalitis frequently associated with intracranial hemorrhage, including subarachnoid and intracerebral hemorrhage. Higher mortality than other forms of bacterial meningitis suggests that antimicrobials and cardiopulmonary support alone may be insufficient and that strategies targeting the hemorrhage might improve outcomes. In this review, we describe the toxic role of intracranial hemorrhage in anthrax meningoencephalitis. We first examine the high incidence of intracranial hemorrhage in patients with anthrax meningoencephalitis. We then review common diseases that present with intracranial hemorrhage, including aneurysmal subarachnoid hemorrhage and spontaneous intracerebral hemorrhage, postulating applicability of established and potential neurointensive treatments to the multimodal management of hemorrhagic anthrax meningoencephalitis. Finally, we examine the therapeutic potential of minocycline, an antimicrobial that is effective against B. anthracis and that has been shown in preclinical studies to have neuroprotective properties, which thus might be repurposed for this historically fatal disease.
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Affiliation(s)
- Nicholas Caffes
- Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - Katherine Hendricks
- Division of High-Consequence Pathogens and Pathology, Centers for Disease Control and Prevention, Atlanta, Georgia, USA
| | - John S Bradley
- Department of Pediatrics, San Diego School of Medicine and Rady Children’s Hospital, University of California, San Diego, California, USA
| | - Nancy A Twenhafel
- Division of Pathology, United States Army Medical Research Institute of Infectious Diseases, Frederick, Maryland, USA
| | - J Marc Simard
- Correspondence: J. M. Simard, Department of Neurosurgery, University of Maryland School of Medicine, 22 S Greene St, Suite S12D, Baltimore, MD 21201, USA ()
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Bhat A, Dalvi H, Jain H, Rangaraj N, Singh SB, Srivastava S. Perspective insights of repurposing the pleiotropic efficacy of statins in neurodegenerative disorders: An expository appraisal. CURRENT RESEARCH IN PHARMACOLOGY AND DRUG DISCOVERY 2021; 2:100012. [PMID: 34909647 PMCID: PMC8663947 DOI: 10.1016/j.crphar.2020.100012] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2020] [Revised: 12/15/2020] [Accepted: 12/18/2020] [Indexed: 10/26/2022] Open
Abstract
Neurodegenerative disorders which affects a larger population pose a great clinical challenge. These disorders impact the quality of life of an individual by damaging the neurons, which are the unit cells of the brain. Clinicians are faced with the grave challenge of inhibiting the progression of these diseases as available treatment options fail to meet the clinical demand. Thus, treating the disease/disorder symptomatically is the Hobson's choice. The goal of the researchers is to introduce newer therapies in this segment and introducing a new molecule will take long years of development. Hence, drug repurposing/repositioning can be a better substitute in comparison to time consuming and expensive drug discovery and development cycle. Presently, a paradigm shift towards the re-purposing of drugs can be witnessed. Statins which have been previously approved as anti-hyperlipidemic agents are in the limelight of research for re-purposed drugs. Owing to their anti-inflammatory and antioxidant nature, statins act as neuroprotective in several brain disorders. Further they attenuate the amyloid plaques and protein aggregation which are the triggering factors in the Alzheimer's and Parkinson's respectively. In case of Huntington disease and Multiple sclerosis they help in improving the psychomotor symptoms and stimulate remyelination thus acting as neuroprotective. This article reviews the potential of statins in treating neurodegenerative disorders along with a brief discussion on the safety concerns associated with use of statins and human clinical trial data linked with re-tasking statins for neurodegenerative disorders along with the regulatory perspectives involved with the drug repositioning.
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Affiliation(s)
- Aditi Bhat
- Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, Telangana, 500037, India
| | - Harshita Dalvi
- Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, Telangana, 500037, India
| | - Harsha Jain
- Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, Telangana, 500037, India
| | - Nagarjun Rangaraj
- Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, Telangana, 500037, India
| | - Shashi Bala Singh
- Department of Pharmacology and Regulatory Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, Telangana, 500037, India
| | - Saurabh Srivastava
- Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, Telangana, 500037, India
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Fernandez KA, Allen P, Campbell M, Page B, Townes T, Li CM, Cheng H, Garrett J, Mulquin M, Clements A, Mulford D, Ortiz C, Brewer C, Dubno JR, Newlands S, Schmitt NC, Cunningham LL. Atorvastatin is associated with reduced cisplatin-induced hearing loss. J Clin Invest 2021; 131:142616. [PMID: 33393488 DOI: 10.1172/jci142616] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2020] [Accepted: 09/23/2020] [Indexed: 12/14/2022] Open
Abstract
BACKGROUNDCisplatin is widely used to treat adult and pediatric cancers. It is the most ototoxic drug in clinical use, resulting in permanent hearing loss in approximately 50% of treated patients. There is a major need for therapies that prevent cisplatin-induced hearing loss. Studies in mice suggest that concurrent use of statins reduces cisplatin-induced hearing loss.METHODSWe examined hearing thresholds from 277 adults treated with cisplatin for head and neck cancer. Pretreatment and posttreatment audiograms were collected within 90 days of initiation and completion of cisplatin therapy. The primary outcome measure was a change in hearing as defined by the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE).RESULTSAmong patients on concurrent atorvastatin, 9.7% experienced a CTCAE grade 2 or higher cisplatin-induced hearing loss compared with 29.4% in nonstatin users (P < 0.0001). A mixed-effect model analysis showed that atorvastatin use was significantly associated with reduced cisplatin-induced hearing loss (P ≤ 0.01). An adjusted odds ratio (OR) analysis indicated that an atorvastatin user is 53% less likely to acquire a cisplatin-induced hearing loss than a nonstatin user (OR = 0.47; 95% CI, 0.30-0.78). Three-year survival rates were not different between atorvastatin users and nonstatin users (P > 0.05).CONCLUSIONSOur data indicate that atorvastatin use is associated with reduced incidence and severity of cisplatin-induced hearing loss in adults being treated for head and neck cancer.TRIAL REGISTRATIONClinicalTrials.gov identifier NCT03225157.FUNDINGFunding was provided by the Division of Intramural Research at the National Institute on Deafness and Other Communication Disorders (1 ZIA DC000079, ZIA DC000090).
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Affiliation(s)
- Katharine A Fernandez
- National Institute on Deafness and Other Communication Disorders, NIH, Bethesda, Maryland, USA
| | - Paul Allen
- Department of Otolaryngology, University of Rochester Medical Center, Rochester, New York, USA
| | - Maura Campbell
- Department of Otolaryngology, University of Rochester Medical Center, Rochester, New York, USA
| | - Brandi Page
- Department of Radiation Oncology and Molecular Sciences, Johns Hopkins University, Baltimore, Maryland, USA
| | - Thomas Townes
- Walter Reed National Military Medical Center, Bethesda, Maryland, USA
| | - Chuan-Ming Li
- National Institute on Deafness and Other Communication Disorders, NIH, Bethesda, Maryland, USA
| | - Hui Cheng
- National Institute on Deafness and Other Communication Disorders, NIH, Bethesda, Maryland, USA
| | - Jaylon Garrett
- Department of Radiation Oncology and Molecular Sciences, Johns Hopkins University, Baltimore, Maryland, USA
| | - Marcia Mulquin
- National Institute on Deafness and Other Communication Disorders, NIH, Bethesda, Maryland, USA
| | - Anna Clements
- National Institute on Deafness and Other Communication Disorders, NIH, Bethesda, Maryland, USA
| | - Deborah Mulford
- Department of Medicine, University of Rochester Medical Center, Rochester, New York, USA
| | - Candice Ortiz
- Walter Reed National Military Medical Center, Bethesda, Maryland, USA
| | - Carmen Brewer
- National Institute on Deafness and Other Communication Disorders, NIH, Bethesda, Maryland, USA
| | - Judy R Dubno
- Department of Otolaryngology - Head and Neck Surgery, Medical University of South Carolina, Charleston, South Carolina, USA
| | - Shawn Newlands
- Department of Otolaryngology, University of Rochester Medical Center, Rochester, New York, USA
| | - Nicole C Schmitt
- National Institute on Deafness and Other Communication Disorders, NIH, Bethesda, Maryland, USA.,Department of Otolaryngology - Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Lisa L Cunningham
- National Institute on Deafness and Other Communication Disorders, NIH, Bethesda, Maryland, USA
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McFarlane O, Kędziora-Kornatowska K. Cholesterol and Dementia: A Long and Complicated Relationship. Curr Aging Sci 2020; 13:42-51. [PMID: 31530269 PMCID: PMC7403650 DOI: 10.2174/1874609812666190917155400] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2019] [Revised: 08/09/2019] [Accepted: 08/16/2019] [Indexed: 11/22/2022]
Abstract
BACKGROUND There is a huge demand for efficient strategies for maintaining cognitive wellbeing with age, especially in the context of population aging. Dementia constitutes the main reason for disability and dependency in the elderly. Identification of potential risk and protective factors, as well as determinants of conversion from MCI to dementia, is therefore crucial. In case of Alzheimer's disease, the most prevalent dementia syndrome amongst the members of modern societies, neurodegenerative processes in the brain can begin many years before first clinical symptoms appear. First functional changes typically mean advanced neuron loss, therefore, the earliest possible diagnosis is critical for implementation of promising early pharmaceutical interventions. OBJECTIVE The study aimed to discuss the relationships between both circulating and brain cholesterol with cognition, and explore its potential role in early diagnosis of cognitive disorders. METHODS Literature review. RESULTS The causal role of high cholesterol levels in AD or MCI has not been confirmed. It has been postulated that plasma levels of 24(S)-OHC can potentially be used as an early biochemical marker of altered cholesterol homeostasis in the CNS. Some studies brought conflicting results, finding normal or lowered levels of 24(S)-OHC in dementia patients compared to controls. In spite of decades of research on the relationship between cholesterol and dementia, so far, no single trusted indicator of an early cognitive deterioration has been identified. CONCLUSION The current state of knowledge makes the use of cholesterol markers of cognitive decline in clinical practice impossible.
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Affiliation(s)
- Oliwia McFarlane
- Address correspondence to this author at the Department of Public Health, Faculty of Health Sciences, Nicolaus Copernicus University, Ludwik Rydygier Collegium Medicum in Bydgoszcz, P.O. Box: 85-830, Bydgoszcz, Poland; Tel/Fax: ++48-52-585-5408; E-mail:
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Chong AJ, Lim SW, Lee YL, Chio CC, Chang CH, Kuo JR, Wang CC. The Neuroprotective Effects of Simvastatin on High Cholesterol Following Traumatic Brain Injury in Rats. World Neurosurg 2019; 132:e99-e108. [PMID: 31518751 DOI: 10.1016/j.wneu.2019.08.250] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2019] [Revised: 08/29/2019] [Accepted: 08/30/2019] [Indexed: 11/16/2022]
Abstract
BACKGROUND High cholesterol has been correlated with a greater risk of cerebrovascular diseases. Whether pre-existing high cholesterol exacerbates traumatic brain injury (TBI), and whether treatment with the cholesterol-lowering agent simvastatin has neuroprotective effects, especially anti-neuroinflammatory effects, after TBI are not well investigated. METHODS Five-week-old male Sprague-Dawley rats were fed a high-fat diet for 8 weeks to induce hypercholesterolemia. Anesthetized male Sprague-Dawley rats were divided into 5 groups, including the sham-operated control, TBI control, and TBI with simvastatin treatment (4 mg/kg, 10 mg/kg, or 20 mg/kg) groups. Simvastatin was intraperitoneally injected at 0, 24, and 48 hours after TBI. Motor function was measured using an inclined plane. Neuronal apoptosis (maker Neu-N, terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling), tumor necrosis factor-α expression in microglia (marker OX42) and astrocytes (marker glial fibrillary acidic protein), and Tumor necrosis factor-alpha receptor (TNFR) 1 and TNFR2 expression in neurons in the ischemic cortex were investigated using an immunofluorescence assay. All of the parameters were measured on the third day after TBI. RESULTS TBI significantly increased the serum levels of cholesterol. The TBI-induced motor deficit was significantly attenuated by 4, 10, and 20 mg/kg simvastatin therapy on the third day after TBI. TBI-induced neuronal TNFR1 activation and apoptosis, as well as tumor necrosis factor-α expression in astrocytes in the ischemic cortex, were significantly attenuated by simvastatin, particularly when 20 mg/kg was administered. Simultaneously, the serum cholesterol remained high despite simvastatin treatment. CONCLUSIONS The neuroprotection effects of simvastatin on the pre-existing hypercholesterolemia during TBI in rats may be related to its anti-neuroinflammatory effects but not to its cholesterol-lowing effects.
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Affiliation(s)
- Arng Jack Chong
- Department of Neurosurgery, Chi-Mei Medical Center, Tainan, Taiwan
| | - Sher-Wei Lim
- Department of Neurosurgery, Chi-Mei Medical Center, Chiali, Tainan, Taiwan; Department of Nursing, Min-Hwei College of Health Care Management, Tainan, Taiwan
| | - Yao-Lin Lee
- Department of Neurosurgery, Chi-Mei Medical Center, Tainan, Taiwan
| | - Chung-Ching Chio
- Department of Neurosurgery, Chi-Mei Medical Center, Tainan, Taiwan
| | - Chin-Hung Chang
- Department of Neurosurgery, Chi-Mei Medical Center, Tainan, Taiwan
| | - Jinn-Rung Kuo
- Department of Neurosurgery, Chi-Mei Medical Center, Tainan, Taiwan; Department of Medical Research Chi-Mei Medical Center, Tainan, Taiwan.
| | - Che-Chuan Wang
- Department of Neurosurgery, Chi-Mei Medical Center, Tainan, Taiwan; Department of General Education, Southern Taiwan University of Science and Technology, Tainan, Taiwan; Department of Medical Research Chi-Mei Medical Center, Tainan, Taiwan
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Freedman DM, Kuncl RW, Cahoon EK, Rivera DR, Pfeiffer RM. Relationship of statins and other cholesterol-lowering medications and risk of amyotrophic lateral sclerosis in the US elderly. Amyotroph Lateral Scler Frontotemporal Degener 2018; 19:538-546. [DOI: 10.1080/21678421.2018.1511731] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Affiliation(s)
- D. Michal Freedman
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, DHHS, Bethesda, MD, USA
| | - Ralph W. Kuncl
- Department of Biology, University of the Redlands, Redlands, CA, USA
| | - Elizabeth K. Cahoon
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, DHHS, Bethesda, MD, USA
| | - Donna R. Rivera
- Division of Cancer Control and Population Sciences, National Cancer Institute, NIH, DHHS, Bethesda, MD, USA
| | - Ruth M. Pfeiffer
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, DHHS, Bethesda, MD, USA
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Abstract
Previous studies have indicated that statins use is associated with risk of dementia, but presented controversial results. Medline, Embase, Web of Science, and the Cochrane Database were searched update to November 2017 to identify the potential relationship between statins use and dementia. Thirty-one eligible studies involving a total of 3332,706 participants with 184,666 incident cases were included in this meta-analysis. Statins use was associated with dementia risk decrement (relevant risk [RR]: 0.85; 95% confidence interval [CI], 0.80-0.89). Subgroup analysis showed statins use was associated with Alzheimer disease (AD) (RR: 0.81; 95% CI, 0.73-0.89) and non-AD dementia (RR: 0.81; 95% CI, 0.73-0.89) risk decrement. Furthermore, statins use was associated with dementia risk decrement in female (RR: 0.89; 95% CI, 0.80-0.98) and male (RR: 0.88; 95% CI, 0.83-0.93). In addition, a dose-response showed per 1 year of duration of statins use incremental increase was associated with 20% dementia risk decrement (RR: 0.80; 95% CI, 0.73-0.87), and per 5-mg mean daily dose incremental increase in statins use was associated with 11% dementia risk decrement (RR: 0.89; 95% CI, 0.83-0.96). Statins use was associated with dementia risk decrement. The potency and the cumulative duration of statin utilized played critical roles.
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Affiliation(s)
- Xiaoyu Zhang
- Department of General Rehabilitation, Capital Medical University School of Rehabilitation Medicine, China Rehabilitation Research Center, Beijing Boai Hospital, Beijing
| | - Jianzhong Wen
- Department of Anesthesiology, Second Affiliated Hospital of Shanxi Medical University, Taiyuan, Shanxi
| | - Zhiqiang Zhang
- Department of Community Chronic Disease Research Center, Institute of Chinese Basic Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, China
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Li Y, Liu Q, Sun J, Wang J, Liu X, Gao J. Mitochondrial protective mechanism of simvastatin protects against amyloid β peptide-induced injury in SH-SY5Y cells. Int J Mol Med 2018; 41:2997-3005. [PMID: 29436584 DOI: 10.3892/ijmm.2018.3456] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2016] [Accepted: 01/25/2018] [Indexed: 11/06/2022] Open
Abstract
Mitochondrial dysfunction is implicated in the pathology of neuronal damage during Alzheimer's disease (AD). Previous studies suggest that simvastatin (SV) ameliorates amyloid β (Aβ)‑mediated cognitive impairment in AD patients and transgenic mice; however, the mechanisms remain unknown. To investigate the potential mechanisms by which SV protects against AD neurotoxicity, the present study used a series of cellular and molecular assays to analyze the effects of SV in an in vitro model of Aβ1‑42-induced injury. The results demonstrated that SV protected against Aβ1‑42‑induced SH‑SY5Y cell injury by inhibiting the release of cytochrome c from the mitochondria to the cytoplasm, and reducing the production of intracellular reactive oxygen species. In addition, SV downregulated cleaved‑caspase‑3 protein levels, increased the ratio of B cell lymphoma 2 (Bcl-2) to Bcl-2-associated X protein, and increased the protein levels of peroxisome proliferator-activated receptor γ coactivator-1α in the Aβ1‑42‑treated cells. Furthermore, SV increased the mitochondrial membrane potential and adenosine triphosphate levels, and enhanced the cell respiratory function and mitochondrial mass of the cells. In conclusion, the present study revealed that SV protected SH‑SY5Y cells against Aβ1‑42-induced injury through regulating the mitochondrial apoptosis pathway and mitochondrial function.
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Affiliation(s)
- Yunzi Li
- School of Pharmacy, Jiangsu University, Zhenjiang, Jiangsu 212013, P.R. China
| | - Qian Liu
- Department of Neurology, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu 210002, P.R. China
| | - Jing Sun
- School of Pharmacy, Jiangsu University, Zhenjiang, Jiangsu 212013, P.R. China
| | - Jin Wang
- School of Pharmacy, Jiangsu University, Zhenjiang, Jiangsu 212013, P.R. China
| | - Xinfeng Liu
- Department of Neurology, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu 210002, P.R. China
| | - Jing Gao
- School of Pharmacy, Jiangsu University, Zhenjiang, Jiangsu 212013, P.R. China
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Mettang M, Reichel SN, Lattke M, Palmer A, Abaei A, Rasche V, Huber-Lang M, Baumann B, Wirth T. IKK2/NF-κB signaling protects neurons after traumatic brain injury. FASEB J 2018; 32:1916-1932. [PMID: 29187362 PMCID: PMC5893169 DOI: 10.1096/fj.201700826r] [Citation(s) in RCA: 63] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Traumatic brain injury (TBI) is the leading cause of death in young adults. After the initial injury, a poorly understood secondary phase, including a strong inflammatory response determines the final outcome of TBI. The inhibitor of NF-κB kinase (IKK)/NF-κB signaling system is the key regulator of inflammation and also critically involved in regulation of neuronal survival and synaptic plasticity. We addressed the neuron-specific function of IKK2/NF-κB signaling pathway in TBI using an experimental model of closed-head injury (CHI) in combination with mouse models allowing conditional regulation of IKK/NF-κB signaling in excitatory forebrain neurons. We found that repression of IKK2/NF-κB signaling in neurons increases the acute posttraumatic mortality rate, worsens the neurological outcome, and promotes neuronal cell death by apoptosis, thus resulting in enhanced proinflammatory gene expression. As a potential mechanism, we identified elevated levels of the proapoptotic mediators Bax and Bad and enhanced expression of stress response genes. This phenotype is also observed when neuronal IKK/NF-κB activity is inhibited just before CHI. In contrast, neuron-specific activation of IKK/NF-κB signaling does not alter the TBI outcome. Thus, this study demonstrates that physiological neuronal IKK/NF-κB signaling is necessary and sufficient to protect neurons from trauma consequences.-Mettang, M., Reichel, S. N., Lattke, M., Palmer, A., Abaei, A., Rasche, V., Huber-Lang, M., Baumann, B., Wirth, T. IKK2/NF-κB signaling protects neurons after traumatic brain injury.
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Affiliation(s)
- Melanie Mettang
- Institute of Physiological Chemistry, Ulm University, Ulm, Germany
| | | | - Michael Lattke
- Institute of Physiological Chemistry, Ulm University, Ulm, Germany.,Neural Stem Cell Biology Laboratory, The Francis Crick Institute, London, United Kingdom
| | - Annette Palmer
- Institute of Clinical and Experimental Trauma-Immunology, University Hospital Ulm, Ulm, Germany
| | - Alireza Abaei
- Core Facility Small Animal Magnetic Resonance Imaging, Ulm University, Ulm, Germany
| | - Volker Rasche
- Core Facility Small Animal Magnetic Resonance Imaging, Ulm University, Ulm, Germany
| | - Markus Huber-Lang
- Institute of Clinical and Experimental Trauma-Immunology, University Hospital Ulm, Ulm, Germany
| | - Bernd Baumann
- Institute of Physiological Chemistry, Ulm University, Ulm, Germany
| | - Thomas Wirth
- Institute of Physiological Chemistry, Ulm University, Ulm, Germany
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Lim SW, Shiue YL, Liao JC, Wee HY, Wang CC, Chio CC, Chang CH, Hu CY, Kuo JR. Simvastatin Therapy in the Acute Stage of Traumatic Brain Injury Attenuates Brain Trauma-Induced Depression-Like Behavior in Rats by Reducing Neuroinflammation in the Hippocampus. Neurocrit Care 2017; 26:122-132. [PMID: 27406816 DOI: 10.1007/s12028-016-0290-6] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
BACKGROUND The antidepressant-like effects of simvastatin on traumatic brain injury (TBI) remain unclear. The present study aimed to investigate the neuroprotective effects of simvastatin and determine whether simvastatin attenuates TBI-induced depression-like behavior and, more specifically, acts as an antineuroinflammatory. METHODS Anesthetized male Sprague-Dawley rats were divided into five groups: sham-operated controls, TBI controls, and TBI treatment with simvastatin 4, 10, or 20 mg/kg. Simvastatin was intraperitoneally injected 0, 24, and 48 h after TBI. The motor function was measured using an inclined plane, and depression-like behavior was evaluated using forced swimming tests. Neuronal apoptosis (markers: NeuN, TUNEL, caspase-3), microglia (marker: OX42) and astrocyte (marker: GFAP) activation, and TNF-α expression in the microglia and astrocytes of the hippocampal CA3 area were investigated using immunofluorescence assay. All parameters were measured on the 4th, 8th, and 15th day, or only on the 15th day after TBI. RESULTS TBI-induced depression-like behavior, which increased duration of immobility, was significantly attenuated by 20 mg simvastatin therapy on day 15 after TBI. TBI-induced neuronal apoptosis, microglia and astrocyte activation, and TNF-α expression in the microglia and astrocytes of the CA3 area of the hippocampus were significantly reduced by simvastatin treatment, particularly when 20 mg/kg was administered for 3 days. CONCLUSIONS Intraperitoneal injection of simvastatin attenuated TBI in rats during the acute stage by reducing neuronal apoptosis, microglia, and TNF-α expression, thereby resulting in a reduction of depressive-like behavior. Our results suggest that simvastatin may be a promising treatment for TBI-induced depression-like behavior.
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Affiliation(s)
- Sher-Wei Lim
- Institute of Biomedical Sciences, National Sun Yat-sen University, Kaohsiung, Taiwan
- Department of Neurosurgery, Chi-Mei Medical Center, Chiali, Tainan, Taiwan
- Department of Nursing, Min-Hwei College of Health Care Management, Tainan, Taiwan
| | - Yow-Ling Shiue
- Institute of Biomedical Sciences, National Sun Yat-sen University, Kaohsiung, Taiwan
| | - Jen-Chieh Liao
- Departments of Neurosurgery, Chi-Mei Medical Center, Tainan, Taiwan
| | - Hsiao-Yue Wee
- Department of Neurosurgery, Chi-Mei Medical Center, Liouying, Tainan, Taiwan
| | - Che-Chuan Wang
- Departments of Neurosurgery, Chi-Mei Medical Center, Tainan, Taiwan
- Departments of Child Care, Southern Taiwan University of Science and Technology, Tainan, Taiwan
| | - Chung-Ching Chio
- Departments of Neurosurgery, Chi-Mei Medical Center, Tainan, Taiwan
| | - Chin-Hung Chang
- Departments of Neurosurgery, Chi-Mei Medical Center, Tainan, Taiwan
| | - Chiao-Ya Hu
- Department of Medical Research, Chi-Mei Medical Center, Tainan, Taiwan
| | - Jinn-Rung Kuo
- Departments of Neurosurgery, Chi-Mei Medical Center, Tainan, Taiwan.
- Departments of Biotechnology, Southern Taiwan University of Science and Technology, Tainan, Taiwan.
- Department of Medical Research, Chi-Mei Medical Center, Tainan, Taiwan.
- Chi-Mei Medical Center, #901 Chung Hwa Road, Yung Kang, Tainan, Taiwan.
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14
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Joseph B, Khan M, Rhee P. Non-invasive diagnosis and treatment strategies for traumatic brain injury: an update. J Neurosci Res 2017; 96:589-600. [PMID: 28836292 DOI: 10.1002/jnr.24132] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2017] [Revised: 06/26/2017] [Accepted: 07/10/2017] [Indexed: 12/28/2022]
Abstract
PURPOSE OF REVIEW Traumatic Brain Injury (TBI) remains the leading cause of morbidity and mortality in U.S. Since the last decade, there have been several advances in the understanding and management of TBI that have shown the potential to improve outcomes. The aim of this review is to provide a useful overview of these potential diagnostic and treatment strategies that have yet to be proven, along with an assessment of their impact on outcomes after a TBI. RECENT FINDINGS Recent technical advances in the management of a TBI are grounded in a better understanding of the pathophysiology of primary and secondary insult to the brain after a TBI. Hence, clinical trials on humans should proceed in order to evaluate their efficacy and safety. SUMMARY Mortality associated with TBI remains high. Nonetheless, new diagnostic and therapeutic techniques have the potential to enhance early detection and prevention of secondary brain insult.
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Affiliation(s)
- Bellal Joseph
- Division of Trauma, Critical Care, Emergency Surgery, and Burns, Department of Surgery, University of Arizona, Tucson, Arizona, USA
| | - Muhammad Khan
- Division of Trauma, Critical Care, Emergency Surgery, and Burns, Department of Surgery, University of Arizona, Tucson, Arizona, USA
| | - Peter Rhee
- Division of Acute Care Surgery, Department of Surgery, Grady Memorial Hospital, Atlanta, Georgia, USA
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15
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Banach M, Rizzo M, Nikolic D, Howard G, Howard V, Mikhailidis D. Intensive LDL-cholesterol lowering therapy and neurocognitive function. Pharmacol Ther 2017; 170:181-191. [DOI: 10.1016/j.pharmthera.2016.11.001] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
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16
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Massari CM, Castro AA, Dal-Cim T, Lanznaster D, Tasca CI. In vitro 6-hydroxydopamine-induced toxicity in striatal, cerebrocortical and hippocampal slices is attenuated by atorvastatin and MK-801. Toxicol In Vitro 2016; 37:162-168. [PMID: 27647473 DOI: 10.1016/j.tiv.2016.09.015] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2016] [Revised: 09/09/2016] [Accepted: 09/16/2016] [Indexed: 11/20/2022]
Abstract
Parkinson's disease (PD) involves the loss of striatal dopaminergic neurons, although other neurotransmitters and brain areas are also involved in its pathophysiology. In rodent models to PD it has been shown statins improve cognitive and motor deficits and attenuate inflammatory responses evoked by PD-related toxins. Statins are the drugs most prescribed to hypercholesterolemia, but neuroprotective effects have also been attributed to statins treatment in humans and in animal models. This study aimed to establish an in vitro model of 6-hydroxydopamine (6-OHDA)-induced toxicity, used as an initial screening test to identify effective drugs against neural degeneration related to PD. The putative neuroprotective effect of atorvastatin against 6-OHDA-induced toxicity in rat striatal, cerebrocortical and hippocampal slices was also evaluated. 6-OHDA (100μM) decreased cellular viability in slices obtained from rat cerebral cortex, hippocampus and striatum. 6-OHDA also induced an increased reactive oxygen species (ROS) production and mitochondrial dysfunction. Co-incubation of 6-OHDA with atorvastatin (10μM) or MK-801 (50μM) an N-methyl-d-aspartate (NMDA) receptor antagonist, partially attenuated the cellular damage evoked by 6-OHDA in the three brain areas. Atorvastatin partially reduced ROS production in the hippocampus and striatum and disturbances of mitochondria membrane potential in cortex and striatum. 6-OHDA-induced toxicity in vitro displays differences among the brain structures, but it is also observed in cerebrocortical and hippocampal slices, besides striatum.
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Affiliation(s)
- Caio M Massari
- Programa de Pós-graduação em Bioquímica, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Trindade, 88040-900 Florianópolis, SC, Brazil
| | - Adalberto A Castro
- Programa de Pós-graduação em Bioquímica, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Trindade, 88040-900 Florianópolis, SC, Brazil
| | - Tharine Dal-Cim
- Programa de Pós-graduação em Neurociências, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Trindade, 88040-900 Florianópolis, SC, Brazil
| | - Débora Lanznaster
- Programa de Pós-graduação em Neurociências, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Trindade, 88040-900 Florianópolis, SC, Brazil
| | - Carla I Tasca
- Departamento de Bioquímica, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Trindade, 88040-900 Florianópolis, SC, Brazil.
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Kline AE, Leary JB, Radabaugh HL, Cheng JP, Bondi CO. Combination therapies for neurobehavioral and cognitive recovery after experimental traumatic brain injury: Is more better? Prog Neurobiol 2016; 142:45-67. [PMID: 27166858 DOI: 10.1016/j.pneurobio.2016.05.002] [Citation(s) in RCA: 72] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2016] [Revised: 04/26/2016] [Accepted: 05/01/2016] [Indexed: 12/18/2022]
Abstract
Traumatic brain injury (TBI) is a significant health care crisis that affects two million individuals in the United Sates alone and over ten million worldwide each year. While numerous monotherapies have been evaluated and shown to be beneficial at the bench, similar results have not translated to the clinic. One reason for the lack of successful translation may be due to the fact that TBI is a heterogeneous disease that affects multiple mechanisms, thus requiring a therapeutic approach that can act on complementary, rather than single, targets. Hence, the use of combination therapies (i.e., polytherapy) has emerged as a viable approach. Stringent criteria, such as verification of each individual treatment plus the combination, a focus on behavioral outcome, and post-injury vs. pre-injury treatments, were employed to determine which studies were appropriate for review. The selection process resulted in 37 papers that fit the specifications. The review, which is the first to comprehensively assess the effects of combination therapies on behavioral outcomes after TBI, encompasses five broad categories (inflammation, oxidative stress, neurotransmitter dysregulation, neurotrophins, and stem cells, with and without rehabilitative therapies). Overall, the findings suggest that combination therapies can be more beneficial than monotherapies as indicated by 46% of the studies exhibiting an additive or synergistic positive effect versus on 19% reporting a negative interaction. These encouraging findings serve as an impetus for continued combination studies after TBI and ultimately for the development of successful clinically relevant therapies.
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Affiliation(s)
- Anthony E Kline
- Physical Medicine & Rehabilitation, University of Pittsburgh, Pittsburgh, PA 15213, United States; Safar Center for Resuscitation Research, University of Pittsburgh, Pittsburgh, PA 15213, United States; Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA 15213, United States, United States; Psychology, University of Pittsburgh, Pittsburgh, PA 15213, United States; Center for Neuroscience, University of Pittsburgh, Pittsburgh, PA 15213, United States; Center for the Neural Basis of Cognition, University of Pittsburgh, Pittsburgh, PA 15213, United States.
| | - Jacob B Leary
- Physical Medicine & Rehabilitation, University of Pittsburgh, Pittsburgh, PA 15213, United States; Safar Center for Resuscitation Research, University of Pittsburgh, Pittsburgh, PA 15213, United States
| | - Hannah L Radabaugh
- Physical Medicine & Rehabilitation, University of Pittsburgh, Pittsburgh, PA 15213, United States; Safar Center for Resuscitation Research, University of Pittsburgh, Pittsburgh, PA 15213, United States
| | - Jeffrey P Cheng
- Physical Medicine & Rehabilitation, University of Pittsburgh, Pittsburgh, PA 15213, United States; Safar Center for Resuscitation Research, University of Pittsburgh, Pittsburgh, PA 15213, United States
| | - Corina O Bondi
- Physical Medicine & Rehabilitation, University of Pittsburgh, Pittsburgh, PA 15213, United States; Safar Center for Resuscitation Research, University of Pittsburgh, Pittsburgh, PA 15213, United States; Neurobiology, University of Pittsburgh, Pittsburgh, PA 15213, United States
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Atorvastatin Prevents Glutamate Uptake Reduction Induced by Quinolinic Acid Via MAPKs Signaling. Neurochem Res 2016; 41:2017-28. [DOI: 10.1007/s11064-016-1913-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2015] [Revised: 04/04/2016] [Accepted: 04/08/2016] [Indexed: 10/21/2022]
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Desai P, Shete H, Adnaik R, Disouza J, Patravale V. Therapeutic targets and delivery challenges for Alzheimer’s disease. World J Pharmacol 2015; 4:236-264. [DOI: 10.5497/wjp.v4.i3.236] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2014] [Revised: 05/29/2015] [Accepted: 08/11/2015] [Indexed: 02/06/2023] Open
Abstract
Dementia, including Alzheimer’s disease, the 21st Century epidemic, is one of the most significant social and health crises which has currently afflicted nearly 44 million patients worldwide and about new 7.7 million cases are reported every year. This portrays the unmet need towards better understanding of Alzheimer’s disease pathomechanisms and related research towards more effective treatment strategies. The review thus comprehensively addresses Alzheimer’s disease pathophysiology with an insight of underlying multicascade pathway and elaborates possible therapeutic targets- particularly anti-amyloid approaches, anti-tau approaches, acetylcholinesterase inhibitors, glutamatergic system modifiers, immunotherapy, anti-inflammatory targets, antioxidants, 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitors and insulin. In spite of extensive research leading to identification of newer targets and potent drugs, complete cure of Alzheimer’s disease appears to be an unreached holy grail. This can be attributed to their ineffective delivery across blood brain barrier and ultimately to the brain. With this understanding, researchers are now focusing on development of drug delivery systems to be delivered via suitable route that can circumvent blood brain barrier effectively with enhanced patient compliance. In this context, we have summarized current drug delivery strategies by oral, transdermal, intravenous, intranasal and other miscellaneous routes and have accentuated the future standpoint towards promising therapy ultimately leading to Alzheimer’s disease cure.
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20
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Li Y, Wu Z, Jin Y, Wu A, Cao M, Sun K, Jia X, Chen M. Analysis of hippocampal gene expression profile of Alzheimer's disease model rats using genome chip bioinformatics. Neural Regen Res 2015; 7:332-40. [PMID: 25774171 PMCID: PMC4350114 DOI: 10.3969/j.issn.1673-5374.2012.05.002] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2011] [Accepted: 12/20/2011] [Indexed: 02/06/2023] Open
Abstract
In this study, an Alzheimer's disease model was established in rats through stereotactic injection of condensed amyloid beta 1–40 into the bilateral hippocampus, and the changes of gene expression profile in the hippocampus of rat models and sham-operated rats were compared by genome expression profiling analysis. Results showed that the expression of 50 genes was significantly up-regulated (fold change ≥ 2), while 21 genes were significantly down-regulated in the hippocampus of Alzheimer's disease model rats (fold change ≤ 0.5) compared with the sham-operation group. The differentially expressed genes are involved in many functions, such as brain nerve system development, neuronal differentiation and functional regulation, cellular growth, differentiation and apoptosis, synaptogenesis and plasticity, inflammatory and immune responses, ion channels/transporters, signal transduction, cell material/energy metabolism. Our findings indicate that several genes were abnormally expressed in the metabolic and signal transduction pathways in the hippocampus of amyloid beta 1–40-induced rat model of Alzheimer's disease, thereby affecting the hippocampal and brain functions.
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Affiliation(s)
- Yinghong Li
- First Affiliated Hospital of Shenzhen University/Second People's Hospital of Shenzhen City, Shenzhen 518035, Guangdong Province, China
| | - Zhengzhi Wu
- First Affiliated Hospital of Shenzhen University/Second People's Hospital of Shenzhen City, Shenzhen 518035, Guangdong Province, China ; Second Clinical Medical College of Jinan University/Shenzhen Institute of Geriatrics, Shenzhen 518020, Guangdong Province, China
| | - Yu Jin
- First Affiliated Hospital of Shenzhen University/Second People's Hospital of Shenzhen City, Shenzhen 518035, Guangdong Province, China
| | - Anmin Wu
- First Affiliated Hospital of Shenzhen University/Second People's Hospital of Shenzhen City, Shenzhen 518035, Guangdong Province, China
| | - Meiqun Cao
- Second Clinical Medical College of Jinan University/Shenzhen Institute of Geriatrics, Shenzhen 518020, Guangdong Province, China
| | - Kehuan Sun
- First Affiliated Hospital of Shenzhen University/Second People's Hospital of Shenzhen City, Shenzhen 518035, Guangdong Province, China
| | - Xiuqin Jia
- First Affiliated Hospital of Shenzhen University/Second People's Hospital of Shenzhen City, Shenzhen 518035, Guangdong Province, China
| | - Manyin Chen
- First Affiliated Hospital of Shenzhen University/Second People's Hospital of Shenzhen City, Shenzhen 518035, Guangdong Province, China
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Abstract
Traumatic brain injury (TBI) is a major cause of mortality and morbidity worldwide. Despite extensive preclinical research supporting the effectiveness of neuroprotective therapies for brain trauma, there have been no successful randomized controlled clinical trials to date. TBI results in delayed secondary tissue injury due to neurochemical, metabolic and cellular changes; modulating such effects has provided the basis for neuroprotective interventions. To establish more effective neuroprotective treatments for TBI it is essential to better understand the complex cellular and molecular events that contribute to secondary injury. Here we critically review relevant research related to causes and modulation of delayed tissue damage, with particular emphasis on cell death mechanisms and post-traumatic neuroinflammation. We discuss the concept of utilizing multipotential drugs that target multiple secondary injury pathways, rather than more specific "laser"-targeted strategies that have uniformly failed in clinical trials. Moreover, we assess data supporting use of neuroprotective drugs that are currently being evaluated in human clinical trials for TBI, as well as promising emerging experimental multipotential drug treatment strategies. Finally, we describe key challenges and provide suggestions to improve the likelihood of successful clinical translation.
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Affiliation(s)
- David J Loane
- Department of Anesthesiology and Center for Shock, Trauma and Anesthesiology Research (STAR), National Study Center for Trauma and EMS, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Bogdan A Stoica
- Department of Anesthesiology and Center for Shock, Trauma and Anesthesiology Research (STAR), National Study Center for Trauma and EMS, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Alan I Faden
- Department of Anesthesiology and Center for Shock, Trauma and Anesthesiology Research (STAR), National Study Center for Trauma and EMS, University of Maryland School of Medicine, Baltimore, MD, USA.
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Statins in neurological disorders: An overview and update. Pharmacol Res 2014; 88:74-83. [DOI: 10.1016/j.phrs.2014.06.007] [Citation(s) in RCA: 61] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2014] [Revised: 06/11/2014] [Accepted: 06/11/2014] [Indexed: 01/16/2023]
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Li YH, Wu ZZ, Cao MQ, Li M, Sun KH, Yang M, Chen MY, Huang ACJ. Effect of Tiantai No.1 on gene expression profiles in hippocampus of Alzheimer's disease rats by bioinformatic analysis. Chin J Integr Med 2014; 21:123-31. [PMID: 25081895 DOI: 10.1007/s11655-014-1773-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2012] [Indexed: 11/28/2022]
Abstract
OBJECTIVE To study the effect of Tiantai No. 1 [symbol in text] on gene expression profile in hippocampus of Alzheimer's disease (AD) rat, molecular genetic target points of the effect of this drug were defined, its molecular genetic pharmacodynamic mechanism of anti-AD was further explored at molecular gene level, and a scientific basis was provided for its clinical availability and promotion. METHODS Thirty male Sprague-Dawley rats were divided into three groups with 10 rats per group: sham-operation group, model group and Tiantai No. 1 group. Sterile surgical procedure was applied, the model group with bilateral hippocampal injection of Aβ1-40 was established, and normal saline was used instead of Aβ1-40 in the sham-operation group. One week after the models was made, rats were administered by gastric lavage once every day for three consecutive weeks. The rats of the sham-operation group and the model group were daily fed with purified water by lavage; the rats of the Tiantai No.1 group treated group were administered with Tiantai No.1 by lavage. Total RNAs of hippocampus tissues were extracted with Trizol, the changes of hippocampus gene expression profiles in the above three groups were analyzed by using Affymetrix rat whole genome expression profile microarray. RESULTS Microarray analysis showed that, compared with the sham-operation group, the hippocampus of the model group had 50 up-regulated genes with significant difference (fold change >2), and 21 down-regulated genes with significant difference (fold change <0.5); compared with the hippocampus of the model group, the hippocampus of the Tiantai No. 1 group was found to have 5 up-regulated genes with significant difference (fold change >2) and 20 down-regulated genes with significant difference (fold change <0.5). The functions of differentially expressed genes of the groups were involved in nervous system's development, neuronic differentiation and function-regulation, cellular growth and differentiation and apoptosis, synaptic occurrence and plasticity, inflammation and immune response, ion channels/transporters, cellular signal transduction, cellular material/energy metabolism and so on. CONCLUSION Tiantai No. 1 can regulate hippocampal function, and further regulate the brain function of animals in multiple gene target points by a number of ways.
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Affiliation(s)
- Ying-hong Li
- The First Affiliated Hospital of Shenzhen University, Shenzhen, Guangdong Province, 518035, China
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Abstract
Statins form the pharmacologic cornerstone of the primary and secondary prevention of atherosclerotic cardiovascular disease. In addition to beneficial cardiovascular effects, statins seem to have multiple non-cardiovascular effects. Although early concerns about statin induced hepatotoxicity and cancer have subsided owing to reassuring evidence, two of the most common concerns that clinicians have are myopathy and diabetes. Randomized controlled trials suggest that statins are associated with a modest increase in the risk of myositis but not the risk of myalgia. Severe myopathy (rhabdomyolysis) is rare and often linked to a statin regimen that is no longer recommended (simvastatin 80 mg). Randomized controlled trials and meta-analyses suggest an increase in the risk of diabetes with statins, particularly with higher intensity regimens in people with two or more components of the metabolic syndrome. Other non-cardiovascular effects covered in this review are contrast induced nephropathy, cognition, cataracts, erectile dysfunction, and venous thromboembolism. Currently, systematic reviews and clinical practice guidelines indicate that the cardiovascular benefits of statins generally outweigh non-cardiovascular harms in patients above a certain threshold of cardiovascular risk. Literature is also accumulating on the potential non-cardiovascular benefits of statins, which could lead to novel applications of this class of drug in the future.
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Affiliation(s)
- Chintan S Desai
- Johns Hopkins Ciccarone Center for the Prevention of Heart Disease, Baltimore, MD 21287, USA
| | - Seth S Martin
- Johns Hopkins Ciccarone Center for the Prevention of Heart Disease, Baltimore, MD 21287, USA
| | - Roger S Blumenthal
- Johns Hopkins Ciccarone Center for the Prevention of Heart Disease, Baltimore, MD 21287, USA
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Sławińska-Brych A, Zdzisińska B, Kandefer-Szerszeń M. Fluvastatin inhibits growth and alters the malignant phenotype of the C6 glioma cell line. Pharmacol Rep 2014; 66:121-9. [DOI: 10.1016/j.pharep.2014.01.002] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2012] [Revised: 07/07/2013] [Accepted: 08/02/2013] [Indexed: 11/24/2022]
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Kabadi SV, Faden AI. Neuroprotective strategies for traumatic brain injury: improving clinical translation. Int J Mol Sci 2014; 15:1216-36. [PMID: 24445258 PMCID: PMC3907865 DOI: 10.3390/ijms15011216] [Citation(s) in RCA: 123] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2013] [Revised: 01/07/2014] [Accepted: 01/13/2014] [Indexed: 01/15/2023] Open
Abstract
Traumatic brain injury (TBI) induces secondary biochemical changes that contribute to delayed neuroinflammation, neuronal cell death, and neurological dysfunction. Attenuating such secondary injury has provided the conceptual basis for neuroprotective treatments. Despite strong experimental data, more than 30 clinical trials of neuroprotection in TBI patients have failed. In part, these failures likely reflect methodological differences between the clinical and animal studies, as well as inadequate pre-clinical evaluation and/or trial design problems. However, recent changes in experimental approach and advances in clinical trial methodology have raised the potential for successful clinical translation. Here we critically analyze the current limitations and translational opportunities for developing successful neuroprotective therapies for TBI.
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Affiliation(s)
- Shruti V Kabadi
- Department of Anesthesiology, Center for Shock, Trauma and Anesthesiology Research (STAR), National Study Center for Trauma and EMS, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
| | - Alan I Faden
- Department of Anesthesiology, Center for Shock, Trauma and Anesthesiology Research (STAR), National Study Center for Trauma and EMS, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
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Cornelius C, Crupi R, Calabrese V, Graziano A, Milone P, Pennisi G, Radak Z, Calabrese EJ, Cuzzocrea S. Traumatic brain injury: oxidative stress and neuroprotection. Antioxid Redox Signal 2013; 19:836-53. [PMID: 23547621 DOI: 10.1089/ars.2012.4981] [Citation(s) in RCA: 262] [Impact Index Per Article: 21.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
SIGNIFICANCE A vast amount of circumstantial evidence implicates high energy oxidants and oxidative stress as mediators of secondary damage associated with traumatic brain injury. The excessive production of reactive oxygen species due to excitotoxicity and exhaustion of the endogenous antioxidant system induces peroxidation of cellular and vascular structures, protein oxidation, cleavage of DNA, and inhibition of the mitochondrial electron transport chain. RECENT ADVANCES Different integrated responses exist in the brain to detect oxidative stress, which is controlled by several genes termed vitagens. Vitagens encode for cytoprotective heat shock proteins, and thioredoxin and sirtuins. CRITICAL ISSUES AND FUTURE DIRECTIONS This article discusses selected aspects of secondary brain injury after trauma and outlines key mechanisms associated with toxicity, oxidative stress, inflammation, and necrosis. Finally, this review discusses the role of different oxidants and presents potential clinically relevant molecular targets that could be harnessed to treat secondary injury associated with brain trauma.
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Affiliation(s)
- Carolin Cornelius
- Department of Clinical and Experimental Medicine and Pharmacology, School of Medicine, University of Messina, Messina, Italy
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Therapeutic Options to Reduce Lp-PLA2 Levels and the Potential Impact on Vascular Risk Reduction. CURRENT TREATMENT OPTIONS IN CARDIOVASCULAR MEDICINE 2013; 15:313-21. [DOI: 10.1007/s11936-013-0239-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
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Abstract
Sickle cell disease (SCD) is caused by a mutation in both beta globin genes, resulting in chronic hemolysis and multiorgan disease that ultimately leads to premature death. Although hemoglobin S (HbS) polymerization and vaso-occlusion are central to the pathogenesis of SCD, overlapping pathways implicated in SCD-related endothelial dysfunction include hemolysis, defects in nitric oxide metabolism, ischemia-reperfusion injury, oxidative stress, increased cell-to-cell adhesion, and proinflammatory and coagulation mediators. Progression of organ-specific vasculopathy often precedes organ dysfunction and may provide targets for therapeutic intervention. SCD-related vasculopathies include, but are not limited to, moyamoya that often precedes cerebral infarcts or hemorrhage, proliferative retinopathy prior to loss of eyesight, pulmonary vasculopathy associated with pulmonary hypertension, and renal vasculopathy prior to the onset of chronic renal disease. This review evaluates evidence that SCD vasculopathy is a harbinger for organ dysfunction and reviews the potential for targeted antivasculopathy therapies.
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Affiliation(s)
- Adetola A Kassim
- Department of Medicine, Hematology/Stem Cell Transplant, Vanderbilt and Meharry Center for Excellence in Sickle Cell Disease, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA.
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Wu H, Mahmood A, Qu C, Xiong Y, Chopp M. Simvastatin attenuates axonal injury after experimental traumatic brain injury and promotes neurite outgrowth of primary cortical neurons. Brain Res 2012; 1486:121-30. [PMID: 23026078 DOI: 10.1016/j.brainres.2012.09.039] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2012] [Revised: 09/12/2012] [Accepted: 09/23/2012] [Indexed: 11/29/2022]
Abstract
The beneficial effects of simvastatin on experimental traumatic brain injury (TBI) have been demonstrated in previous studies. In this study, we investigated the effects of simvastatin on axonal injury and neurite outgrowth after experimental TBI and explored the underlying mechanisms. Wistar rats were subjected to controlled cortical impact or sham surgery. Saline or simvastatin was administered for 14 days. A modified neurological severity score (mNSS) test was performed to evaluate functional recovery. Immunohistochemistry studies using synaptophysin, neurofilament H (NF-H) and amyloid-β precursor protein (APP) were performed to examine synaptogenesis and axonal injury. Primary cortical neurons (PCNs) were subjected to oxygen glucose deprivation (OGD) followed by various treatments. Western blot analysis was utilized to assess the activation of phosphatidylinositol-3 kinase (PI-3K)/Akt/mammalian target of rapamycin (mTOR) and glycogen synthase kinase 3β (GSK-3β)/adenomatous polyposis coli (APC) pathways. Simvastatin decreased the density of APP-positive profiles and increased the density of NF-H -positive profiles. Simvastatin reduced mNSS, which was correlated with the increase of axonal density. Simvastatin treatment stimulated the neurite outgrowth of PCNs after OGD, which was attenuated by LY294002 and enhanced by lithium chloride (LiCl). Simvastatin activated Akt and mTOR, inactivated GSK-3β and dephosphorylated APC in the injured PCNs. Our data suggest that simvastatin reduces axonal injury, enhances neurite outgrowth and promotes neurological functional recovery after experimental TBI. The beneficial effects of simvastatin on neurite outgrowth may be mediated through manipulation of the PI-3K/Akt/mTOR and PI-3K/GSK-3β/APC pathways.
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Affiliation(s)
- Hongtao Wu
- Department of Neurosurgery, Henry Ford Hospital, Detroit, MI 48202, USA
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Affiliation(s)
- Mary A Johnson
- Department of Ophthalmology and Visual Science, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Diego Cadavid
- MS Clinical Development Group, Biogen Idec, Cambridge, MA, USA
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Moezi L, Shafaroodi H, Hassanipour M, Fakhrzad A, Hassanpour S, Dehpour AR. Chronic administration of atorvastatin induced anti-convulsant effects in mice: the role of nitric oxide. Epilepsy Behav 2012; 23:399-404. [PMID: 22405864 DOI: 10.1016/j.yebeh.2012.02.001] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2011] [Revised: 01/25/2012] [Accepted: 02/01/2012] [Indexed: 10/28/2022]
Abstract
Atorvastatin has neuroprotective effects, and there is some evidence that nitric oxide is involved in atorvastatin effects. In this study, we evaluated whether the nitrergic system is involved in the anticonvulsant effects of chronic atorvastatin administration. Intravenous and intraperitoneal pentylenetetrazol were used to induce seizures in mice. Chronic atorvastatin treatment significantly increased the seizure threshold which is induced by both intravenous and intraperitoneal pentylenetetrazol. Intraperitoneal pentylenetetrazol also decreased the incidence of tonic seizure and death in atorvastatin-treated groups. Chronic co-administration of a non-selective nitric oxide synthase inhibitor, l-NAME, or a selective inducible nitric oxide synthase inhibitor, aminoguanidine, with atorvastatin inhibited atorvastatin-induced anticonvulsant effects in intravenous model of pentylenetetrazol. Acute injection of l-NAME or aminoguanidine inhibited the anticonvulsant effects of atorvastatin in both models of intravenous- and intraperitoneal-pentylenetetrazol-induced seizures. In conclusion, we demonstrated that nitric oxide signaling probably through inducible nitric oxide synthase could be involved in the anticonvulsant effects of atorvastatin.
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Affiliation(s)
- Leila Moezi
- Department of Pharmacology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
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Tsakiri A, Kallenbach K, Fuglø D, Wanscher B, Larsson H, Frederiksen J. Simvastatin improves final visual outcome in acute optic neuritis: a randomized study. Mult Scler 2011; 18:72-81. [DOI: 10.1177/1352458511415452] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Background: In recent years, small-scale clinical trials have indicated that statins or 3-hydroxy-3-methylglutaryl coenzyme A (HMGCoA) reductase inhibitors exert pleiotropic immunomodulatory effects, with potential therapeutic implications in multiple sclerosis (MS). Objective: To investigate whether simvastatin treatment (80 mg daily for 6 months) in patients with optic neuritis (ON) had a beneficial effect on visual outcome and on brain MRI. Methods: Sixty-four patients with acute ON were randomized to simvastatin treatment ( n = 32) or placebo ( n = 32) for 6 months. None of the patients had been on immunosuppressive therapy for 6 months prior to inclusion or treated with steroids from symptom onset. Contrast sensitivity (Arden plates), visual acuity, colour perception, visual evoked potentials (VEP) – latency and amplitude, Visual Analogue Scale (VAS) score, and gadolinium enhancing and T2 lesions on brain MRI were evaluated at screening visit, day 14 (except brain MRI), day 90 and day 180. Results: Simvastatin had a beneficial effect on VEP in both latency ( p = 0.01) and amplitude ( p = 0.01), a borderline effect on the Arden score ( p = 0.06) and VAS ( p = 0.04), and no effect on brain MRI or on relapse rate between the groups. Conclusion: This study provides Class I evidence that simvastatin 80 mg daily is well tolerated and possibly effective in patients with acute ON.
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Affiliation(s)
- Anna Tsakiri
- Department of Neurology, Glostrup Hospital, University of Copenhagen, Denmark
| | - Klaus Kallenbach
- Department of Neurology, Glostrup Hospital, University of Copenhagen, Denmark
| | - Dan Fuglø
- Department of Clinical Physiology and Nuclear Medicine, Unit of Functional Imaging, Glostrup Hospital, University of Copenhagen, Denmark
| | - Benedikte Wanscher
- Department of Neurophysiology, Glostrup Hospital, University of Copenhagen, Denmark
| | - Henrik Larsson
- Department of Clinical Physiology and Nuclear Medicine, Unit of Functional Imaging, Glostrup Hospital, University of Copenhagen, Denmark
| | - Jette Frederiksen
- Department of Neurology, Glostrup Hospital, University of Copenhagen, Denmark
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Hoppe C, Kuypers F, Larkin S, Hagar W, Vichinsky E, Styles L. A pilot study of the short-term use of simvastatin in sickle cell disease: effects on markers of vascular dysfunction. Br J Haematol 2011; 153:655-63. [PMID: 21477202 PMCID: PMC3601917 DOI: 10.1111/j.1365-2141.2010.08480.x] [Citation(s) in RCA: 58] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Sickle cell disease (SCD) is characterized by progressive vascular injury and its pathophysiology is strikingly similar to that of atherosclerosis. Statins decrease inflammation and improve endothelial function in cardiovascular disease, but their effect in SCD is not known. In this pilot study, we examined the safety and effect of short-term simvastatin on biomarkers of vascular dysfunction in SCD. We treated 26 SCD patients with simvastatin, 20 or 40 mg/d, for 21 d. Plasma nitric oxide metabolites (NOx), C-reactive protein (CRP), interleukin-6 (IL-6), vascular cell adhesion molecule-1 (VCAM-1), tissue factor (TF) and vascular endothelial growth factor (VEGF) were analyzed and responses to simvastatin were compared between the two treatment groups. Simvastatin increased NOx levels by 23% in the low-dose (P =0·01) and 106% in the moderate-dose (P =0·01) groups, and by 52% overall (P=0·0008). CRP decreased similarly in both dose groups and by 68% overall (P =0·02). Levels of IL-6 decreased by 50% (P=0·04) and 71% (P<0·05) in the low- and moderate-dose groups, respectively. Simvastatin had no effect on VEGF, VCAM1 or TF. Simvastatin was well-tolerated and safe. Our preliminary findings showing a dose-related effect of simvastatin on levels of NOx, CRP and IL-6 suggest a potential therapeutic role for simvastatin in SCD.
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Affiliation(s)
- Carolyn Hoppe
- Department of Haematology/Oncology, Children's Hospital & Research Center Oakland, 747 52nd Street, Oakland, CA 94609, USA.
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Mills JD, Hadley K, Bailes JE. Dietary Supplementation With the Omega-3 Fatty Acid Docosahexaenoic Acid in Traumatic Brain Injury. Neurosurgery 2011; 68:474-81; discussion 481. [DOI: 10.1227/neu.0b013e3181ff692b] [Citation(s) in RCA: 95] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Affiliation(s)
- James D. Mills
- Department of Neurosurgery, West Virginia University School of Medicine, Morgantown, West Virginia
| | | | - Julian E. Bailes
- Department of Neurosurgery, West Virginia University School of Medicine, Morgantown, West Virginia
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Loane DJ, Faden AI. Neuroprotection for traumatic brain injury: translational challenges and emerging therapeutic strategies. Trends Pharmacol Sci 2010; 31:596-604. [PMID: 21035878 PMCID: PMC2999630 DOI: 10.1016/j.tips.2010.09.005] [Citation(s) in RCA: 436] [Impact Index Per Article: 29.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2010] [Revised: 09/25/2010] [Accepted: 09/27/2010] [Indexed: 11/30/2022]
Abstract
Traumatic brain injury (TBI) causes secondary biochemical changes that contribute to subsequent tissue damage and associated neuronal cell death. Neuroprotective treatments that limit secondary tissue loss and/or improve behavioral outcome have been well established in multiple animal models of TBI. However, translation of such neuroprotective strategies to human injury have been disappointing, with the failure of more than thirty controlled clinical trials. Both conceptual issues and methodological differences between preclinical and clinical injury have undoubtedly contributed to these translational difficulties. More recently, changes in experimental approach, as well as altered clinical trial methodologies, have raised cautious optimism regarding the outcomes of future clinical trials. Here we critically review developing experimental neuroprotective strategies that show promise, and we propose criteria for improving the probability of successful clinical translation.
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Affiliation(s)
- David J. Loane
- Department of Anesthesiology & Center for Shock, Trauma and Anesthesiology Research (STAR), National Study Center for Trauma and EMS, University of Maryland School of Medicine, Baltimore, MD
| | - Alan I. Faden
- Department of Anesthesiology & Center for Shock, Trauma and Anesthesiology Research (STAR), National Study Center for Trauma and EMS, University of Maryland School of Medicine, Baltimore, MD
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The effects of atorvastatin on memory deficit and seizure susceptibility in pentylentetrazole-kindled rats. Epilepsy Behav 2010; 19:284-9. [PMID: 20888302 DOI: 10.1016/j.yebeh.2010.07.024] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2010] [Revised: 07/21/2010] [Accepted: 07/26/2010] [Indexed: 11/22/2022]
Abstract
Deficits in memory function have been observed in pentylentetrazole (PTZ)-kindled rats. In the present study we examined the effects of atorvastatin ((3-hydroxy-3-methylglutaryl-coenzyme A [HMG-CoA] reductase inhibitor) on PTZ kindling and related memory deficits in rats trained with the passive avoidance test. Subconvulsive PTZ doses rendered a gradual increase in seizure activity. PTZ kindling caused long-term memory to deteriorate. Atorvastatin per se and in PTZ-kindled rats improved learning and memory functions. It also prolonged latency (time to appearance of spike potentials) and diminished the amplitude and frequency of spike potentials, which indicate epileptic discharges. These novel findings suggest that the favorable effect of the atorvastatin on memory deficits provoked by PTZ kindling might be of clinical utility.
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Ritz B, Manthripragada AD, Qian L, Schernhammer E, Wermuth L, Olsen J, Friis S. Statin use and Parkinson's disease in Denmark. Mov Disord 2010; 25:1210-6. [PMID: 20629142 PMCID: PMC2910157 DOI: 10.1002/mds.23102] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022] Open
Abstract
The objective of this study was to investigate whether statin (3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor) use is associated with risk of Parkinson's disease (PD) in Denmark. We identified 1,931 patients with a first time diagnosis of PD reported in hospital or outpatient clinic records between 2001 and 2006. We density matched to these patients 9,651 population controls by birth year and sex relying on the Danish population register. For every participant, we identified pharmacy records of statin and anti-Parkinson drug prescriptions since 1995 and before index date from a prescription medication use database for all Danish residents. Whenever applicable, the index dates for cases and their corresponding controls were advanced to the date of first recorded prescription for anti-Parkinson drugs. In our primary analyses, we excluded all statin prescriptions 2-years before PD diagnosis. Employing logistic regression adjusting for age, sex, diagnosis of chronic obstructive pulmonary disease, and Charlson comorbidity, we observed none to slightly inverse associations between PD diagnosis and statin prescription drug use. Inverse associations with statin use were only observed for short-term (
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Affiliation(s)
- Beate Ritz
- Department of Epidemiology, UCLA School of Public Health, Los Angeles, California, USA
| | | | - Lei Qian
- Department of Biostatistics, UCLA School of Public Health, Los Angeles, California, USA
| | - Eva Schernhammer
- Channing Laboratory, Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA
| | - Lene Wermuth
- Department of Neurology, Odense University Hospital, Denmark
| | - Jorgen Olsen
- Institute of Cancer Epidemiology, Danish Cancer Society, Copenhagen, Denmark
| | - Soren Friis
- Institute of Cancer Epidemiology, Danish Cancer Society, Copenhagen, Denmark
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Diet and age interactions with regards to cholesterol regulation and brain pathogenesis. Curr Gerontol Geriatr Res 2010:219683. [PMID: 20396385 PMCID: PMC2852598 DOI: 10.1155/2010/219683] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2009] [Accepted: 02/15/2010] [Indexed: 01/10/2023] Open
Abstract
Cholesterol is an essential molecule for brain homeostasis; yet, hypercholesterolemia and its numerous complications are believed to play a role in promoting multiple aspects of brain pathogenesis. An ever increasing number of individuals in modern Western Society are regularly consuming diets high in fat which promote the development of hypercholesterolemia. Additionally, modern societies are becoming increasingly aged, causing a collision between increased hypercholesterolemia and increased aging, which will likely lead to the development of increased pathological conditions due to hypercholesterolemia, thereby promoting deleterious neurochemical and behavioral changes in the brain. Lastly, while beneficial in controlling cholesterol levels, the long-term use of statins itself may potentially promote adverse effects on brain homeostasis, although specifics on this remain largely unknown. This review will focus on linking the current understanding of diet-induced hypercholesterolemia (as well as statin use) to the development of oxidative stress, neurochemical alterations, and cognitive disturbances in the aging brain.
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Wible EF, Laskowitz DT. Statins in traumatic brain injury. Neurotherapeutics 2010; 7:62-73. [PMID: 20129498 PMCID: PMC5084113 DOI: 10.1016/j.nurt.2009.11.003] [Citation(s) in RCA: 64] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2009] [Revised: 11/17/2009] [Accepted: 11/18/2009] [Indexed: 10/20/2022] Open
Abstract
Traumatic brain injury (TBI) is a common cause of long-term neurological morbidity, with devastating personal and societal consequences. At present, no pharmacological intervention clearly improves outcomes, and therefore a compelling unmet clinical need remains. 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, or "statins," offer a potential novel therapeutic strategy for TBI. Statins are well tolerated, easy to administer, and have a long clinical track record in critically ill patients. Their side effects are well defined and easily monitored. Preclinical studies have shown significant benefit of statins in models of TBI and related disease processes, including cerebral ischemia, intracerebral hemorrhage, and subarachnoid hemorrhage. In fact, multiple mechanisms have been defined by which statins may exert benefit after acute brain injury. Statins are currently positioned to be translated into clinical trials in acute brain injury and have the potential to improve outcomes after TBI.
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Affiliation(s)
- Elissa F. Wible
- grid.26009.3d0000000419367961Department of Medicine (Neurology), Duke University School of Medicine, 27710 Durham, North Carolina
| | - Daniel T. Laskowitz
- grid.26009.3d0000000419367961Department of Medicine (Neurology), Duke University School of Medicine, 27710 Durham, North Carolina
- grid.26009.3d0000000419367961Department of Anesthesiology, Duke University School of Medicine, 27710 Durham, North Carolina
- grid.26009.3d0000000419367961Department of Neurobiology, Duke University School of Medicine, 27710 Durham, North Carolina
- grid.189509.c0000000100241216Duke University Medical Center, Box 2900, 27710 Durham, NC
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Green RC, McNagny SE, Jayakumar P, Cupples LA, Benke K, Farrer LA. Statin use and the risk of Alzheimer's disease: the MIRAGE study. Alzheimers Dement 2009; 2:96-103. [PMID: 19595865 DOI: 10.1016/j.jalz.2006.02.003] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2005] [Revised: 02/08/2006] [Accepted: 02/08/2006] [Indexed: 01/24/2023]
Abstract
BACKGROUND The aim of this study was to examine the association between statin use before the onset of Alzheimer's disease (AD) symptoms and risk of having AD, and to explore the potential impact of APOE genotype and race on this association. METHODS Data were collected through standardized, validated questionnaires from 895 subjects with probable or definite AD by research criteria, and 1,483 of their nondemented relatives in this family-based, case-control study of AD patients and their relatives enrolled at 15 research centers from 1996 through 2002. To minimize temporal and prescription biases, exposure to statin use within each family was ignored in the one year before the first appearance of AD symptoms in that family's affected member. Associations were estimated using generalized estimating equations for a logistic model, adjusting for age, sex, race, education, history of heart disease, stroke, diabetes, smoking and APOE genotype. RESULTS Statin use was associated with lowered odds of having AD (adjusted odds ratio [OR], 0.61; 95% confidence interval [CI], 0.38 to 0.98). Nonstatin cholesterol-lowering medications were not associated significantly with lowered odds of having had AD (adjusted OR, 1.7; 95% CI, 0.61 to 5.0). CONCLUSIONS Statin medications were associated with lowered risk of AD in this population. Neither African-American race, nor the presence of the APOE 4 allele modified the statin-AD association.
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Affiliation(s)
- Robert C Green
- Department of Neurology, Boston University School of Medicine, Boston, MA, USA.
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Garenc C, Julien P, Levy E. Oxysterols in biological systems: The gastrointestinal tract, liver, vascular wall and central nervous system. Free Radic Res 2009; 44:47-73. [DOI: 10.3109/10715760903321804] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
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Alcalá A, Jansen S, Téllez T, Gómez-Huelgas R, Pérez O, Egido J, Farkouh ME. Statins improve visual field alterations related to hypercholesterolemia. Atherosclerosis 2009; 209:510-4. [PMID: 19892351 DOI: 10.1016/j.atherosclerosis.2009.10.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2009] [Revised: 10/01/2009] [Accepted: 10/01/2009] [Indexed: 10/20/2022]
Abstract
OBJECTIVE To determine whether lipid-lowering treatment with diet or statins would provide beneficial effects on visual field alterations associated with hypercholesterolemia. METHODS 180 subjects with hypercholesterolemia were randomly assigned to a low fat diet (diet group) or to a low fat diet plus 40 mg/day of pravastatin (pravastatin group). At the beginning of the study and 6 months after the assigned treatment, all subjects underwent a computerized perimetry test and a determination of plasma concentration of glucose, total cholesterol, LDL-cholesterol (LDL-C), HDL-cholesterol (HDL-C) and triglycerides. RESULTS At 6 months, both groups showed a significant decrease in total cholesterol, LDL-C and triglycerides compared to basal values, and a significant increase in the HDL-C. The pravastatin group had a significantly greater reduction in total cholesterol (-85+/-21 mg/dl) and LDL-C (-86+/-23 mg/dl) than the diet group (-28+/-9 and -28+/-10mg/dl, respectively). All perimetry parameters improved in both groups after the intervention period, although the improvement was greater in the pravastatin group. Using a general linear model, a significant effect of treatment with pravastatin compared to diet was observed in the improvement of all the perimetry parameters, whereas the change in LDL-C concentrations only had a significant effect on the improvement of one of them. CONCLUSION In subjects with hypercholesterolemia, the decrease of blood lipids improves visual field parameters. The major beneficial effect noted with pravastatin, compared to diet, suggests that this effect could be due to the lipid-lowering and pleiotropic actions.
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Affiliation(s)
- Antonio Alcalá
- Department of Clinical Biochemistry and Molecular Biology, Malaga University, School of Medicine, C/Liborio Garcia, 8, 29005 Malaga, Spain.
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Abstract
Traumatic brain injury (TBI) initiates a cascade of numerous pathophysiological events that evolve over time.Despite the complexity of TBI, research aimed at therapy development has almost exclusively focused on single therapies, all of which have failed in multicenter clinical trials. Therefore, in February 2008 the National Institute of Neurological Disorders and Stroke, with support from the National Institute of Child Health and Development, the National Heart, Lung, and Blood Institute, and the Department of Veterans Affairs, convened a workshop to discuss the opportunities and challenges of testing combination therapies for TBI. Workshop participants included clinicians and scientists from a variety of disciplines, institutions, and agencies. The objectives of the workshop were to: (1) identify the most promising combinations of therapies for TBI; (2) identify challenges of testing combination therapies in clinical and pre-clinical studies; and (3) propose research methodologies and study designs to overcome these challenges. Several promising combination therapies were discussed, but no one combination was identified as being the most promising. Rather, the general recommendation was to combine agents with complementary targets and effects (e.g., mechanisms and time-points), rather than focusing on a single target with multiple agents. In addition, it was recommended that clinical management guidelines be carefully considered when designing pre-clinical studies for therapeutic development.To overcome the challenges of testing combination therapies it was recommended that statisticians and the U.S. Food and Drug Administration be included in early discussions of experimental design. Furthermore, it was agreed that an efficient and validated screening platform for candidate therapeutics, sensitive and clinically relevant biomarkers and outcome measures, and standardization and data sharing across centers would greatly facilitate the development of successful combination therapies for TBI. Overall there was great enthusiasm for working collaboratively to act on these recommendations.
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Affiliation(s)
- Susan Margulies
- School of Engineering and Applied Science, Department of Bioengineering, University of Pennsylvania, 210 S. 33rd Street, Philadelphia, PA 19104-6321, USA.
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Becker C, Meier CR. Statins and the risk of Parkinson disease: an update on the controversy. Expert Opin Drug Saf 2009; 8:261-71. [DOI: 10.1517/14740330902859956] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
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Renshaw PF, Parsegian A, Yang CK, Novero A, Yoon SJ, Lyoo IK, Cohen BM, Carlezon WA. Lovastatin potentiates the antidepressant efficacy of fluoxetine in rats. Pharmacol Biochem Behav 2009; 92:88-92. [PMID: 19026674 PMCID: PMC2666925 DOI: 10.1016/j.pbb.2008.10.017] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2008] [Revised: 10/23/2008] [Accepted: 10/24/2008] [Indexed: 01/22/2023]
Abstract
BACKGROUND Cholesterol may have a role in the pathophysiology of depression. Lowering cholesterol levels with statins reduces risks for cardiovascular events, and there is clinical evidence that statins exert neuroprotective properties not fully explained by their effects on serum cholesterol levels. Altered cholesterol levels can affect serotonergic neurotransmission, which might be involved in the clinical efficacy of standard antidepressants. METHODS We examined interactions between a statin (lovastatin) and a selective serotonin reuptake inhibitor (fluoxetine) using the forced swim test (FST) in rats, a behavioral assay that identifies treatments with antidepressant effects in humans. Specifically, we determined if the addition of lovastatin to the diet would increase the efficacy of a subeffective dose of fluoxetine. RESULTS Rats maintained on a lovastatin-enriched diet for 30 days were more sensitive to the antidepressant-like effects of a low (subthreshold) dose of fluoxetine. The behavior of rats treated with this combination resembled that normally seen with higher doses of fluoxetine. No effects were observed in rats maintained on a lovastatin-enriched diet for 3 days. CONCLUSIONS Lovastatin can augment the antidepressant-like effects of a low dose of fluoxetine in rats, raising the possibility that statins could be used to facilitate the effects of antidepressants in humans.
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Affiliation(s)
- Perry F Renshaw
- Department of Psychiatry, Harvard Medical School, Belmont, MA 02478, USA.
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Management of Transient Ischemia Attacks in the Twenty-First Century. Emerg Med Clin North Am 2009; 27:51-69, viii. [DOI: 10.1016/j.emc.2008.08.008] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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Coetsee T, Pretorius P, Terre’Blanche G, Bergh J. Investigating the potential neuroprotective effects of statins on DNA damage in mouse striatum. Food Chem Toxicol 2008; 46:3186-92. [DOI: 10.1016/j.fct.2008.07.006] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2007] [Revised: 06/04/2008] [Accepted: 07/14/2008] [Indexed: 01/22/2023]
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Abstract
A major challenge facing the physician evaluating patients with transient ischemic attack is determining which patients are at highest short-term risk of stroke. A number of stratification schemes have been recently developed incorporating easily obtainable clinical information about the individual patient. Further, emerging data suggest a role for brain and vascular imaging in risk stratification. Many aspects of acute management of transient ischemic attack, such as which patients should be hospitalized and choice of acute antithrombotic therapy, remain controversial because of a lack of evidence from controlled trials. For longer-term prevention, there is much firmer evidence from multiple large randomized trials, and these data are reviewed in this article.
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Affiliation(s)
- Brett Cucchiara
- Department of Neurology, University of Pennsylvania Medical Center, Philadelphia, PA 19104, USA.
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Bifulco M, Malfitano AM, Marasco G. Potential therapeutic role of statins in neurological disorders. Expert Rev Neurother 2008; 8:827-37. [PMID: 18457539 DOI: 10.1586/14737175.8.5.827] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Statins, the inhibitors of HMG-CoA reductase, are currently among the most commonly prescribed agents for the prevention of cardiovascular disease. It is well established that statins reduce cholesterol levels and prevent coronary heart disease. Moreover, evidence suggests that statins have additional properties such as endothelial protection via actions on the nitric oxide synthetase system as well as antioxidant, anti-inflammatory and antiplatelet effects. There is evidence that all these actions might have potential therapeutic implications not only in stroke, but also in various neurological disorders, such as Alzheimer's disease, Parkinson's disease, multiple sclerosis and primary brain tumors. In this review, we summarize the protective effects of statins on various neurological diseases. Currently available data suggest that statins are safe and effective in the treatment of these neurological disorders, although further experiments and new data are required.
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Affiliation(s)
- Maurizio Bifulco
- Dipartimento di Scienze Farmaceutiche, University di Salerno, Via Ponte Don Melillo 84084 Fisciano, Salerno, Italy.
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