Othman, Muhammad Zulfadhli
(2022)
The effects of zolpidem on spatial memory, cellular and ionic co-transporters (KCC2/NKCC1) in the hippocampus of lithium-pilocarpine rat model.
Masters thesis, Universiti Sains Malaysia.
Abstract
Patients with status epilepticus are susceptible to cognitive impairment due to
injuries on the hippocampus, a structure associated with cognition. Hippocampus high
susceptibility to initiation of convulsive seizure and epilepsy-related damages is the
primary cause mediating the impairment. Convulsive seizure as per se exhibited in
status epilepticus can result in various hippocampal pathologies such as inflammation,
aberrant neurogenesis, and neuronal death. Promisingly, vast evidence has been
suggesting the potential therapeutic hallmark of sedative/hypnotic zolpidem in
mediating behavioural and physiological recovery in patients with brain injury, since
serendipitous discovery about paradoxical awakening effect of zolpidem. In this study,
an ideally isomorphic lithium-pilocarpine rat model of status epilepticus with high
morbidity and low mortality rate was developed. Subsequently, using the Morris Water
Maze task, the rat model was utilised to investigate the potential therapeutic effect of
zolpidem in mediating recovery of learning and memory. Moreover, quantitative
haematoxylin and eosin histological evaluation was performed to evaluate the effect
of zolpidem on cellular morphology in the hippocampus of the rat model. Finally,
fluorescence immunohistochemistry was conducted to assess the potential effect of
zolpidem on the dysregulated KCC2 and NKCC1 protein expression in multiple
hippocampal subregions. We successfully developed an ideal lithium-pilocarpine rat
model of status epilepticus with respective morbidity and mortality rate of 78 % and
22 %, that showed significant impairments (p < 0.0001) on learning and memory,
consistent with the exhibition of abnormal anxiety-like behaviour (p < 0.0001).
Besides, in Morris Water Maze, zolpidem administration did not enhance memory
function in the rats with status epilepticus (p > 0.05). Nonetheless, our results indicated
that zolpidem sedative/hypnotic effect was unnoticeable in the status epilepticus
condition (p > 0.05). Furthermore, histological analysis discovered insignificant
zolpidem effect on the hippocampal morphological changes (p > 0.05). However,
interestingly, our immunohistochemical findings indicated the potential of zolpidem
to restore altered KCC2 (DG, p < 0.05; CA3, p > 0.05; CA1, p > 0.05; SUB, p > 0.05)
and NKCC1 (DG, p < 0.001; CA3, p < 0.001, CA1, p < 0.01; SUB, p < 0.001)
expression levels in certain hippocampal subregions, comparable to those observed in
the normal rats. These results suggest that despite unobservable overt recovery in
learning and memory impairment and histopathological changes, zolpidem may partly
involve in molecular restoration especially through KCC2 and NKCC1 protein
expression in the hippocampus, which is vital for an efficient inhibitory
neurotransmission in the brain.
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