Flumazenil Pretreatment Reduces Mefenamic Acid-Induced Central Nervous System Toxicity in Mice
Background: Mefenamic acid (MFA), a common analgesic, causes central nervous system (CNS) toxicity at high doses with a proposed activity on the Gamma-aminobutyric acid (GABA) system. However, it remains unknown whether flumazenil (FMZ), a GABA type A receptor (GABAAR) antagonist, can reverse MFA to...
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my.sunway.eprints.28902024-07-25T08:21:21Z http://eprints.sunway.edu.my/2890/ Flumazenil Pretreatment Reduces Mefenamic Acid-Induced Central Nervous System Toxicity in Mice Jarrar, Qais Ayoub, Rami Jarrar, Yazun Aburass, Hadeel Goh, Khang Wen Ardianto, Chrismawan Long, Chiau Ming * Moshawih, Said Alfaqih, Hussain QL Zoology QM Human anatomy QP Physiology RC Internal medicine Background: Mefenamic acid (MFA), a common analgesic, causes central nervous system (CNS) toxicity at high doses with a proposed activity on the Gamma-aminobutyric acid (GABA) system. However, it remains unknown whether flumazenil (FMZ), a GABA type A receptor (GABAAR) antagonist, can reverse MFA toxicity. Methods: The behavioral and neurophysiological effects of MFA were investigated in mice with and without FMZ pre-treatment. The elevated zero maze (EZM) and marble burying tests were used to assess anxiety-like behaviors and burying activities, respectively. The standard bar test was used to evaluate catalepsy, while the actophotometer test was used to measure locomotor activity. Seizure intensity was scored, and fatalities were counted. Results: Without FMZ pre-treatment, MFA induced behavioral and neurophysiological effects in a dose-dependent manner as follows: At a dose of 20 mg/kg, i.p, MFA-treated mice exhibited anxiety-like behaviors, which was determined by a significant increase in the time spent in the closed areas and a significant decrease in the number of entries to the open areas of the EZM apparatus. These mice also showed a significant decrease in the burying activity, manifested as a significant decrease in the number of buried marbles. At 40 mg/kg, i.p., MFA-treated mice showed catalepsy that was associated with a significant decrease in locomotor activity. At a dose of 80 mg/kg, i.p., mice developed fatal tonic-clonic seizures (seizure score = 4). Pre-treatment with FMZ (5 mg/kg, i.p.) significantly reversed the anxiety-like behaviors and restored marble-burying activity. Additionally, FMZ prevented catalepsy, significantly restored locomotor activity, reduced seizure intensity (seizure score = 0.3) and significantly reduced mortalities. Conclusions: The present study's findings indicate that activation of the GABAAR is involved in the CNS toxicity of MFA, and FMZ reverses MFA toxicity by interfering with this receptor. IMR Press 2023 Article PeerReviewed Jarrar, Qais and Ayoub, Rami and Jarrar, Yazun and Aburass, Hadeel and Goh, Khang Wen and Ardianto, Chrismawan and Long, Chiau Ming * and Moshawih, Said and Alfaqih, Hussain (2023) Flumazenil Pretreatment Reduces Mefenamic Acid-Induced Central Nervous System Toxicity in Mice. Journal of Integrative Neuroscience, 22 (4). ISSN 1757-448X https://www.imrpress.com/journal/JIN/22/4/10.31083/j.jin2204104 10.31083/j.jin2204104 |
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QL Zoology QM Human anatomy QP Physiology RC Internal medicine Jarrar, Qais Ayoub, Rami Jarrar, Yazun Aburass, Hadeel Goh, Khang Wen Ardianto, Chrismawan Long, Chiau Ming * Moshawih, Said Alfaqih, Hussain Flumazenil Pretreatment Reduces Mefenamic Acid-Induced Central Nervous System Toxicity in Mice |
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Background: Mefenamic acid (MFA), a common analgesic, causes central nervous system (CNS) toxicity at high doses with a proposed activity on the Gamma-aminobutyric acid (GABA) system. However, it remains unknown whether flumazenil (FMZ), a GABA type A receptor (GABAAR) antagonist, can reverse MFA toxicity.
Methods: The behavioral and neurophysiological effects of MFA were investigated in mice with and without FMZ pre-treatment. The elevated zero maze (EZM) and marble burying tests were used to assess anxiety-like behaviors and burying activities, respectively. The standard bar test was used to evaluate catalepsy, while the actophotometer test was used to measure locomotor activity. Seizure intensity was scored, and fatalities were counted.
Results: Without FMZ pre-treatment, MFA induced behavioral and neurophysiological effects in a dose-dependent manner as follows: At a dose of 20 mg/kg, i.p, MFA-treated mice exhibited anxiety-like behaviors, which was determined by a significant increase in the time spent in the closed areas and a significant decrease in the number of entries to the open areas of the EZM apparatus. These mice also showed a significant decrease in the burying activity, manifested as a significant decrease in the number of buried marbles. At 40 mg/kg, i.p., MFA-treated mice showed catalepsy that was associated with a significant decrease in locomotor activity. At a dose of 80 mg/kg, i.p., mice developed fatal tonic-clonic seizures (seizure score = 4). Pre-treatment with FMZ (5 mg/kg, i.p.) significantly reversed the anxiety-like behaviors and restored marble-burying activity. Additionally, FMZ prevented catalepsy, significantly restored locomotor activity, reduced seizure intensity (seizure score = 0.3) and significantly reduced mortalities.
Conclusions: The present study's findings indicate that activation of the GABAAR is involved in the CNS toxicity of MFA, and FMZ reverses MFA toxicity by interfering with this receptor. |
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Article |
author |
Jarrar, Qais Ayoub, Rami Jarrar, Yazun Aburass, Hadeel Goh, Khang Wen Ardianto, Chrismawan Long, Chiau Ming * Moshawih, Said Alfaqih, Hussain |
author_facet |
Jarrar, Qais Ayoub, Rami Jarrar, Yazun Aburass, Hadeel Goh, Khang Wen Ardianto, Chrismawan Long, Chiau Ming * Moshawih, Said Alfaqih, Hussain |
author_sort |
Jarrar, Qais |
title |
Flumazenil Pretreatment Reduces Mefenamic Acid-Induced Central Nervous System Toxicity in Mice |
title_short |
Flumazenil Pretreatment Reduces Mefenamic Acid-Induced Central Nervous System Toxicity in Mice |
title_full |
Flumazenil Pretreatment Reduces Mefenamic Acid-Induced Central Nervous System Toxicity in Mice |
title_fullStr |
Flumazenil Pretreatment Reduces Mefenamic Acid-Induced Central Nervous System Toxicity in Mice |
title_full_unstemmed |
Flumazenil Pretreatment Reduces Mefenamic Acid-Induced Central Nervous System Toxicity in Mice |
title_sort |
flumazenil pretreatment reduces mefenamic acid-induced central nervous system toxicity in mice |
publisher |
IMR Press |
publishDate |
2023 |
url |
http://eprints.sunway.edu.my/2890/ https://www.imrpress.com/journal/JIN/22/4/10.31083/j.jin2204104 |
_version_ |
1805893831809302528 |
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13.188404 |