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Trimetazidine Modulates Mitochondrial Redox Status and Disrupted Glutamate Homeostasis in a Rat Model of Epilepsy

Mitochondrial oxidative status exerts an important role in modulating glia–neuron interplay during epileptogenesis. Trimetazidine (TMZ), a well-known anti-ischemic drug, has shown promising potential against a wide range of neurodegenerative disorders including epilepsy. Nevertheless, the exact mech...

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Autores principales: Al-Shorbagy, Muhammad Y., Wadie, Walaa, El-Tanbouly, Dalia M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8531497/
https://www.ncbi.nlm.nih.gov/pubmed/34690772
http://dx.doi.org/10.3389/fphar.2021.735165
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author Al-Shorbagy, Muhammad Y.
Wadie, Walaa
El-Tanbouly, Dalia M.
author_facet Al-Shorbagy, Muhammad Y.
Wadie, Walaa
El-Tanbouly, Dalia M.
author_sort Al-Shorbagy, Muhammad Y.
collection PubMed
description Mitochondrial oxidative status exerts an important role in modulating glia–neuron interplay during epileptogenesis. Trimetazidine (TMZ), a well-known anti-ischemic drug, has shown promising potential against a wide range of neurodegenerative disorders including epilepsy. Nevertheless, the exact mechanistic rationale behind its anti-seizure potential has not been fully elucidated yet. Herein, the impact of TMZ against mitochondrial oxidative damage as well as glutamate homeostasis disruption in the hippocampus has been investigated in rats with lithium/pilocarpine (Li/PIL) seizures. Animals received 3 mEq/kg i.p. LiCl(3) followed by PIL (single i.p.; 150 mg/kg) 20 h later for induction of seizures with or without TMZ pretreatment (25 mg/kg; i.p.) for five consecutive days. Seizure score and seizure latency were observed. Mitochondrial redox status as well as ATP and uncoupling protein 2 was recorded. Moreover, glutamate homeostasis was unveiled. The present findings demonstrate the TMZ-attenuated Li/PIL seizure score and latency. It improved mitochondrial redox status, preserved energy production mechanisms, and decreased reactive astrocytes evidenced as decreased glial fibrillary acidic protein immune-stained areas in hippocampal tissue. In addition, it modulated phosphorylated extracellular signal-regulated kinases (p-ERK1/2) and p-AMP–activated protein kinase (p-AMPK) signaling pathways to reflect a verified anti-apoptotic effect. Consequently, it upregulated mRNA expression of astroglial glutamate transporters and reduced the elevated glutamate level. The current study demonstrates that TMZ exhibits robust anti-seizure and neuroprotective potentials. These effects are associated with its ability to modulate mitochondrial redox status, boost p-ERK1/2 and p-AMPK signaling pathways, and restore glutamate homeostasis in hippocampus.
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spelling pubmed-85314972021-10-23 Trimetazidine Modulates Mitochondrial Redox Status and Disrupted Glutamate Homeostasis in a Rat Model of Epilepsy Al-Shorbagy, Muhammad Y. Wadie, Walaa El-Tanbouly, Dalia M. Front Pharmacol Pharmacology Mitochondrial oxidative status exerts an important role in modulating glia–neuron interplay during epileptogenesis. Trimetazidine (TMZ), a well-known anti-ischemic drug, has shown promising potential against a wide range of neurodegenerative disorders including epilepsy. Nevertheless, the exact mechanistic rationale behind its anti-seizure potential has not been fully elucidated yet. Herein, the impact of TMZ against mitochondrial oxidative damage as well as glutamate homeostasis disruption in the hippocampus has been investigated in rats with lithium/pilocarpine (Li/PIL) seizures. Animals received 3 mEq/kg i.p. LiCl(3) followed by PIL (single i.p.; 150 mg/kg) 20 h later for induction of seizures with or without TMZ pretreatment (25 mg/kg; i.p.) for five consecutive days. Seizure score and seizure latency were observed. Mitochondrial redox status as well as ATP and uncoupling protein 2 was recorded. Moreover, glutamate homeostasis was unveiled. The present findings demonstrate the TMZ-attenuated Li/PIL seizure score and latency. It improved mitochondrial redox status, preserved energy production mechanisms, and decreased reactive astrocytes evidenced as decreased glial fibrillary acidic protein immune-stained areas in hippocampal tissue. In addition, it modulated phosphorylated extracellular signal-regulated kinases (p-ERK1/2) and p-AMP–activated protein kinase (p-AMPK) signaling pathways to reflect a verified anti-apoptotic effect. Consequently, it upregulated mRNA expression of astroglial glutamate transporters and reduced the elevated glutamate level. The current study demonstrates that TMZ exhibits robust anti-seizure and neuroprotective potentials. These effects are associated with its ability to modulate mitochondrial redox status, boost p-ERK1/2 and p-AMPK signaling pathways, and restore glutamate homeostasis in hippocampus. Frontiers Media S.A. 2021-10-08 /pmc/articles/PMC8531497/ /pubmed/34690772 http://dx.doi.org/10.3389/fphar.2021.735165 Text en Copyright © 2021 Al-Shorbagy, Wadie and El-Tanbouly. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Pharmacology
Al-Shorbagy, Muhammad Y.
Wadie, Walaa
El-Tanbouly, Dalia M.
Trimetazidine Modulates Mitochondrial Redox Status and Disrupted Glutamate Homeostasis in a Rat Model of Epilepsy
title Trimetazidine Modulates Mitochondrial Redox Status and Disrupted Glutamate Homeostasis in a Rat Model of Epilepsy
title_full Trimetazidine Modulates Mitochondrial Redox Status and Disrupted Glutamate Homeostasis in a Rat Model of Epilepsy
title_fullStr Trimetazidine Modulates Mitochondrial Redox Status and Disrupted Glutamate Homeostasis in a Rat Model of Epilepsy
title_full_unstemmed Trimetazidine Modulates Mitochondrial Redox Status and Disrupted Glutamate Homeostasis in a Rat Model of Epilepsy
title_short Trimetazidine Modulates Mitochondrial Redox Status and Disrupted Glutamate Homeostasis in a Rat Model of Epilepsy
title_sort trimetazidine modulates mitochondrial redox status and disrupted glutamate homeostasis in a rat model of epilepsy
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8531497/
https://www.ncbi.nlm.nih.gov/pubmed/34690772
http://dx.doi.org/10.3389/fphar.2021.735165
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