Exploring the effects of zolpidem on cognitive impairment and cellular changes using a lithium-pilocarpine rat model

Post traumatic epilepsy occurs when seizures persist for > 1 week following a traumatic brain injury. The temporal lobe that houses the hippocampal formation is a common site for seizure initiation in these patients, resulting in cognitive and memory deficits. More than 30% of patients with po...

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Main Author: Ahmed, Iman Imtiyaz
Format: Thesis
Language:English
Published: 2021
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Online Access:http://eprints.usm.my/52630/1/Iman%20Imtiyaz%20Ahmed%20Juvale-24%20pages.pdf
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spelling my-usm-ep.526302022-05-30T02:59:39Z Exploring the effects of zolpidem on cognitive impairment and cellular changes using a lithium-pilocarpine rat model 2021-06 Ahmed, Iman Imtiyaz R Medicine Post traumatic epilepsy occurs when seizures persist for > 1 week following a traumatic brain injury. The temporal lobe that houses the hippocampal formation is a common site for seizure initiation in these patients, resulting in cognitive and memory deficits. More than 30% of patients with post traumatic epilepsy are resistant to conventional anti-epileptic drugs such as diazepam, prompting the need to find new therapeutic options. There is also a lack of clinically translatable disease models of post traumatic epilepsy due to high animal mortality rates and low status epilepticus induction rates, making it difficult to test potential therapeutics. Therefore, in our study we utilized a new lithium-pilocarpine status epilepticus induction protocol that spanned a period of 4 days and comprised of fractionated doses of pilocarpine. Status epilepticus was graded using the Racine scale, completion of which was followed by the application of a suitable drug cocktail (diazepam- or zolpidem-cocktail) designed to reduce mortality rates. We also tested the effects of zolpidem on cognitive function in these animals using Morris water maze, while also utilizing Haematoxylin and Eosin staining to investigate morphological changes in the hippocampal formation following post traumatic epilepsy before and after zolpidem application. Our results showed a 100% status epilepticus induction rate with the 4-day induction protocol. We also observed a 0% mortality rate with the diazepam-cocktail which was successfully able to stop status epilepticus in the animals compared to the zolpidem-cocktail. The recovery time for animals treated with the diazepam-cocktail was also relatively shorter as compared to that of the zolpidem-cocktail, compelling us to proceed with diazepam-cocktail treated animals for further tests. Our behavioural test revealed that while most animals displayed exploratory behaviour, animals with post traumatic epilepsy that were administered zolpidem 30 minutes prior to the test exhibited thigmotaxic swimming pattern in the Morris water maze, a phenomenon common in models of fear and anxiety, suggesting zolpidem having a paradoxical anti-anxiolytic effect. Histological analysis of animals with post traumatic epilepsy showed a significant amount of cell loss and damage to the layers of the CA1, CA3, upper dentate gyrus, and subiculum. Comparatively, analysis of brain images from animals that were previously administered zolpidem during behavioural testing revealed an improvement in both the cell count and thickness of cell layers in the CA1, CA3, upper dentate gyrus, and subiculum regions, suggesting zolpidem to have a potential restorative effect. 2021-06 Thesis http://eprints.usm.my/52630/ http://eprints.usm.my/52630/1/Iman%20Imtiyaz%20Ahmed%20Juvale-24%20pages.pdf application/pdf en public masters Universiti Sains Malaysia Pusat Pengajian Sains Perubatan
institution Universiti Sains Malaysia
collection USM Institutional Repository
language English
topic R Medicine
spellingShingle R Medicine
Ahmed, Iman Imtiyaz
Exploring the effects of zolpidem on cognitive impairment and cellular changes using a lithium-pilocarpine rat model
description Post traumatic epilepsy occurs when seizures persist for > 1 week following a traumatic brain injury. The temporal lobe that houses the hippocampal formation is a common site for seizure initiation in these patients, resulting in cognitive and memory deficits. More than 30% of patients with post traumatic epilepsy are resistant to conventional anti-epileptic drugs such as diazepam, prompting the need to find new therapeutic options. There is also a lack of clinically translatable disease models of post traumatic epilepsy due to high animal mortality rates and low status epilepticus induction rates, making it difficult to test potential therapeutics. Therefore, in our study we utilized a new lithium-pilocarpine status epilepticus induction protocol that spanned a period of 4 days and comprised of fractionated doses of pilocarpine. Status epilepticus was graded using the Racine scale, completion of which was followed by the application of a suitable drug cocktail (diazepam- or zolpidem-cocktail) designed to reduce mortality rates. We also tested the effects of zolpidem on cognitive function in these animals using Morris water maze, while also utilizing Haematoxylin and Eosin staining to investigate morphological changes in the hippocampal formation following post traumatic epilepsy before and after zolpidem application. Our results showed a 100% status epilepticus induction rate with the 4-day induction protocol. We also observed a 0% mortality rate with the diazepam-cocktail which was successfully able to stop status epilepticus in the animals compared to the zolpidem-cocktail. The recovery time for animals treated with the diazepam-cocktail was also relatively shorter as compared to that of the zolpidem-cocktail, compelling us to proceed with diazepam-cocktail treated animals for further tests. Our behavioural test revealed that while most animals displayed exploratory behaviour, animals with post traumatic epilepsy that were administered zolpidem 30 minutes prior to the test exhibited thigmotaxic swimming pattern in the Morris water maze, a phenomenon common in models of fear and anxiety, suggesting zolpidem having a paradoxical anti-anxiolytic effect. Histological analysis of animals with post traumatic epilepsy showed a significant amount of cell loss and damage to the layers of the CA1, CA3, upper dentate gyrus, and subiculum. Comparatively, analysis of brain images from animals that were previously administered zolpidem during behavioural testing revealed an improvement in both the cell count and thickness of cell layers in the CA1, CA3, upper dentate gyrus, and subiculum regions, suggesting zolpidem to have a potential restorative effect.
format Thesis
qualification_level Master's degree
author Ahmed, Iman Imtiyaz
author_facet Ahmed, Iman Imtiyaz
author_sort Ahmed, Iman Imtiyaz
title Exploring the effects of zolpidem on cognitive impairment and cellular changes using a lithium-pilocarpine rat model
title_short Exploring the effects of zolpidem on cognitive impairment and cellular changes using a lithium-pilocarpine rat model
title_full Exploring the effects of zolpidem on cognitive impairment and cellular changes using a lithium-pilocarpine rat model
title_fullStr Exploring the effects of zolpidem on cognitive impairment and cellular changes using a lithium-pilocarpine rat model
title_full_unstemmed Exploring the effects of zolpidem on cognitive impairment and cellular changes using a lithium-pilocarpine rat model
title_sort exploring the effects of zolpidem on cognitive impairment and cellular changes using a lithium-pilocarpine rat model
granting_institution Universiti Sains Malaysia
granting_department Pusat Pengajian Sains Perubatan
publishDate 2021
url http://eprints.usm.my/52630/1/Iman%20Imtiyaz%20Ahmed%20Juvale-24%20pages.pdf
_version_ 1747822202002079744