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Nakamura A, Tanaka Y, Amano T, Takebayashi A, Takahashi A, Hanada T, Tsuji S, Murakami T. mTOR inhibitors as potential therapeutics for endometriosis: a narrative review. Mol Hum Reprod 2024; 30:gaae041. [PMID: 39579091 PMCID: PMC11634386 DOI: 10.1093/molehr/gaae041] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2024] [Revised: 10/15/2024] [Indexed: 11/25/2024] Open
Abstract
Mammalian target of rapamycin (mTOR) inhibitors have been used clinically as anticancer and immunosuppressive agents for over 20 years, demonstrating their safety after long-term administration. These inhibitors exhibit various effects, including inhibition of cell proliferation, interaction with the oestrogen and progesterone pathways, immunosuppression, regulation of angiogenesis, and control of autophagy. We evaluated the potential of mTOR inhibitors as therapeutic agents for endometriosis, examined the secondary benefits related to reproductive function, and assessed how their side effects can be managed. We conducted a thorough review of publications on the role of the mTOR pathway and the effectiveness of mTOR inhibitors in endometriosis patients. These results indicate that the mTOR pathway is activated in endometriosis. Additionally, mTOR inhibitors have shown efficacy as monotherapies for endometriosis. They may alleviate resistance to hormonal therapy in endometriosis, suggesting a potential synergistic effect when used in combination with hormonal therapy. The potential reproductive benefits of mTOR inhibitors include decreased miscarriage rates, improved implantation, and prevention of age-related follicular loss and ovarian hyperstimulation syndrome. Activation of the mTOR pathway has also been implicated in the malignant transformation of endometriosis. Preclinical studies suggest that the dosage of mTOR inhibitors needed for treating endometriosis may be lower than that required for anticancer or immunosuppressive therapy, potentially reducing dosage-dependent side effects. In conclusion, while mTOR inhibitors, which allow for pregnancy during oral administration, show potential for clinical use in all stages of endometriosis, current evidence is limited to preclinical studies, and further research is needed to confirm clinical effectiveness.
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Affiliation(s)
- Akiko Nakamura
- Department of Obstetrics and Gynaecology, Shiga University of Medical Science, Otsu, Shiga, Japan
| | - Yuji Tanaka
- Department of Obstetrics and Gynaecology, Shiga University of Medical Science, Otsu, Shiga, Japan
| | - Tsukuru Amano
- Department of Obstetrics and Gynaecology, Shiga University of Medical Science, Otsu, Shiga, Japan
| | - Akie Takebayashi
- Department of Obstetrics and Gynaecology, Shiga University of Medical Science, Otsu, Shiga, Japan
| | - Akimasa Takahashi
- Department of Obstetrics and Gynaecology, Shiga University of Medical Science, Otsu, Shiga, Japan
| | - Tetsuro Hanada
- Department of Obstetrics and Gynaecology, Shiga University of Medical Science, Otsu, Shiga, Japan
| | - Shunichiro Tsuji
- Department of Obstetrics and Gynaecology, Shiga University of Medical Science, Otsu, Shiga, Japan
| | - Takashi Murakami
- Department of Obstetrics and Gynaecology, Shiga University of Medical Science, Otsu, Shiga, Japan
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Jakobs M, Trautmann L, Hadamitzky M, Bihorac J, Jacquet L, Christians U, Schniedewind B, Lückemann L, Schedlowski M. Behavioral Analyses in Dark Agouti Rats Following Repeated Systemic Treatment With Fingolimod (FTY720). Brain Behav 2024; 14:e70146. [PMID: 39552126 PMCID: PMC11570679 DOI: 10.1002/brb3.70146] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2024] [Revised: 08/28/2024] [Accepted: 10/24/2024] [Indexed: 11/19/2024] Open
Abstract
BACKGROUND Studies in experimental animals revealed that acute and chronic treatment with small-molecule immunosuppressive drugs lead to neurobehavioral alterations in rodents. METHODS Against this background, this study investigated behavioral alterations in rats after repeated administration of FTY720, an immunosuppressive drug used for the treatment of multiple sclerosis, employing the open field, elevated plus maze, and dark/light tests. RESULTS Compared to controls, repeated FTY720 treatment affected behavior in rats, reflected by a reduction in distance traveled as well as increased time engaged in freezing in the open field and elevated plus maze. Furthermore, the time spent freezing in the elevated plus maze test positively correlated with FTY720 concentrations in the amygdala and insular cortex, two brain regions involved in regulation of emotionality. Since no changes in plasma corticosterone levels were observed, stress effects due to treatment, behavioral testing, or handling can be ruled out. CONCLUSION The present findings indicate that treatment with FTY720 did not induce typical anxiety-like behavioral patterns in otherwise healthy rats as seen following treatment with other immunosuppressive drugs. Nevertheless, it remains of great importance to evaluate behavioral effects in clinical practice to shed more light onto possible detrimental side effects emerging during treatment with small-molecule immunosuppressive drugs.
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Affiliation(s)
- Marie Jakobs
- Institute of Medical Psychology and Behavioral Immunobiology, Center for Translational Neuro‐Behavioral Sciences (C‐TNBS)University Medicine Essen, University Duisburg‐EssenEssenGermany
| | - Lisa Trautmann
- Institute of Medical Psychology and Behavioral Immunobiology, Center for Translational Neuro‐Behavioral Sciences (C‐TNBS)University Medicine Essen, University Duisburg‐EssenEssenGermany
| | - Martin Hadamitzky
- Institute of Medical Psychology and Behavioral Immunobiology, Center for Translational Neuro‐Behavioral Sciences (C‐TNBS)University Medicine Essen, University Duisburg‐EssenEssenGermany
| | - Julia Bihorac
- Institute of Medical Psychology and Behavioral Immunobiology, Center for Translational Neuro‐Behavioral Sciences (C‐TNBS)University Medicine Essen, University Duisburg‐EssenEssenGermany
| | - Lucie Jacquet
- Institute of Medical Psychology and Behavioral Immunobiology, Center for Translational Neuro‐Behavioral Sciences (C‐TNBS)University Medicine Essen, University Duisburg‐EssenEssenGermany
- Department of Infectious Diseases, West German Centre of Infectious DiseasesUniversity Medicine Essen, University Duisburg‐EssenEssenGermany
| | - Uwe Christians
- iC42 Clinical Research and Development, Department of Anesthesiology, School of MedicineUniversity of Colorado Anschutz Medical CampusAuroraColoradoUSA
| | - Björn Schniedewind
- iC42 Clinical Research and Development, Department of Anesthesiology, School of MedicineUniversity of Colorado Anschutz Medical CampusAuroraColoradoUSA
| | - Laura Lückemann
- Institute of Medical Psychology and Behavioral Immunobiology, Center for Translational Neuro‐Behavioral Sciences (C‐TNBS)University Medicine Essen, University Duisburg‐EssenEssenGermany
| | - Manfred Schedlowski
- Institute of Medical Psychology and Behavioral Immunobiology, Center for Translational Neuro‐Behavioral Sciences (C‐TNBS)University Medicine Essen, University Duisburg‐EssenEssenGermany
- Department of Clinical NeuroscienceOsher Center for Integrative Medicine, Karolinska InstitutetStockholmSweden
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Jakobs M, Hörbelt-Grünheidt T, Hadamitzky M, Bihorac J, Salem Y, Leisengang S, Christians U, Schniedewind B, Schedlowski M, Lückemann L. The Effects of Fingolimod (FTY720) on Leukocyte Subset Circulation cannot be Behaviourally Conditioned in Rats. J Neuroimmune Pharmacol 2024; 19:18. [PMID: 38733535 PMCID: PMC11088542 DOI: 10.1007/s11481-024-10122-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2023] [Accepted: 04/26/2024] [Indexed: 05/13/2024]
Abstract
Suppression of immune functions can be elicited by behavioural conditioning using drugs such as cyclosporin A or rapamycin. Nevertheless, little is known about the underlying mechanisms and generalisability of this phenomenon. Against this background, the present study investigated whether the pharmacological properties of fingolimod (FTY720), an immunosuppressive drug widely applied to treat multiple sclerosis, can be conditioned in rats by means of taste-immune associative learning. For this purpose, a conditioned taste avoidance paradigm was used, pairing the presentation of a novel sweet drinking solution (saccharin or sucrose) as conditioned stimulus (CS) with therapeutically effective doses of FTY720 as unconditioned stimulus (US). Subsequent re-exposure to the CS at a later time point revealed that conditioning with FTY720 induced a mild conditioned taste avoidance only when saccharin was employed as CS. However, on an immunological level, neither re-exposure with saccharin nor sucrose altered blood immune cell subsets or splenic cytokine production. Despite the fact that intraperitonally administered FTY720 could be detected in brain regions known to mediate neuro-immune interactions, the present findings show that the physiological action of FTY720 is not inducible by mere taste-immune associative learning. Whether conditioning generalises across all small-molecule drugs with immunosuppressive properties still needs to be investigated with modified paradigms probably using distinct sensory CS. Moreover, these findings emphasize the need to further investigate the underlying mechanisms of conditioned immunomodulation to assess the generalisability and usability of associative learning protocols as supportive therapies in clinical contexts.
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Affiliation(s)
- Marie Jakobs
- Institute of Medical Psychology and Behavioral Immunobiology, Center for Translational Neuro- & Behavioral Sciences, University Hospital Essen, 45147, Essen, Germany.
| | - Tina Hörbelt-Grünheidt
- Institute of Medical Psychology and Behavioral Immunobiology, Center for Translational Neuro- & Behavioral Sciences, University Hospital Essen, 45147, Essen, Germany
| | - Martin Hadamitzky
- Institute of Medical Psychology and Behavioral Immunobiology, Center for Translational Neuro- & Behavioral Sciences, University Hospital Essen, 45147, Essen, Germany
| | - Julia Bihorac
- Institute of Medical Psychology and Behavioral Immunobiology, Center for Translational Neuro- & Behavioral Sciences, University Hospital Essen, 45147, Essen, Germany
| | - Yasmin Salem
- Institute of Medical Psychology and Behavioral Immunobiology, Center for Translational Neuro- & Behavioral Sciences, University Hospital Essen, 45147, Essen, Germany
| | - Stephan Leisengang
- Institute of Medical Psychology and Behavioral Immunobiology, Center for Translational Neuro- & Behavioral Sciences, University Hospital Essen, 45147, Essen, Germany
| | - Uwe Christians
- iC42 Clinical Research and Development, Department of Anesthesiology, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Björn Schniedewind
- iC42 Clinical Research and Development, Department of Anesthesiology, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Manfred Schedlowski
- Institute of Medical Psychology and Behavioral Immunobiology, Center for Translational Neuro- & Behavioral Sciences, University Hospital Essen, 45147, Essen, Germany
- Department of Clinical Neuroscience, Osher Center for Integrative Medicine, Karolinska Institutet, Stockholm, 171 77, Sweden
| | - Laura Lückemann
- Institute of Medical Psychology and Behavioral Immunobiology, Center for Translational Neuro- & Behavioral Sciences, University Hospital Essen, 45147, Essen, Germany
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Svensson JE, Bolin M, Thor D, Williams PA, Brautaset R, Carlsson M, Sörensson P, Marlevi D, Spin-Neto R, Probst M, Hagman G, Morén AF, Kivipelto M, Plavén-Sigray P. Evaluating the effect of rapamycin treatment in Alzheimer's disease and aging using in vivo imaging: the ERAP phase IIa clinical study protocol. BMC Neurol 2024; 24:111. [PMID: 38575854 PMCID: PMC10993488 DOI: 10.1186/s12883-024-03596-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2024] [Accepted: 03/08/2024] [Indexed: 04/06/2024] Open
Abstract
BACKGROUND Rapamycin is an inhibitor of the mechanistic target of rapamycin (mTOR) protein kinase, and preclinical data demonstrate that it is a promising candidate for a general gero- and neuroprotective treatment in humans. Results from mouse models of Alzheimer's disease have shown beneficial effects of rapamycin, including preventing or reversing cognitive deficits, reducing amyloid oligomers and tauopathies and normalizing synaptic plasticity and cerebral glucose uptake. The "Evaluating Rapamycin Treatment in Alzheimer's Disease using Positron Emission Tomography" (ERAP) trial aims to test if these results translate to humans through evaluating the change in cerebral glucose uptake following six months of rapamycin treatment in participants with early-stage Alzheimer's disease. METHODS ERAP is a six-month-long, single-arm, open-label, phase IIa biomarker-driven study evaluating if the drug rapamycin can be repurposed to treat Alzheimer's disease. Fifteen patients will be included and treated with a weekly dose of 7 mg rapamycin for six months. The primary endpoint will be change in cerebral glucose uptake, measured using [18F]FDG positron emission tomography. Secondary endpoints include changes in cognitive measures, markers in cerebrospinal fluid as well as cerebral blood flow measured using magnetic resonance imaging. As exploratory outcomes, the study will assess change in multiple age-related pathological processes, such as periodontal inflammation, retinal degeneration, bone mineral density loss, atherosclerosis and decreased cardiac function. DISCUSSION The ERAP study is a clinical trial using in vivo imaging biomarkers to assess the repurposing of rapamycin for the treatment of Alzheimer's disease. If successful, the study would provide a strong rationale for large-scale evaluation of mTOR-inhibitors as a potential disease-modifying treatment in Alzheimer's disease. TRIAL REGISTRATION ClinicalTrials.gov ID NCT06022068, date of registration 2023-08-30.
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Affiliation(s)
- Jonas E Svensson
- Department of Clinical Neuroscience, Centre for Psychiatry Research, Karolinska Institutet and Stockholm Health Care Services, Region Stockholm, Stockholm, Sweden
- Theme Inflammation and Aging, Karolinska University Hospital, Stockholm, Sweden
| | - Martin Bolin
- Department of Clinical Neuroscience, Centre for Psychiatry Research, Karolinska Institutet and Stockholm Health Care Services, Region Stockholm, Stockholm, Sweden
| | - Daniel Thor
- Department of Medical Radiation Physics and Nuclear Medicine, Karolinska University Hospital, Stockholm, Sweden
- Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden
| | - Pete A Williams
- Department of Clinical Neuroscience, Division of Eye and Vision, St. Erik Eye Hospital, Karolinska Institutet, Stockholm, Sweden
| | - Rune Brautaset
- Department of Clinical Neuroscience, Division of Eye and Vision, St. Erik Eye Hospital, Karolinska Institutet, Stockholm, Sweden
| | - Marcus Carlsson
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
| | - Peder Sörensson
- Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden
| | - David Marlevi
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
- Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Rubens Spin-Neto
- Department of Dentistry and Oral Health, Section for Oral Radiology, Aarhus University, Aarhus C, Denmark
| | - Monika Probst
- Department of Diagnostic and Interventional Neuroradiology, Klinikum Rechts Der Isar, School of Medicine, Technical University of Munich, Munich, Germany
| | - Göran Hagman
- Theme Inflammation and Aging, Karolinska University Hospital, Stockholm, Sweden
- Department of Neurobiology, Care Sciences, and Society, Division of Clinical Geriatrics, Karolinska Institutet, Stockholm, Sweden
| | - Anton Forsberg Morén
- Department of Clinical Neuroscience, Centre for Psychiatry Research, Karolinska Institutet and Stockholm Health Care Services, Region Stockholm, Stockholm, Sweden
| | - Miia Kivipelto
- Theme Inflammation and Aging, Karolinska University Hospital, Stockholm, Sweden
- Department of Neurobiology, Care Sciences, and Society, Division of Clinical Geriatrics, Karolinska Institutet, Stockholm, Sweden
- Ageing Epidemiology Research Unit (AGE), School of Public Health, Faculty of Medicine, Imperial College London, London, UK
- Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland
| | - Pontus Plavén-Sigray
- Department of Clinical Neuroscience, Centre for Psychiatry Research, Karolinska Institutet and Stockholm Health Care Services, Region Stockholm, Stockholm, Sweden.
- Neurobiology Research Unit, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
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Abstract
Major depressive disorder (MDD) is a leading cause of suicide in the world. Monoamine-based antidepressant drugs are a primary line of treatment for this mental disorder, although the delayed response and incomplete efficacy in some patients highlight the need for improved therapeutic approaches. Over the past two decades, ketamine has shown rapid onset with sustained (up to several days) antidepressant effects in patients whose MDD has not responded to conventional antidepressant drugs. Recent preclinical studies have started to elucidate the underlying mechanisms of ketamine's antidepressant properties. Herein, we describe and compare recent clinical and preclinical findings to provide a broad perspective of the relevant mechanisms for the antidepressant action of ketamine.
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Affiliation(s)
- Ji-Woon Kim
- Department of Pharmacology, School of Medicine, Vanderbilt University, Nashville, Tennessee, USA;
- College of Pharmacy, Kyung Hee University, Seoul, Republic of Korea
- Department of Regulatory Science, Graduate School, Kyung Hee University, Seoul, Republic of Korea
- Institute of Regulatory Innovation through Science, Kyung Hee University, Seoul, Republic of Korea
| | - Kanzo Suzuki
- Department of Pharmacology, School of Medicine, Vanderbilt University, Nashville, Tennessee, USA;
- Department of Biological Science and Technology, Faculty of Advanced Engineering, Tokyo University of Science, Katsushika-ku, Tokyo, Japan
| | - Ege T Kavalali
- Department of Pharmacology, School of Medicine, Vanderbilt University, Nashville, Tennessee, USA;
| | - Lisa M Monteggia
- Department of Pharmacology, School of Medicine, Vanderbilt University, Nashville, Tennessee, USA;
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Zhou JJ, Shao JY, Chen SR, Pan HL. Brain α2δ-1-Bound NMDA Receptors Drive Calcineurin Inhibitor-Induced Hypertension. Circ Res 2023; 133:611-627. [PMID: 37605933 PMCID: PMC10529656 DOI: 10.1161/circresaha.123.322562] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2023] [Accepted: 08/09/2023] [Indexed: 08/23/2023]
Abstract
BACKGROUND Calcineurin is highly enriched in immune T cells and the nervous system. Calcineurin inhibitors, including cyclosporine and tacrolimus (FK506), are the cornerstone of immunosuppressive regimens for preserving transplanted organs and tissues. However, these drugs often cause persistent hypertension owing to excess sympathetic outflow, which is maintained by N-methyl-D-aspartate receptor (NMDAR)-mediated excitatory input to the hypothalamic paraventricular nucleus (PVN). It is unclear how calcineurin inhibitors increase NMDAR activity in the PVN to augment sympathetic vasomotor activity. α2δ-1 (encoded by the Cacna2d1 gene), known colloquially as a calcium channel subunit, is a newly discovered NMDAR-interacting protein. In this study, we determined whether α2δ-1 plays a role in calcineurin inhibitor-induced synaptic NMDAR hyperactivity in the PVN and hypertension development. METHODS Immunoblotting and coimmunoprecipitation assays were used to quantify synaptic protein levels and the physical interaction between GluN1 (the obligatory NMDAR subunit) and α2δ-1. Whole-cell patch-clamp recordings of retrogradely labeled, spinally projecting PVN were conducted in perfused brain slices to measure presynaptic and postsynaptic NMDAR activity. Radio-telemetry was implanted in rodents to continuously record arterial blood pressure in conscious states. RESULTS Prolonged treatment with FK506 in rats significantly increased protein levels of α2δ-1, GluN1, and the α2δ-1-GluN1 complex in PVN synaptosomes. These effects were blocked by inhibiting α2δ-1 with gabapentin or interrupting the α2δ-1-NMDAR interaction with an α2δ-1 C-terminus peptide. Treatment with FK506 potentiated the activity of presynaptic and postsynaptic NMDARs in spinally projecting PVN neurons; such effects were abolished by gabapentin, Cacna2d1 knockout, or α2δ-1 C-terminus peptide. Furthermore, microinjection of α2δ-1 C-terminus peptide into the PVN diminished renal sympathetic nerve discharges and arterial blood pressure that had been increased by FK506 treatment. Remarkably, concurrent administration of gabapentin prevented the development of FK506-induced hypertension in rats. Additionally, FK506 treatment induced sustained hypertension in wild-type mice but not in Cacna2d1 knockout mice. CONCLUSIONS α2δ-1 is essential for calcineurin inhibitor-induced increases in synaptic NMDAR activity in PVN presympathetic neurons and sympathetic outflow. Thus, α2δ-1 and α2δ-1-bound NMDARs represent new targets for treating calcineurin inhibitor-induced hypertension. Gabapentinoids (gabapentin and pregabalin) could be repurposed for treating calcineurin inhibitor-induced neurogenic hypertension.
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Affiliation(s)
- Jing-Jing Zhou
- Center for Neuroscience and Pain Research, Department of Anesthesiology and Perioperative Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA
| | - Jian-Ying Shao
- Center for Neuroscience and Pain Research, Department of Anesthesiology and Perioperative Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA
| | - Shao-Rui Chen
- Center for Neuroscience and Pain Research, Department of Anesthesiology and Perioperative Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA
| | - Hui-Lin Pan
- Center for Neuroscience and Pain Research, Department of Anesthesiology and Perioperative Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA
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Zhou JJ, Shao JY, Chen SR, Pan HL. Calcineurin Controls Hypothalamic NMDA Receptor Activity and Sympathetic Outflow. Circ Res 2022; 131:345-360. [PMID: 35862168 PMCID: PMC9357136 DOI: 10.1161/circresaha.122.320976] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Rationale:
Hypertension is a common and serious adverse effect of calcineurin inhibitors, including cyclosporine and tacrolimus (FK506). Although increased sympathetic nerve discharges are associated with calcineurin inhibitor–induced hypertension, the sources of excess sympathetic outflow and underlying mechanisms remain elusive. Calcineurin (protein phosphatase-2B) is broadly expressed in the brain, including the paraventricular nuclear (PVN) of the hypothalamus, which is critically involved in regulating sympathetic vasomotor tone.
Objective:
We determined whether prolonged treatment with the calcineurin inhibitor causes elevated sympathetic output and persistent hypertension by potentiating synaptic N-methyl-D-aspartate (NMDA) receptor activity in the PVN.
Methods and Results:
Telemetry recordings showed that systemic administration of FK506 (3 mg/kg per day) for 14 days caused a gradual and profound increase in arterial blood pressure in rats, which lasted at least 7 days after discontinuing FK506 treatment. Correspondingly, systemic treatment with FK506 markedly reduced calcineurin activity in the PVN and circumventricular organs, but not rostral ventrolateral medulla, and increased the phosphorylation level and synaptic trafficking of NMDA receptors in the PVN. Immunocytochemistry labeling showed that calcineurin was expressed in presympathetic neurons in the PVN. Whole-cell patch-clamp recordings in brain slices revealed that treatment with FK506 increased baseline firing activity of PVN presympathetic neurons; this increase was blocked by the NMDA or α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor antagonist. Also, treatment with FK506 markedly increased presynaptic and postsynaptic NMDA receptor activity of PVN presympathetic neurons. Furthermore, microinjection of the NMDA or α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor antagonist into the PVN of anesthetized rats preferentially attenuated renal sympathetic nerve discharges and blood pressure elevated by FK506 treatment. In addition, systemic administration of memantine, a clinically used NMDA receptor antagonist, effectively attenuated FK506 treatment–induced hypertension in conscious rats.
Conclusions:
Our findings reveal that normal calcineurin activity in the PVN constitutively restricts sympathetic vasomotor tone via suppressing NMDA receptor activity, which may be targeted for treating calcineurin inhibitor–induced hypertension.
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Affiliation(s)
- Jing-Jing Zhou
- Center for Neuroscience and Pain Research, Department of Anesthesiology and Perioperative Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Jian-Ying Shao
- Center for Neuroscience and Pain Research, Department of Anesthesiology and Perioperative Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Shao-Rui Chen
- Center for Neuroscience and Pain Research, Department of Anesthesiology and Perioperative Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Hui-Lin Pan
- Center for Neuroscience and Pain Research, Department of Anesthesiology and Perioperative Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX
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Dalla C, Pavlidi P, Sakelliadou DG, Grammatikopoulou T, Kokras N. Sex Differences in Blood–Brain Barrier Transport of Psychotropic Drugs. Front Behav Neurosci 2022; 16:844916. [PMID: 35677576 PMCID: PMC9169874 DOI: 10.3389/fnbeh.2022.844916] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2021] [Accepted: 04/27/2022] [Indexed: 11/13/2022] Open
Abstract
Treatment of neuropsychiatric disorders relies on the effective delivery of therapeutic molecules to the target organ, the brain. The blood–brain barrier (BBB) hinders such delivery and proteins acting as transporters actively regulate the influx and importantly the efflux of both endo- and xeno-biotics (including medicines). Neuropsychiatric disorders are also characterized by important sex differences, and accumulating evidence supports sex differences in the pharmacokinetics and pharmacodynamics of many drugs that act on the brain. In this minireview we gather preclinical and clinical findings on how sex and sex hormones can influence the activity of those BBB transporter systems and affect the brain pharmacokinetics of psychotropic medicines. It emerges that it is not well understood which psychotropics are substrates for each of the many and not well-studied brain transporters. Indeed, most evidence originates from studies performed in peripheral tissues, such as the liver and the kidneys. None withstanding, accumulated evidence supports the existence of several sex differences in expression and activity of transport proteins, and a further modulating role of gonadal hormones. It is proposed that a closer study of sex differences in the active influx and efflux of psychotropics from the brain may provide a better understanding of sex-dependent brain pharmacokinetics and pharmacodynamics of psychotropic medicines.
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Affiliation(s)
- Christina Dalla
- Department of Pharmacology, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Pavlina Pavlidi
- Department of Pharmacology, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Danai-Georgia Sakelliadou
- Department of Pharmacology, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Tatiana Grammatikopoulou
- Department of Pharmacology, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Nikolaos Kokras
- Department of Pharmacology, Medical School, National and Kapodistrian University of Athens, Athens, Greece
- First Department of Psychiatry, Eginition Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece
- *Correspondence: Nikolaos Kokras,
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Eng ME, Bloise E, Matthews SG. Fetal glucocorticoid exposure leads to sex-specific changes in drug-transporter function at the blood-brain barrier in juvenile guinea pigs. FASEB J 2022; 36:e22245. [PMID: 35262963 PMCID: PMC9311705 DOI: 10.1096/fj.202101552rr] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2021] [Revised: 02/17/2022] [Accepted: 02/22/2022] [Indexed: 11/18/2022]
Abstract
Antenatal synthetic glucocorticoids (sGCs) are a life‐saving treatment in managing pre‐term birth. However, off‐target effects of sGCs can impact blood‐brain barrier (BBB) drug transporters essential for fetal brain protection, including P‐glycoprotein (P‐gp/Abcb1) and breast cancer resistance protein (BCRP/Abcg2). We hypothesized that maternal antenatal sGC treatment modifies BBB function in juvenile offspring in a sex‐dependent manner. Thus, the objective of this study was to determine the long‐term impact of a single or multiple courses of betamethasone on P‐gp/Abcb1 and BCRP/Abcg2 expression and function at the BBB. Pregnant guinea pigs (N = 42) received 3 courses (gestation days (GDs) 40, 50, and 60) or a single course (GD50) of betamethasone (1 mg/kg) or vehicle (saline). Cerebral microvessels and brain endothelial cells (BEC) were collected from the post‐natal day (PND) 14 offspring to measure protein, gene expression, and function of the drug transporters P‐gp/Abcb1 and BCRP/Abcg2. P‐gp protein expression was decreased (p < .05) in microvessels from male offspring that had been exposed to multiple courses and a single course of sGC, in utero. Multiple courses of sGC resulted in a significant decrease in P‐gp function in BECs from males (p < .05), but not females. There was a very strong trend for increased P‐gp function in males compared to females (p = .055). Reduced P‐gp expression and function at the BBB of young male offspring following multiple prenatal sGC exposures, is clinically relevant as many drugs administered postnatally are P‐gp substrates. These novel sex differences in drug transporter function may underlie potential sexual dimorphism in drug sensitivity and toxicity in the newborn and juvenile brain.
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Affiliation(s)
- Margaret Elizabeth Eng
- Department of Physiology, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Enrrico Bloise
- Department of Morphology, Federal University of Minas Gerais, Belo Horizonte, Brazil
| | - Stephen G Matthews
- Department of Physiology, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.,Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario, Canada.,Department of Obstetrics and Gynecology, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.,Department of Medicine, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
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Wang Y, Zheng Y, Wen J, Ren J, Yuan X, Yang T, Hu J. Cyclosporine A-related neurotoxicity after haploidentical hematopoietic stem cell transplantation in children with hematopathy. Ital J Pediatr 2021; 47:83. [PMID: 33794964 PMCID: PMC8017700 DOI: 10.1186/s13052-021-01037-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/24/2020] [Accepted: 03/23/2021] [Indexed: 12/02/2022] Open
Abstract
Background To evaluate cyclosporine A (CSA)-related neurotoxicity after haploidentical hematopoietic stem cell transplantation (HID-HSCT) in children with hematopathy. Methods This retrospective case series study included children with hematopathy who underwent HID-HSCT at Fujian Medical University Union Hospital between February 2013 and January 2017. Results Fifty-one children (39 males) were included in the study with a median age of 8 (range, 1.1–18) years. Seven patients (13.7%) developed CSA-related neurotoxicity after a median 38 (range, − 3 to 161) days from HID-HSCT. Hypertension (5/7, 71%) was the most common prodrome. Brain magnetic resonance imaging showed posterior reversible encephalopathy syndrome in six patients and atypical abnormalities in one patient. One patient died from grade IV graft-versus-host disease (GvHD) on day + 160, and six patients were alive at the last follow-up. Four patients (71.4%) achieved complete remission, while two patients developed secondary epilepsy and exhibited persistent MRI and electroencephalogram abnormalities at the 5-year follow-up. Hypertension after CSA was more common in patients with CSA-related neurotoxicity than in those without (71% vs. 11%, P = 0.002). Five-year overall survival did not differ significantly between patients with CSA-related neurotoxicity (85.7 ± 13.2%) and those without (65.8 ± 7.2%). Conclusions The incidence of CSA-related neurotoxicity in children with hematopathy undergoing HID-HSCT is relatively high.
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Affiliation(s)
- Yong Wang
- Department of Pediatric, Fujian Medical University Union Hospital, No. 29 Xinquan Road, Gulou District, Fuzhou City, Fujian Province, China
| | - Yongzhi Zheng
- Department of Hematology, Fujian Institute of Hematology, Fujian Provincial Key Laboratory of Hematology, Fujian Medical University Union Hospital, No. 29 Xinquan Road, Gulou District, Fuzhou City, Fujian Province, China
| | - Jingjing Wen
- Department of Hematology, Fujian Institute of Hematology, Fujian Provincial Key Laboratory of Hematology, Fujian Medical University Union Hospital, No. 29 Xinquan Road, Gulou District, Fuzhou City, Fujian Province, China
| | - Jinhua Ren
- Department of Hematology, Fujian Institute of Hematology, Fujian Provincial Key Laboratory of Hematology, Fujian Medical University Union Hospital, No. 29 Xinquan Road, Gulou District, Fuzhou City, Fujian Province, China
| | - Xiaohong Yuan
- Department of Hematology, Fujian Institute of Hematology, Fujian Provincial Key Laboratory of Hematology, Fujian Medical University Union Hospital, No. 29 Xinquan Road, Gulou District, Fuzhou City, Fujian Province, China
| | - Ting Yang
- Department of Hematology, Fujian Institute of Hematology, Fujian Provincial Key Laboratory of Hematology, Fujian Medical University Union Hospital, No. 29 Xinquan Road, Gulou District, Fuzhou City, Fujian Province, China.
| | - Jianda Hu
- Department of Hematology, Fujian Institute of Hematology, Fujian Provincial Key Laboratory of Hematology, Fujian Medical University Union Hospital, No. 29 Xinquan Road, Gulou District, Fuzhou City, Fujian Province, China.
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11
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Abdallah CG, Averill LA, Gueorguieva R, Goktas S, Purohit P, Ranganathan M, Sherif M, Ahn KH, D'Souza DC, Formica R, Southwick SM, Duman RS, Sanacora G, Krystal JH. Modulation of the antidepressant effects of ketamine by the mTORC1 inhibitor rapamycin. Neuropsychopharmacology 2020; 45:990-997. [PMID: 32092760 PMCID: PMC7162891 DOI: 10.1038/s41386-020-0644-9] [Citation(s) in RCA: 126] [Impact Index Per Article: 25.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2019] [Revised: 01/08/2020] [Accepted: 02/12/2020] [Indexed: 02/08/2023]
Abstract
Twenty-four hours after administration, ketamine exerts rapid and robust antidepressant effects that are thought to be mediated by activation of the mechanistic target of rapamycin complex 1 (mTORC1). To test this hypothesis, depressed patients were pretreated with rapamycin, an mTORC1 inhibitor, prior to receiving ketamine. Twenty patients suffering a major depressive episode were randomized to pretreatment with oral rapamycin (6 mg) or placebo 2 h prior to the intravenous administration of ketamine 0.5 mg/kg in a double-blind cross-over design with treatment days separated by at least 2 weeks. Depression severity was assessed using Montgomery-Åsberg Depression Rating Scale (MADRS). Rapamycin pretreatment did not alter the antidepressant effects of ketamine at the 24-h timepoint. Over the subsequent 2-weeks, we found a significant treatment by time interaction (F(8,245) = 2.02, p = 0.04), suggesting a prolongation of the antidepressant effects of ketamine by rapamycin. Two weeks following ketamine administration, we found higher response (41%) and remission rates (29%) following rapamycin + ketamine compared to placebo + ketamine (13%, p = 0.04, and 7%, p = 0.003, respectively). In summary, single dose rapamycin pretreatment failed to block the antidepressant effects of ketamine, but it prolonged ketamine's antidepressant effects. This observation raises questions about the role of systemic vs. local blockade of mTORC1 in the antidepressant effects of ketamine, provides preliminary evidence that rapamycin may extend the benefits of ketamine, and thereby potentially sheds light on mechanisms that contribute to depression relapse after ketamine administration.
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Affiliation(s)
- Chadi G Abdallah
- National Center for PTSD - Clinical Neurosciences Division, US Department of Veterans Affairs, West Haven, CT, USA.
- Departments of Psychiatry, Neuroscience, and Psychology Yale University, New Haven, CT, USA.
| | - Lynnette A Averill
- National Center for PTSD - Clinical Neurosciences Division, US Department of Veterans Affairs, West Haven, CT, USA
- Departments of Psychiatry, Neuroscience, and Psychology Yale University, New Haven, CT, USA
| | - Ralitza Gueorguieva
- Department of Biostatistics, Yale University School of Public Health, New Haven, CT, USA
| | - Selin Goktas
- National Center for PTSD - Clinical Neurosciences Division, US Department of Veterans Affairs, West Haven, CT, USA
- Departments of Psychiatry, Neuroscience, and Psychology Yale University, New Haven, CT, USA
| | - Prerana Purohit
- National Center for PTSD - Clinical Neurosciences Division, US Department of Veterans Affairs, West Haven, CT, USA
- Departments of Psychiatry, Neuroscience, and Psychology Yale University, New Haven, CT, USA
| | - Mohini Ranganathan
- Departments of Psychiatry, Neuroscience, and Psychology Yale University, New Haven, CT, USA
| | - Mohamed Sherif
- Departments of Psychiatry, Neuroscience, and Psychology Yale University, New Haven, CT, USA
| | - Kyung-Heup Ahn
- Departments of Psychiatry, Neuroscience, and Psychology Yale University, New Haven, CT, USA
| | - Deepak Cyril D'Souza
- Departments of Psychiatry, Neuroscience, and Psychology Yale University, New Haven, CT, USA
| | - Richard Formica
- Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA
| | - Steven M Southwick
- National Center for PTSD - Clinical Neurosciences Division, US Department of Veterans Affairs, West Haven, CT, USA
- Departments of Psychiatry, Neuroscience, and Psychology Yale University, New Haven, CT, USA
| | - Ronald S Duman
- National Center for PTSD - Clinical Neurosciences Division, US Department of Veterans Affairs, West Haven, CT, USA
- Departments of Psychiatry, Neuroscience, and Psychology Yale University, New Haven, CT, USA
| | - Gerard Sanacora
- National Center for PTSD - Clinical Neurosciences Division, US Department of Veterans Affairs, West Haven, CT, USA
- Departments of Psychiatry, Neuroscience, and Psychology Yale University, New Haven, CT, USA
| | - John H Krystal
- National Center for PTSD - Clinical Neurosciences Division, US Department of Veterans Affairs, West Haven, CT, USA
- Departments of Psychiatry, Neuroscience, and Psychology Yale University, New Haven, CT, USA
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12
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Calcineurin signaling as a target for the treatment of alcohol abuse and neuroinflammatory disorders. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2019. [PMID: 31601401 DOI: 10.1016/bs.pmbts.2019.06.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/28/2023]
Abstract
Converging lines of evidence point to a significant role of neuroinflammation in a host of psychiatric conditions, including alcohol use disorder, TBI, and PTSD. A complex interaction of both peripheral and central signaling underlies processes involved in neuroinflammation. Calcineurin is a molecule that sits at the nexus of these processes and has been clearly linked to a number of psychiatric disorders including alcohol use disorder (AUD). Like its role in regulating peripheral immune cells, calcineurin (CN) plays an integral role in processes regulating neuroimmune function and neuroinflammatory processes. Targeting CN or elements of its signaling pathways at critical points may aid in the functional recovery from neuroinflammatory related disorders. In this review we will highlight the role of neuroinflammation and calcineurin signaling in AUD, TBI and stress-induced disorders and discuss recent findings demonstrating a therapeutic effect of immunosuppressant-induced calcineurin inhibition in a pre-clinical model of binge alcohol drinking.
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13
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Chellappa K, Brinkman JA, Mukherjee S, Morrison M, Alotaibi MI, Carbajal KA, Alhadeff AL, Perron IJ, Yao R, Purdy CS, DeFelice DM, Wakai MH, Tomasiewicz J, Lin A, Meyer E, Peng Y, Arriola Apelo SI, Puglielli L, Betley JN, Paschos GK, Baur JA, Lamming DW. Hypothalamic mTORC2 is essential for metabolic health and longevity. Aging Cell 2019; 18:e13014. [PMID: 31373126 PMCID: PMC6718533 DOI: 10.1111/acel.13014] [Citation(s) in RCA: 46] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2018] [Revised: 05/26/2019] [Accepted: 07/03/2019] [Indexed: 12/16/2022] Open
Abstract
The mechanistic target of rapamycin (mTOR) is an evolutionarily conserved protein kinase that regulates growth and metabolism. mTOR is found in two protein complexes, mTORC1 and mTORC2, that have distinct components and substrates and are both inhibited by rapamycin, a macrolide drug that robustly extends lifespan in multiple species including worms and mice. Although the beneficial effect of rapamycin on longevity is generally attributed to reduced mTORC1 signaling, disruption of mTORC2 signaling can also influence the longevity of worms, either positively or negatively depending on the temperature and food source. Here, we show that loss of hypothalamic mTORC2 signaling in mice decreases activity level, increases the set point for adiposity, and renders the animals susceptible to diet-induced obesity. Hypothalamic mTORC2 signaling normally increases with age, and mice lacking this pathway display higher fat mass and impaired glucose homeostasis throughout life, become more frail with age, and have decreased overall survival. We conclude that hypothalamic mTORC2 is essential for the normal metabolic health, fitness, and lifespan of mice. Our results have implications for the use of mTORC2-inhibiting pharmaceuticals in the treatment of brain cancer and diseases of aging.
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Affiliation(s)
- Karthikeyani Chellappa
- Department of Physiology and Institute for Diabetes, Obesity and Metabolism, Perelman School of MedicineUniversity of PennsylvaniaPhiladelphiaPAUSA
| | - Jacqueline A. Brinkman
- Department of MedicineUniversity of Wisconsin‐MadisonMadisonWIUSA
- William S. Middleton Memorial Veterans HospitalMadisonWIUSA
| | - Sarmistha Mukherjee
- Department of Physiology and Institute for Diabetes, Obesity and Metabolism, Perelman School of MedicineUniversity of PennsylvaniaPhiladelphiaPAUSA
| | - Mark Morrison
- Department of MedicineUniversity of Wisconsin‐MadisonMadisonWIUSA
- William S. Middleton Memorial Veterans HospitalMadisonWIUSA
| | - Mohammed I. Alotaibi
- Department of MedicineUniversity of Wisconsin‐MadisonMadisonWIUSA
- William S. Middleton Memorial Veterans HospitalMadisonWIUSA
- Endocrinology and Reproductive Physiology Graduate Training ProgramUniversity of Wisconsin‐MadisonMadisonWIUSA
| | - Kathryn A. Carbajal
- Department of MedicineUniversity of Wisconsin‐MadisonMadisonWIUSA
- William S. Middleton Memorial Veterans HospitalMadisonWIUSA
| | - Amber L. Alhadeff
- Department of Biology, School of Arts and SciencesUniversity of PennsylvaniaPhiladelphiaPAUSA
| | - Isaac J. Perron
- Center for Sleep and Circadian Neurobiology, Perelman School of MedicineUniversity of PennsylvaniaPhiladelphiaPAUSA
| | - Rebecca Yao
- Department of Physiology and Institute for Diabetes, Obesity and Metabolism, Perelman School of MedicineUniversity of PennsylvaniaPhiladelphiaPAUSA
| | - Cole S. Purdy
- Department of Physiology and Institute for Diabetes, Obesity and Metabolism, Perelman School of MedicineUniversity of PennsylvaniaPhiladelphiaPAUSA
| | - Denise M. DeFelice
- Department of Physiology and Institute for Diabetes, Obesity and Metabolism, Perelman School of MedicineUniversity of PennsylvaniaPhiladelphiaPAUSA
| | - Matthew H. Wakai
- Department of MedicineUniversity of Wisconsin‐MadisonMadisonWIUSA
- William S. Middleton Memorial Veterans HospitalMadisonWIUSA
| | - Jay Tomasiewicz
- Department of MedicineUniversity of Wisconsin‐MadisonMadisonWIUSA
| | - Amy Lin
- Department of MedicineUniversity of Wisconsin‐MadisonMadisonWIUSA
- William S. Middleton Memorial Veterans HospitalMadisonWIUSA
- Department of Dairy ScienceUniversity of Wisconsin‐MadisonMadisonWIUSA
| | - Emma Meyer
- Department of MedicineUniversity of Wisconsin‐MadisonMadisonWIUSA
- William S. Middleton Memorial Veterans HospitalMadisonWIUSA
- Department of Dairy ScienceUniversity of Wisconsin‐MadisonMadisonWIUSA
| | - Yajing Peng
- Department of MedicineUniversity of Wisconsin‐MadisonMadisonWIUSA
- William S. Middleton Memorial Veterans HospitalMadisonWIUSA
- Waisman CenterUniversity of Wisconsin‐MadisonMadisonWIUSA
| | - Sebastian I. Arriola Apelo
- Department of MedicineUniversity of Wisconsin‐MadisonMadisonWIUSA
- William S. Middleton Memorial Veterans HospitalMadisonWIUSA
- Department of Dairy ScienceUniversity of Wisconsin‐MadisonMadisonWIUSA
| | - Luigi Puglielli
- Department of MedicineUniversity of Wisconsin‐MadisonMadisonWIUSA
- William S. Middleton Memorial Veterans HospitalMadisonWIUSA
- Waisman CenterUniversity of Wisconsin‐MadisonMadisonWIUSA
| | - J. Nicholas Betley
- Department of Biology, School of Arts and SciencesUniversity of PennsylvaniaPhiladelphiaPAUSA
| | - Georgios K. Paschos
- Center for Sleep and Circadian Neurobiology, Perelman School of MedicineUniversity of PennsylvaniaPhiladelphiaPAUSA
- The Institute for Translational Medicine and Therapeutics, Perelman School of MedicineUniversity of PennsylvaniaPhiladelphiaPAUSA
| | - Joseph A. Baur
- Department of Physiology and Institute for Diabetes, Obesity and Metabolism, Perelman School of MedicineUniversity of PennsylvaniaPhiladelphiaPAUSA
| | - Dudley W. Lamming
- Department of MedicineUniversity of Wisconsin‐MadisonMadisonWIUSA
- William S. Middleton Memorial Veterans HospitalMadisonWIUSA
- Endocrinology and Reproductive Physiology Graduate Training ProgramUniversity of Wisconsin‐MadisonMadisonWIUSA
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14
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Wu Q, Kuca K. Metabolic Pathway of Cyclosporine A and Its Correlation with Nephrotoxicity. Curr Drug Metab 2019; 20:84-90. [DOI: 10.2174/1389200219666181031113505] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2018] [Revised: 10/16/2018] [Accepted: 10/22/2018] [Indexed: 12/15/2022]
Abstract
Background:Cyclosporine A (CsA) is widely used for organ transplantation and autoimmune disorders. However, CsA nephrotoxicity is a serious side effect that limits the clinical use of CsA. The metabolism of CsA has a close relationship with this disease in renal-transplant patients. However, the metabolic pathways of CsA and its metabolizing enzymes have rarely been comprehensively reviewed. In this review, we have summarized the specific metabolic profiles of CsA in humans, especially renal-transplant patients. Moreover, the specific metabolizing enzymes and the potential roles that CsA metabolism plays in CsA nephrotoxicity were summarized and discussed.Methods:Electronic databases including PubMed, Web of Science, and Scifinder were searched with the keywords "Cyclosporine A and metabolism", and "Cyclosporine A and nephrotoxicity", "Cyclosporine A metabolism and nephrotoxicity". All these studies published until 2018 were included in this review.Results:The major metabolic pathways of CsA in humans are hydroxylation and N-demethylation. Normally, these metabolites are relatively less toxic than CsA. However, the metabolism of CsA in the kidneys is much weaker than that in the liver, which explains why CsA is so toxic to the kidneys. CYP3A families, especially CYP3A4 and CYP3A5, play an important role in the biotransformation of CsA. Moreover, increased lines of evidence show that some metabolites (including AM19) associate directly with nephrotoxicity in CsA-treated organ-transplant patients.Conclusion:The findings of this review help to further understand the metabolic activities of CsA in renal-transplant patients and cast some light on the mechanisms of CsA nephrotoxicity.
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Affiliation(s)
- Qinghua Wu
- Department of Chemistry, Faculty of Science, University of Hradec Kralove, Hradec Kralove, Czech Republic
| | - Kamil Kuca
- Department of Chemistry, Faculty of Science, University of Hradec Kralove, Hradec Kralove, Czech Republic
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15
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El-Bassossy HM, Hassanien MA, Bima A, Ghoneim FM, Elsamanoudy AZ. Renal Oxidative Stress and Inflammatory Response in Perinatal Cyclosporine-A Exposed Rat Progeny and its Relation to Gender. J Microsc Ultrastruct 2019; 7:44-49. [PMID: 31008055 PMCID: PMC6442325 DOI: 10.4103/jmau.jmau_52_18] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
Abstract
Background and Aim of the Work: The current study postulated that cyclosporine A (CSA) could induce gender-specific renal damage. Hence, the current study aims to investigate the nephrotoxic effect of perinatal exposure of male and female rat progeny to CSA. Moreover, it aims to evaluate the oxidative stress and inflammation as a possible pathophysiologic mechanism. Materials and Methods: Female rats were randomly allocated to two groups of four and assigned to undergo either CSA (15 mg/kg/day; the 6th day after conception and continuing until the progeny were weaned) or vehicle treatment as control groups. At the age of 6 weeks, the progeny were divided into the following four groups: male progeny of control-group mothers (M-vehicle, 7); male progeny of CSA-treated mothers (M-CSA, 9); female progeny of control-group mothers (F-vehicle, 7); and female progeny of CSA-treated mothers (F-CSA, 6). Serum adiponectin, tumor necrosis factor-α (TNF-α) and creatinine, creatinine clearance, and urinary 8-isoprostane were measured. Histopathological examination by hematoxylin and eosin stain of Kidney was carried out. Results: Proteinuria and decreased creatinine clearance are significant in M-CSA than M-vehicle and F-CSA. 8-isoprostane is lower in F-CSA than F-vehicle. Increased TNF-α and decreased adiponectin levels in M-CSA than M-vehicle were observed. No significant differences were found in female rat groups. Conclusion: From the current study, it could be concluded that CSA could induce renal inflammation as well as oxidative stress that may explain the impaired renal function. The sex difference was a prominent finding in their vulnerability to CSA effects.
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Affiliation(s)
- Hany M El-Bassossy
- Department of Pharmacology, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia.,Department of Pharmacology, Faculty of Pharmacy, Zagazig University, Zagazig, Egypt
| | - Mohammed A Hassanien
- Assessment Centre and Medical Education Department, Fakeeh College for Medical Sciences, Jeddah, Saudi Arabia.,Department of Medical Biochemistry, College of Medicine, Tanta University, Tanta, Egypt
| | - Abdulhadi Bima
- Department of Clinical Biochemistry, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Fatma M Ghoneim
- Department of Medical Histology and Cell Biology, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Ayman Zaky Elsamanoudy
- Department of Clinical Biochemistry, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia.,Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Mansoura University, Mansoura, Egypt
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16
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Serkova NJ, Davis DM, Steiner J, Agarwal R. Quantitative NMR-Based Metabolomics on Tissue Biomarkers and Its Translation into In Vivo Magnetic Resonance Spectroscopy. Methods Mol Biol 2019; 1978:369-387. [PMID: 31119675 DOI: 10.1007/978-1-4939-9236-2_23] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/09/2023]
Abstract
Nuclear magnetic resonance (NMR) spectroscopy is an established analytical platform for analyzing metabolic profiles of cells, tissues, and body fluids. There are several advantages in introducing an NMR-based study design into metabolomics studies, including a fast and comprehensive detection, characterization, and quantification of dozens of endogenous metabolites in a single NMR spectrum. Quantitative proton 1H-NMR is the most useful NMR-based platform for metabolomics. The frozen tissues can be analyzed noninvasively using a high-resolution magic angle spinning (HR-MAS) 1H-NMR spectroscopy; or several extraction techniques can be applied to detect additional metabolites using a conventional liquid-based NMR technique. In this chapter, we report on tissue collection, handling, extraction methods, and 1H-NMR acquisition protocols developed in the past decades for a precise and quantitative NMR-metabolomics approach. The NMR acquisition protocols (both HR-MAS and conventional 1H-NMR spectroscopy) and spectral analysis steps are also presented. Since NMR can be applied "in vivo" using horizontal bore MRI scanners, several in vivo sequences for localized 1H-MRS (magnetic resonance spectroscopy) are presented which can be directly applied for noninvasive detection of brain metabolites.
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Affiliation(s)
- Natalie J Serkova
- Department of Radiology, School of Medicine, University of Colorado Denver, Aurora, CO, USA.
| | - Denise M Davis
- Department of Radiology, School of Medicine, University of Colorado Denver, Aurora, CO, USA
| | - Jenna Steiner
- Department of Radiology, School of Medicine, University of Colorado Denver, Aurora, CO, USA
| | - Rajesh Agarwal
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Denver, Aurora, CO, USA
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17
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Lückemann L, Unteroberdörster M, Kirchhof J, Schedlowski M, Hadamitzky M. Applications and limitations of behaviorally conditioned immunopharmacological responses. Neurobiol Learn Mem 2017; 142:91-98. [PMID: 28216206 DOI: 10.1016/j.nlm.2017.02.012] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2016] [Revised: 02/10/2017] [Accepted: 02/15/2017] [Indexed: 12/17/2022]
Abstract
The importance of placebo responses for the treatment of various medical conditions has increasingly been recognized, whereas knowledge and systematic application in clinical settings are still sparse. One possible application for placebo responses in pharmacotherapy is given by learning paradigms, such as behaviorally conditioned immunosuppression, aiming at drug dose reduction while maintaining therapeutic efficacy of drug treatment. In an established learning paradigm of conditioned taste aversion/avoidance (CTA) in both, rats and humans, respectively, a novel-tasting drinking solution (conditioned stimulus, CS) is paired with an injection of the immunosuppressive drug cyclosporine A (CsA) as unconditioned stimulus (US). The conditioned response, evoked by re-presenting the CS alone at a later time, is reflected by avoidance behavior of consuming the solution (conditioned taste aversion; CTA) and a diminished interleukin (IL)-2 and interferon (IFN)-γ cytokine production as well as mRNA expression of rat splenic T cells or human peripheral T lymphocytes, closely mimicking the immunosuppressive effects of CsA. However, due to unreinforced CS-re-exposure conditioned responses progressively decreases over time (extinction), reflecting a considerable challenge for potential clinical applications of this learned immunosuppression. The present article discusses and critically reviews actual approaches, applications but also limitations of learning paradigms in immune pharmacotherapy.
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Affiliation(s)
- Laura Lückemann
- Institute of Medical Psychology and Behavioral Immunobiology, University Hospital Essen, University of Duisburg-Essen, 45122 Essen, Germany
| | - Meike Unteroberdörster
- Department of Neurosurgery, University Hospital Essen, University of Duisburg-Essen, 45122 Essen, Germany
| | - Julia Kirchhof
- Institute of Medical Psychology and Behavioral Immunobiology, University Hospital Essen, University of Duisburg-Essen, 45122 Essen, Germany
| | - Manfred Schedlowski
- Institute of Medical Psychology and Behavioral Immunobiology, University Hospital Essen, University of Duisburg-Essen, 45122 Essen, Germany
| | - Martin Hadamitzky
- Institute of Medical Psychology and Behavioral Immunobiology, University Hospital Essen, University of Duisburg-Essen, 45122 Essen, Germany.
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18
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Lechpammer M, Tran YP, Wintermark P, Martínez-Cerdeño V, Krishnan VV, Ahmed W, Berman RF, Jensen FE, Nudler E, Zagzag D. Upregulation of cystathionine β-synthase and p70S6K/S6 in neonatal hypoxic ischemic brain injury. Brain Pathol 2016; 27:449-458. [PMID: 27465493 DOI: 10.1111/bpa.12421] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2016] [Accepted: 07/12/2016] [Indexed: 12/20/2022] Open
Abstract
Encephalopathy of prematurity (EOP) is a complex form of cerebral injury that occurs in the setting of hypoxia-ischemia (HI) in premature infants. Using a rat model of EOP, we investigated whether neonatal HI of the brain may alter the expression of cystathionine β-synthase (CBS) and the components of the mammalian target of rapamycin (mTOR) signaling. We performed unilateral carotid ligation and induced HI (UCL/HI) in Long-Evans rats at P6 and found increased CBS expression in white matter (i.e. corpus callosum, cingulum bundle and external capsule) as early as 24 h (P7) postprocedure. CBS remained elevated through P21, and, to a lesser extent, at P40. The mTOR downstream target 70 kDa ribosomal protein S6 kinase (p70S6K and phospho-p70S6K) and 40S ribosomal protein S6 (S6 and phospho-S6) were also overexpressed at the same time points in the UCL/HI rats compared to healthy controls. Overexpression of mTOR components was not observed in rats treated with the mTOR inhibitor everolimus. Behavioral assays performed on young rats (postnatal day 35-37) following UCL/HI at P6 indicated impaired preference for social novelty, a behavior relevant to autism spectrum disorder, and hyperactivity. Everolimus restored behavioral patterns to those observed in healthy controls. A gait analysis has shown that motor deficits in the hind paws of UCL/HI rats were also significantly reduced by everolimus. Our results suggest that neonatal HI brain injury may inflict long-term damage by upregulation of CBS and mTOR signaling. We propose this cascade as a possible new molecular target for EOP-a still untreatable cause of autism, hyperactivity and cerebral palsy.
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Affiliation(s)
- Mirna Lechpammer
- Department of Pathology and Laboratory Medicine, University of California Davis, Sacramento, CA
| | - Yen P Tran
- Department of Pathology and Laboratory Medicine, University of California Davis, Sacramento, CA
| | - Pia Wintermark
- Department of Pediatrics, Division of Newborn Medicine, Montréal Children's Hospital, McGill University, Montréal, QC, Canada
| | - Veronica Martínez-Cerdeño
- Department of Pathology and Laboratory Medicine, University of California Davis, Sacramento, CA.,MIND Institute, University of California Davis, Sacramento, CA.,Institute for Pediatric Regenerative Medicine and Shriners Hospital for Children of Northern California, Sacramento, CA
| | - Viswanathan V Krishnan
- Department of Pathology and Laboratory Medicine, University of California Davis, Sacramento, CA
| | - Waseem Ahmed
- Department of Pathology and Laboratory Medicine, University of California Davis, Sacramento, CA
| | - Robert F Berman
- MIND Institute, University of California Davis, Sacramento, CA.,Department of Neurological Surgery, University of California Davis, Sacramento, CA
| | - Frances E Jensen
- Department of Neurology, University of Pennsylvania, Philadelphia, PA
| | - Evgeny Nudler
- Howard Hughes Medical Institute and Department of Biochemistry, New York University School of Medicine, New York, NY
| | - David Zagzag
- Departments of Pathology and Neurosurgery, Division of Neuropathology, Microvascular and Molecular Neuro-Oncology Laboratory, Perlmutter Cancer Center, New York University Langone Medical Center, New York, NY
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19
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Hadamitzky M, Bösche K, Wirth T, Buck B, Beetz O, Christians U, Schniedewind B, Lückemann L, Güntürkün O, Engler H, Schedlowski M. Memory-updating abrogates extinction of learned immunosuppression. Brain Behav Immun 2016; 52:40-48. [PMID: 26386321 DOI: 10.1016/j.bbi.2015.09.009] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/20/2015] [Revised: 09/09/2015] [Accepted: 09/16/2015] [Indexed: 10/23/2022] Open
Abstract
When memories are recalled, they enter a transient labile phase in which they can be impaired or enhanced followed by a new stabilization process termed reconsolidation. It is unknown, however, whether reconsolidation is restricted to neurocognitive processes such as fear memories or can be extended to peripheral physiological functions as well. Here, we show in a paradigm of behaviorally conditioned taste aversion in rats memory-updating in learned immunosuppression. The administration of sub-therapeutic doses of the immunosuppressant cyclosporin A together with the conditioned stimulus (CS/saccharin) during retrieval blocked extinction of conditioned taste aversion and learned suppression of T cell cytokine (interleukin-2; interferon-γ) production. This conditioned immunosuppression is of clinical relevance since it significantly prolonged the survival time of heterotopically transplanted heart allografts in rats. Collectively, these findings demonstrate that memories can be updated on both neural and behavioral levels as well as on the level of peripheral physiological systems such as immune functioning.
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Affiliation(s)
- Martin Hadamitzky
- Institute of Medical Psychology and Behavioral Immunobiology, University Hospital Essen, University of Duisburg-Essen, 45122 Essen, Germany
| | - Katharina Bösche
- Institute of Medical Psychology and Behavioral Immunobiology, University Hospital Essen, University of Duisburg-Essen, 45122 Essen, Germany
| | - Timo Wirth
- Department of Pedriatric Rheumatology & Immunology, University Children's Hospital Münster, 48149 Münster, Germany
| | - Benjamin Buck
- Department of General, Visceral and Transplant Surgery, Hannover Medical School, 30625 Hannover, Germany
| | - Oliver Beetz
- Department of General, Visceral and Transplant Surgery, Hannover Medical School, 30625 Hannover, Germany
| | - Uwe Christians
- Clinical Research and Development, Department of Anesthesiology, University of Colorado, Aurora, CO 80045-7503, USA
| | - Björn Schniedewind
- Clinical Research and Development, Department of Anesthesiology, University of Colorado, Aurora, CO 80045-7503, USA
| | - Laura Lückemann
- Institute of Medical Psychology and Behavioral Immunobiology, University Hospital Essen, University of Duisburg-Essen, 45122 Essen, Germany
| | - Onur Güntürkün
- Department of Biopsychology, Faculty of Psychology, Ruhr-University Bochum, 44780 Bochum, Germany
| | - Harald Engler
- Institute of Medical Psychology and Behavioral Immunobiology, University Hospital Essen, University of Duisburg-Essen, 45122 Essen, Germany
| | - Manfred Schedlowski
- Institute of Medical Psychology and Behavioral Immunobiology, University Hospital Essen, University of Duisburg-Essen, 45122 Essen, Germany.
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Posterior Reversible Encephalopathy Syndrome After Transplantation: a Review. Mol Neurobiol 2015; 53:6897-6909. [PMID: 26666662 DOI: 10.1007/s12035-015-9560-0] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2015] [Accepted: 11/29/2015] [Indexed: 12/29/2022]
Abstract
Posterior reversible encephalopathy syndrome (PRES) is a rare neurological disease. Recently, an increase in the number of transplantations has led to more cases being associated with PRES than what was previously reported. Calcineurin inhibitors (CNIs) are major risk factors for PRES in posttransplantation patients. The mechanisms of the development of PRES remain to be unclear. The typical clinical symptoms of PRES include seizures, acute encephalopathy syndrome, and visual symptoms. The hyperintense signal on fluid-attenuated inversion recovery image is the characteristic of the imaging appearance in these patients. In addition, other abnormal signals distributed in multiple locations are also reported in some atypical cases. Unfortunately, PRES is often not recognized or diagnosed too late due to complicated differential diagnoses, such as ischemic stroke, progressive multifocal leukoencephalopathy, and neurodegenerative diseases. Thus, this review emphasizes the importance of considering the possibility of PRES when neurological disturbances appear after solid organ transplantation or hematopoietic cell transplantation. Moreover, this review demonstrates the molecular mechanisms of PRES associated with CNIs after transplantation, which aims to help clinicians further understand PRES in the transplantation era.
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Chen LW, Chen JS, Tu YF, Wang ST, Wang LW, Tsai YS, Huang CC. Age-dependent vulnerability of cyclosporine-associated encephalopathy in children. Eur J Paediatr Neurol 2015; 19:464-71. [PMID: 25769225 DOI: 10.1016/j.ejpn.2015.02.003] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2014] [Revised: 02/06/2015] [Accepted: 02/20/2015] [Indexed: 01/08/2023]
Abstract
INTRODUCTION Cyclosporine (CsA) is an immunosuppressant known for its neurotoxicity, which presents with acute encephalopathy and seizures in the most severe form. However, whether there is age-related neurological susceptibility in pediatric population is poorly defined. The study aims to examine the vulnerability of CsA neurotoxicity among different age groups of pediatric patients in terms of occurrence rate, acute presentations, long-term outcomes, and neuroimaging findings. METHODS Pediatric patients (age <18 years) who received CsA in a tertiary referral center between July 1, 1988 and August 31, 2011 were retrospectively reviewed for CsA-related encephalopathy. The clinical presentations, demographic data, and laboratory examinations were analyzed through t-test for numerical and Fisher's exact test for categorical variables. Exact logistic regression was used to examine the effect of each variables. RESULTS Twelve (8%) of the enrolled 146 patients developed CsA-induced encephalopathy. Compared to the non-neurotoxicity group, the neurotoxicity group was significantly younger upon starting CsA (p = 0.008) and had higher percentages of hypertension after CsA treatment (p = 0.01). Regression analysis showed that age <6 years (OR 7.6, 95% CI 1.6-51.5; p = 0.007) and hypertension after CsA (OR 6.3, 95% CI 1.4-35.4; p = 0.016) were significantly associated with CsA encephalopathy. Younger children were prone to have more severe seizures in the acute stage and more epilepsy and neuropsychiatric disorders in the future. Follow-up neuroimaging showed parietal cerebral atrophy in all examined children <6 years of age. CONCLUSIONS Age-dependent susceptibility of CsA neurotoxicity occurs in children, with severe acute presentations and long-term sequelae in children below 6 years old.
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Affiliation(s)
- Li-Wen Chen
- Department of Pediatrics, National Cheng Kung University Hospital and College of Medicine, Tainan, Taiwan
| | - Jiann-Shiuh Chen
- Department of Pediatrics, National Cheng Kung University Hospital and College of Medicine, Tainan, Taiwan
| | - Yi-Fang Tu
- Department of Pediatrics, National Cheng Kung University Hospital and College of Medicine, Tainan, Taiwan
| | - Shan-Tair Wang
- Institute of Gerontology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Lan-Wan Wang
- Department of Pediatrics, Chi Mei Medical Center, Tainan, Taiwan; Department of Pediatrics, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Yi-Shan Tsai
- Department of Diagnostic Radiology, National Cheng Kung University Hospital and College of Medicine, Tainan, Taiwan
| | - Chao-Ching Huang
- Department of Pediatrics, National Cheng Kung University Hospital and College of Medicine, Tainan, Taiwan; Department of Pediatrics, College of Medicine, Taipei Medical University, Taipei, Taiwan; Department of Pediatrics, Wan-Fang Hospital, Taipei Medical University, Taipei, Taiwan.
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Handreck A, Mall EM, Elger DA, Gey L, Gernert M. Different preparations, doses, and treatment regimens of cyclosporine A cause adverse effects but no robust changes in seizure thresholds in rats. Epilepsy Res 2015; 112:1-17. [DOI: 10.1016/j.eplepsyres.2015.02.006] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2014] [Revised: 11/27/2014] [Accepted: 02/04/2015] [Indexed: 10/24/2022]
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Klawitter J, Nashan B, Christians U. Everolimus and sirolimus in transplantation-related but different. Expert Opin Drug Saf 2015; 14:1055-70. [PMID: 25912929 DOI: 10.1517/14740338.2015.1040388] [Citation(s) in RCA: 123] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
INTRODUCTION The inhibitors of the mammalian target of rapamycin (mTOR) sirolimus and everolimus are used not only as immunosuppressants after organ transplantation in combination with calcineurin inhibitors (CNIs) but also as proliferation signal inhibitors coated on drug-eluting stents and in cancer therapy. Notwithstanding their related chemical structures, both have distinct pharmacokinetic, pharmacodynamic and toxicodynamic properties. AREAS COVERED The additional hydroxyethyl group at the C(40) of the everolimus molecule results in different tissue and subcellular distribution, different affinities to active drug transporters and drug-metabolizing enzymes as well as differences in drug-target protein interactions including a much higher potency in terms of interacting with the mTOR complex 2 than sirolimus. Said mechanistic differences as well as differences found in clinical trials in transplant patients are reviewed. EXPERT OPINION In comparison to sirolimus, everolimus has higher bioavailability, a shorter terminal half-life, different blood metabolite patterns, the potential to antagonize the negative effects of CNIs on neuronal and kidney cell metabolism (which sirolimus enhances), the ability to stimulate mitochondrial oxidation (which sirolimus inhibits) and to reduce vascular inflammation to a greater extent. A head-to-head, randomized trial comparing the safety and tolerability of these two mTOR inhibitors in solid organ transplant recipients is merited.
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Affiliation(s)
- Jost Klawitter
- University of Colorado, iC42 Clinical Research and Development , Anschutz Medical Campus, 1999 North Fitzsimons Parkway, Suite 100, Aurora, CO 80045-7503 , USA +1 303 724 5665 ; +1 303 724 5662 ;
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Giovagnoli S, Cassano T, Pace L, Magini A, Polchi A, Tancini B, Perluigi M, De Marco F, Emiliani C, Dolcetta D. Evaluation of a LC–MS method for everolimus preclinical determination in brain by using [13C2D4]RAD001 internal standard. J Chromatogr B Analyt Technol Biomed Life Sci 2015; 985:155-63. [DOI: 10.1016/j.jchromb.2015.01.035] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2014] [Revised: 01/20/2015] [Accepted: 01/24/2015] [Indexed: 12/15/2022]
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El-Gowelli HM, El-Mas MM. Central modulation of cyclosporine-induced hypertension. Naunyn Schmiedebergs Arch Pharmacol 2014; 388:351-61. [DOI: 10.1007/s00210-014-1074-1] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2014] [Accepted: 11/18/2014] [Indexed: 12/25/2022]
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Larsen RH, Kjær MS, Eefsen M, Larsen FS, Bjerring PN. Ciclosporin does not attenuate intracranial hypertension in rats with acute hyperammonaemia. World J Hepatol 2013; 5:513-520. [PMID: 24073303 PMCID: PMC3782689 DOI: 10.4254/wjh.v5.i9.513] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2013] [Revised: 06/08/2013] [Accepted: 08/20/2013] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the neuroprotective potential of ciclosporin during acute liver failure. We evaluated the effect of intrathecally administered ciclosporin on intracranial pressure, brain water content and aquaporin-4 expression in a rat model with acute hyperammonaemia.
METHODS: Twenty-four male Wistar rats with portacaval anastomosis were randomised into four groups receiving ciclosporin or vehicle and ammonia or saline infusion. Ciclosporin or vehicle was given intrathecally prior to the ammonia or saline infusion. The ammonia or saline infusion was given intravenously for 4 h, while intracranial pressure and arterial pressure was recorded. At the end of the experiment, cerebral cortex and cerebellar brain tissue was analysed for water and aquaporin-4 content.
RESULTS: The following intracranial pressures were found at the end of the experiment: ammonia + ciclosporin: 10.0 ± 1.7 mmHg, ammonia + vehicle: 6.8 ± 1.0 mmHg, saline + ciclosporin: 3.1 ± 0.5 mmHg, saline + vehicle: 3.3 ± 0.6 mmHg. Ammonia infusion had a significant effect on intracranial pressure and brain water content, which both were higher in the groups receiving ammonia (P < 0.001, two-way analysis of variance). Treatment with ciclosporin resulted in relevant tissue concentrations of ciclosporin (> 0.2 micromolar) but did not reduce intracranial pressure after 4 h. Furthermore, ciclosporin did not attenuate the increase in cerebral water content, and did not affect aquaporin-4 expression.
CONCLUSION: Intrathecal administration of ciclosporin does not attenuate intracranial hypertension or brain oedema in rats with portacaval anastomosis and 4 h of ammonia infusion.
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Radu BM, Bramanti P, Osculati F, Flonta ML, Radu M, Bertini G, Fabene PF. Neurovascular unit in chronic pain. Mediators Inflamm 2013; 2013:648268. [PMID: 23840097 PMCID: PMC3687484 DOI: 10.1155/2013/648268] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2013] [Accepted: 05/08/2013] [Indexed: 12/27/2022] Open
Abstract
Chronic pain is a debilitating condition with major socioeconomic impact, whose neurobiological basis is still not clear. An involvement of the neurovascular unit (NVU) has been recently proposed. In particular, the blood-brain barrier (BBB) and blood-spinal cord barrier (BSCB), two NVU key players, may be affected during the development of chronic pain; in particular, transient permeabilization of the barrier is suggested by several inflammatory- and nerve-injury-based pain models, and we argue that the clarification of molecular BBB/BSCB permeabilization events will shed new light in understanding chronic pain mechanisms. Possible biases in experiments supporting this theory and its translational potentials are discussed. Moving beyond an exclusive focus on the role of the endothelium, we propose that our understanding of the mechanisms subserving chronic pain will benefit from the extension of research efforts to the NVU as a whole. In this view, the available evidence on the interaction between analgesic drugs and the NVU is here reviewed. Chronic pain comorbidities, such as neuroinflammatory and neurodegenerative diseases, are also discussed in view of NVU changes, together with innovative pharmacological solutions targeting NVU components in chronic pain treatment.
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Affiliation(s)
- Beatrice Mihaela Radu
- Department of Neurological, Neuropsychological, Morphological and Movement Sciences, Section of Anatomy and Histology, University of Verona, Strada Le Grazie 8, 37134 Verona, Italy
- Department of Anatomy, Animal Physiology and Biophysics, Faculty of Biology, University of Bucharest, 050095 Bucharest, Romania
| | | | | | - Maria-Luisa Flonta
- Department of Anatomy, Animal Physiology and Biophysics, Faculty of Biology, University of Bucharest, 050095 Bucharest, Romania
| | - Mihai Radu
- Department of Neurological, Neuropsychological, Morphological and Movement Sciences, Section of Anatomy and Histology, University of Verona, Strada Le Grazie 8, 37134 Verona, Italy
- Department of Life and Environmental Physics, “Horia Hulubei” National Institute for Physics and Nuclear Engineering, 077125 Bucharest-Magurele, Romania
| | - Giuseppe Bertini
- Department of Neurological, Neuropsychological, Morphological and Movement Sciences, Section of Anatomy and Histology, University of Verona, Strada Le Grazie 8, 37134 Verona, Italy
| | - Paolo Francesco Fabene
- Department of Neurological, Neuropsychological, Morphological and Movement Sciences, Section of Anatomy and Histology, University of Verona, Strada Le Grazie 8, 37134 Verona, Italy
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Wong WT, Dresner S, Forooghian F, Glaser T, Doss L, Zhou M, Cunningham D, Shimel K, Harrington M, Hammel K, Cukras CA, Ferris FL, Chew EY. Treatment of geographic atrophy with subconjunctival sirolimus: results of a phase I/II clinical trial. Invest Ophthalmol Vis Sci 2013; 54:2941-50. [PMID: 23548622 DOI: 10.1167/iovs.13-11650] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
PURPOSE To investigate the safety and effects of subconjunctival sirolimus, an mTOR inhibitor and immunosuppressive agent, for the treatment of geographic atrophy (GA). METHODS The study was a single-center, open-label phase II trial, enrolling 11 participants with bilateral GA; eight participants completed 24 months of follow-up. Sirolimus (440 μg) was administered every 3 months as a subconjunctival injection in only one randomly assigned eye in each participant for 24 months. Fellow eyes served as untreated controls. The primary efficacy outcome measure was the change in the total GA area at 24 months. Secondary outcomes included changes in visual acuity, macular sensitivity, central retinal thickness, and total drusen area. RESULTS The study drug was well tolerated with few symptoms and related adverse events. Study treatment in study eyes was not associated with structural or functional benefits relative to the control fellow eyes. At month 24, mean GA area increased by 54.5% and 39.7% in study and fellow eyes, respectively (P = 0.41), whereas mean visual acuity decreased by 21.0 letters and 3.0 letters in study and fellow eyes, respectively (P = 0.03). Substantial differences in mean changes in drusen area, central retinal thickness, and macular sensitivity were not detected for all analysis time points up to 24 months. CONCLUSIONS Repeated subconjunctival sirolimus was well-tolerated in patients with GA, although no positive anatomic or functional effects were identified. Subconjunctival sirolimus may not be beneficial in the prevention of GA progression, and may potentially be associated with effects detrimental to visual acuity. (ClinicalTrials.gov number, NCT00766649.).
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Affiliation(s)
- Wai T Wong
- Unit on Neuron–Glia Interactions in Retinal Disease, Building 6, Room 215, National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA.
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Abstract
Like other physiological responses, immune functions are the subject of behavioural conditioning. Conditioned immunosuppression can be induced by contingently pairing a novel taste with an injection of the immunosuppressant cyclosporine A (CsA) in an associative learning paradigm. This learned immunosuppression is centrally mediated by the insular cortex and the amygdala. However, the afferent mechanisms by which the brain detects CsA are not understood. In this study we analysed whether CsA is sensed via the chemosensitive vagus nerve or whether CsA directly acts on the brain. Our experiments revealed that a single peripheral administration of CsA increases neuronal activity in the insular cortex and the amygdala as evident from increased electric activity, c-Fos expression and amygdaloid noradrenaline release. However, this increased neuronal activity was not affected by prior vagal deafferentation but rather seems to partially be induced by direct action of CsA on cortico-amygdaloid structures and the chemosensitive brainstem regions area postrema and nucleus of the solitary tract. Together, these data indicate that CsA as an unconditioned stimulus may directly act on the brain by a still unknown transduction mechanism.
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Halleck F, Duerr M, Waiser J, Huber L, Matz M, Brakemeier S, Liefeldt L, Neumayer HH, Budde K. An evaluation of sirolimus in renal transplantation. Expert Opin Drug Metab Toxicol 2012; 8:1337-56. [PMID: 22928953 DOI: 10.1517/17425255.2012.719874] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
INTRODUCTION Sirolimus is a powerful antiproliferative immunosuppressive drug approved for the prevention of kidney allograft rejection. By its unique mechanism of action, sirolimus provides a multitude of clinical potential and has been used effectively in different drug combinations. Extensive experience has been gained regarding the best timing of its application, side effect profile and potential benefits and limitations compared with other immunosuppressive drugs. AREAS COVERED The authors evaluate the recent experience with sirolimus in kidney transplantation. Pivotal randomized controlled trials were used to provide an overview with special attention to pharmacokinetic and dynamic aspects of sirolimus, its current clinical use as well as perspectives for its future role. EXPERT OPINION Sirolimus enriches the possibilities of immunosuppressive therapies after renal transplantation. Beneficial effects toward kidney function by allowing CNI sparing, lower incidence of malignancies and less viral infections have been suggested. Sirolimus should be used cautiously in de novo patients for reasons of wound healing. An early conversion to a sirolimus-based CNI-free regimen has shown promising results, whereas late conversion is more challenging. Finally, sirolimus-associated side effects are causing tolerability concerns and frequent discontinuations. Future research should aim to better define the therapeutic window and those patients most likely to benefit.
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Affiliation(s)
- Fabian Halleck
- Department of Nephrology, Charité Universitätsmedizin, Berlin, Germany.
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Learned Immunosuppression: Extinction, Renewal, and the Challenge of Reconsolidation. J Neuroimmune Pharmacol 2012; 8:180-8. [DOI: 10.1007/s11481-012-9388-6] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2012] [Accepted: 07/04/2012] [Indexed: 12/17/2022]
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Drug Interaction Between Cyclosporine and mTOR Inhibitors in Experimental Model of Chronic Cyclosporine Nephrotoxicity and Pancreatic Islet Dysfunction. Transplantation 2012; 93:383-9. [DOI: 10.1097/tp.0b013e3182421604] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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