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Mitochondrial-Protective Effects of R-Phenibut after Experimental Traumatic Brain Injury
Altered neuronal Ca(2+) homeostasis and mitochondrial dysfunction play a central role in the pathogenesis of traumatic brain injury (TBI). R-Phenibut ((3R)-phenyl-4-aminobutyric acid) is an antagonist of the α(2)δ subunit of voltage-dependent calcium channels (VDCC) and an agonist of gamma-aminobuty...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Hindawi
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7700030/ https://www.ncbi.nlm.nih.gov/pubmed/33274011 http://dx.doi.org/10.1155/2020/9364598 |
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author | Kupats, Einars Stelfa, Gundega Zvejniece, Baiba Grinberga, Solveiga Vavers, Edijs Makrecka-Kuka, Marina Svalbe, Baiba Zvejniece, Liga Dambrova, Maija |
author_facet | Kupats, Einars Stelfa, Gundega Zvejniece, Baiba Grinberga, Solveiga Vavers, Edijs Makrecka-Kuka, Marina Svalbe, Baiba Zvejniece, Liga Dambrova, Maija |
author_sort | Kupats, Einars |
collection | PubMed |
description | Altered neuronal Ca(2+) homeostasis and mitochondrial dysfunction play a central role in the pathogenesis of traumatic brain injury (TBI). R-Phenibut ((3R)-phenyl-4-aminobutyric acid) is an antagonist of the α(2)δ subunit of voltage-dependent calcium channels (VDCC) and an agonist of gamma-aminobutyric acid B (GABA-B) receptors. The aim of this study was to evaluate the potential therapeutic effects of R-phenibut following the lateral fluid percussion injury (latFPI) model of TBI in mice and the impact of R- and S-phenibut on mitochondrial functionality in vitro. By determining the bioavailability of R-phenibut in the mouse brain tissue and plasma, we found that R-phenibut (50 mg/kg) reached the brain tissue 15 min after intraperitoneal (i.p.) and peroral (p.o.) injections. The maximal concentration of R-phenibut in the brain tissues was 0.6 μg/g and 0.2 μg/g tissue after i.p. and p.o. administration, respectively. Male Swiss-Webster mice received i.p. injections of R-phenibut at doses of 10 or 50 mg/kg 2 h after TBI and then once daily for 7 days. R-Phenibut treatment at the dose of 50 mg/kg significantly ameliorated functional deficits after TBI on postinjury days 1, 4, and 7. Seven days after TBI, the number of Nissl-stained dark neurons (N-DNs) and interleukin-1beta (IL-1β) expression in the cerebral neocortex in the area of cortical impact were reduced. Moreover, the addition of R- and S-phenibut at a concentration of 0.5 μg/ml inhibited calcium-induced mitochondrial swelling in the brain homogenate and prevented anoxia-reoxygenation-induced increases in mitochondrial H(2)O(2) production and the H(2)O(2)/O ratio. Taken together, these results suggest that R-phenibut could serve as a neuroprotective agent and promising drug candidate for treating TBI. |
format | Online Article Text |
id | pubmed-7700030 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Hindawi |
record_format | MEDLINE/PubMed |
spelling | pubmed-77000302020-12-02 Mitochondrial-Protective Effects of R-Phenibut after Experimental Traumatic Brain Injury Kupats, Einars Stelfa, Gundega Zvejniece, Baiba Grinberga, Solveiga Vavers, Edijs Makrecka-Kuka, Marina Svalbe, Baiba Zvejniece, Liga Dambrova, Maija Oxid Med Cell Longev Research Article Altered neuronal Ca(2+) homeostasis and mitochondrial dysfunction play a central role in the pathogenesis of traumatic brain injury (TBI). R-Phenibut ((3R)-phenyl-4-aminobutyric acid) is an antagonist of the α(2)δ subunit of voltage-dependent calcium channels (VDCC) and an agonist of gamma-aminobutyric acid B (GABA-B) receptors. The aim of this study was to evaluate the potential therapeutic effects of R-phenibut following the lateral fluid percussion injury (latFPI) model of TBI in mice and the impact of R- and S-phenibut on mitochondrial functionality in vitro. By determining the bioavailability of R-phenibut in the mouse brain tissue and plasma, we found that R-phenibut (50 mg/kg) reached the brain tissue 15 min after intraperitoneal (i.p.) and peroral (p.o.) injections. The maximal concentration of R-phenibut in the brain tissues was 0.6 μg/g and 0.2 μg/g tissue after i.p. and p.o. administration, respectively. Male Swiss-Webster mice received i.p. injections of R-phenibut at doses of 10 or 50 mg/kg 2 h after TBI and then once daily for 7 days. R-Phenibut treatment at the dose of 50 mg/kg significantly ameliorated functional deficits after TBI on postinjury days 1, 4, and 7. Seven days after TBI, the number of Nissl-stained dark neurons (N-DNs) and interleukin-1beta (IL-1β) expression in the cerebral neocortex in the area of cortical impact were reduced. Moreover, the addition of R- and S-phenibut at a concentration of 0.5 μg/ml inhibited calcium-induced mitochondrial swelling in the brain homogenate and prevented anoxia-reoxygenation-induced increases in mitochondrial H(2)O(2) production and the H(2)O(2)/O ratio. Taken together, these results suggest that R-phenibut could serve as a neuroprotective agent and promising drug candidate for treating TBI. Hindawi 2020-11-21 /pmc/articles/PMC7700030/ /pubmed/33274011 http://dx.doi.org/10.1155/2020/9364598 Text en Copyright © 2020 Einars Kupats et al. https://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Research Article Kupats, Einars Stelfa, Gundega Zvejniece, Baiba Grinberga, Solveiga Vavers, Edijs Makrecka-Kuka, Marina Svalbe, Baiba Zvejniece, Liga Dambrova, Maija Mitochondrial-Protective Effects of R-Phenibut after Experimental Traumatic Brain Injury |
title | Mitochondrial-Protective Effects of R-Phenibut after Experimental Traumatic Brain Injury |
title_full | Mitochondrial-Protective Effects of R-Phenibut after Experimental Traumatic Brain Injury |
title_fullStr | Mitochondrial-Protective Effects of R-Phenibut after Experimental Traumatic Brain Injury |
title_full_unstemmed | Mitochondrial-Protective Effects of R-Phenibut after Experimental Traumatic Brain Injury |
title_short | Mitochondrial-Protective Effects of R-Phenibut after Experimental Traumatic Brain Injury |
title_sort | mitochondrial-protective effects of r-phenibut after experimental traumatic brain injury |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7700030/ https://www.ncbi.nlm.nih.gov/pubmed/33274011 http://dx.doi.org/10.1155/2020/9364598 |
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