Combinatorial Regimen of Carbamazepine and Imipramine Exhibits Synergism against Grandmal Epilepsy in Rats: Inhibition of Pro-Inflammatory Cytokines and PI3K/Akt/mTOR Signaling Pathway

Epilepsy is a neurodegenerative disorder that causes recurring seizures. Thirty-five percent of patients remain refractory, with a higher prevalence of depression. We investigated the anticonvulsant efficacy of carbamazepine (CBZ; 20 and 50 mg/kg), imipramine (IMI; 10 and 20 mg/kg) alone, and as a l...

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Autores principales:	Faheem Hyder Pottoo, Mohammed Salahuddin, Firdos Alam Khan, Marwa Abdullah AL Dhamen, Walaa Jafar Alsaeed, Mohamed S. Gomaa, Chittibabu Vatte, Mohammad N. Alomary
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	epilepsy neurodegenerative disorder seizures PI3K/Akt/mTOR signaling inflammation cooperative binding Medicine R Pharmacy and materia medica RS1-441
Acceso en línea:	https://doaj.org/article/8adfdae47fab48f5bff0c801efa5ed32
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spelling	oai:doaj.org-article:8adfdae47fab48f5bff0c801efa5ed322021-11-25T18:40:12ZCombinatorial Regimen of Carbamazepine and Imipramine Exhibits Synergism against Grandmal Epilepsy in Rats: Inhibition of Pro-Inflammatory Cytokines and PI3K/Akt/mTOR Signaling Pathway10.3390/ph141112041424-8247https://doaj.org/article/8adfdae47fab48f5bff0c801efa5ed322021-11-01T00:00:00Zhttps://www.mdpi.com/1424-8247/14/11/1204https://doaj.org/toc/1424-8247Epilepsy is a neurodegenerative disorder that causes recurring seizures. Thirty-five percent of patients remain refractory, with a higher prevalence of depression. We investigated the anticonvulsant efficacy of carbamazepine (CBZ; 20 and 50 mg/kg), imipramine (IMI; 10 and 20 mg/kg) alone, and as a low dose combination. This preclinical investigation included dosing of rats for 14 days followed by elicitation of electroshock on the last day of treatment. Along with behavioral monitoring, the rat hippocampus was processed for quantification of mTOR, IL-1β, IL-6 and TNF-α levels. The histopathological analysis of rat hippocampus was performed to ascertain neuroprotection. In vitro studies and in silico studies were also conducted. We found that the low dose combinatorial therapy of CBZ (20 mg/kg) + IMI (10 mg/kg) exhibits synergism (<i>p</i> < 0.001) in abrogation of maximal electroshock (MES) induced convulsions/tonic hind limb extension (THLE), by reducing levels of pro-inflammatory cytokines, and weakening of the PI3K/Akt/mTOR signal. The combination also exhibits cooperative binding at the Akt. As far as neuroprotection is concerned, the said combination increased cell viability by 166.37% compared to Pentylenetetrazol (PTZ) treated HEK-293 cells. Thus, the combination of CBZ (20 mg/kg) + IMI (10 mg/kg) is a fruitful combination therapy to elevate seizure threshold and provide neuroprotection.Faheem Hyder PottooMohammed SalahuddinFirdos Alam KhanMarwa Abdullah AL DhamenWalaa Jafar AlsaeedMohamed S. GomaaChittibabu VatteMohammad N. AlomaryMDPI AGarticleepilepsyneurodegenerative disorderseizuresPI3K/Akt/mTOR signalinginflammationcooperative bindingMedicineRPharmacy and materia medicaRS1-441ENPharmaceuticals, Vol 14, Iss 1204, p 1204 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	epilepsy neurodegenerative disorder seizures PI3K/Akt/mTOR signaling inflammation cooperative binding Medicine R Pharmacy and materia medica RS1-441
spellingShingle	epilepsy neurodegenerative disorder seizures PI3K/Akt/mTOR signaling inflammation cooperative binding Medicine R Pharmacy and materia medica RS1-441 Faheem Hyder Pottoo Mohammed Salahuddin Firdos Alam Khan Marwa Abdullah AL Dhamen Walaa Jafar Alsaeed Mohamed S. Gomaa Chittibabu Vatte Mohammad N. Alomary Combinatorial Regimen of Carbamazepine and Imipramine Exhibits Synergism against Grandmal Epilepsy in Rats: Inhibition of Pro-Inflammatory Cytokines and PI3K/Akt/mTOR Signaling Pathway
description	Epilepsy is a neurodegenerative disorder that causes recurring seizures. Thirty-five percent of patients remain refractory, with a higher prevalence of depression. We investigated the anticonvulsant efficacy of carbamazepine (CBZ; 20 and 50 mg/kg), imipramine (IMI; 10 and 20 mg/kg) alone, and as a low dose combination. This preclinical investigation included dosing of rats for 14 days followed by elicitation of electroshock on the last day of treatment. Along with behavioral monitoring, the rat hippocampus was processed for quantification of mTOR, IL-1β, IL-6 and TNF-α levels. The histopathological analysis of rat hippocampus was performed to ascertain neuroprotection. In vitro studies and in silico studies were also conducted. We found that the low dose combinatorial therapy of CBZ (20 mg/kg) + IMI (10 mg/kg) exhibits synergism (<i>p</i> < 0.001) in abrogation of maximal electroshock (MES) induced convulsions/tonic hind limb extension (THLE), by reducing levels of pro-inflammatory cytokines, and weakening of the PI3K/Akt/mTOR signal. The combination also exhibits cooperative binding at the Akt. As far as neuroprotection is concerned, the said combination increased cell viability by 166.37% compared to Pentylenetetrazol (PTZ) treated HEK-293 cells. Thus, the combination of CBZ (20 mg/kg) + IMI (10 mg/kg) is a fruitful combination therapy to elevate seizure threshold and provide neuroprotection.
format	article
author	Faheem Hyder Pottoo Mohammed Salahuddin Firdos Alam Khan Marwa Abdullah AL Dhamen Walaa Jafar Alsaeed Mohamed S. Gomaa Chittibabu Vatte Mohammad N. Alomary
author_facet	Faheem Hyder Pottoo Mohammed Salahuddin Firdos Alam Khan Marwa Abdullah AL Dhamen Walaa Jafar Alsaeed Mohamed S. Gomaa Chittibabu Vatte Mohammad N. Alomary
author_sort	Faheem Hyder Pottoo
title	Combinatorial Regimen of Carbamazepine and Imipramine Exhibits Synergism against Grandmal Epilepsy in Rats: Inhibition of Pro-Inflammatory Cytokines and PI3K/Akt/mTOR Signaling Pathway
title_short	Combinatorial Regimen of Carbamazepine and Imipramine Exhibits Synergism against Grandmal Epilepsy in Rats: Inhibition of Pro-Inflammatory Cytokines and PI3K/Akt/mTOR Signaling Pathway
title_full	Combinatorial Regimen of Carbamazepine and Imipramine Exhibits Synergism against Grandmal Epilepsy in Rats: Inhibition of Pro-Inflammatory Cytokines and PI3K/Akt/mTOR Signaling Pathway
title_fullStr	Combinatorial Regimen of Carbamazepine and Imipramine Exhibits Synergism against Grandmal Epilepsy in Rats: Inhibition of Pro-Inflammatory Cytokines and PI3K/Akt/mTOR Signaling Pathway
title_full_unstemmed	Combinatorial Regimen of Carbamazepine and Imipramine Exhibits Synergism against Grandmal Epilepsy in Rats: Inhibition of Pro-Inflammatory Cytokines and PI3K/Akt/mTOR Signaling Pathway
title_sort	combinatorial regimen of carbamazepine and imipramine exhibits synergism against grandmal epilepsy in rats: inhibition of pro-inflammatory cytokines and pi3k/akt/mtor signaling pathway
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/8adfdae47fab48f5bff0c801efa5ed32
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Combinatorial Regimen of Carbamazepine and Imipramine Exhibits Synergism against Grandmal Epilepsy in Rats: Inhibition of Pro-Inflammatory Cytokines and PI3K/Akt/mTOR Signaling Pathway

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