Ahmed, Iman Imtiyaz
(2021)
Exploring the effects of zolpidem on cognitive impairment and cellular changes using a lithium-pilocarpine rat model.
Masters thesis, Universiti Sains Malaysia.
Abstract
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.
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