The effects of zolpidem on spatial memory, cellular and ionic co-transporters (KCC2/NKCC1) in the hippocampus of lithium-pilocarpine rat model

• Main Author: Othman, Muhammad Zulfadhli
• Format: Thesis
• Language: English
• Published: 2022
• Subjects: R Medicine
• Online Access: http://eprints.usm.my/54567/1/MUHAMMAD%20ZULFADHLI%20BIN%20OTHMAN-FINAL%20THESIS%20P-UM001719%28R%29%20PWD_-24%20pages.pdf; http://eprints.usm.my/54567/
• Institution: Universiti Sains Malaysia

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.