Exploring the role of zolpidem in alleviating cognitive and motor impairments in chronic cerebral hypoperfusion: a rat model study with in vivo and in silico insights
The ε-containing GABA(A) receptors (GABAARs), a lesser-studied subtype within the GABAAR family, have garnered attention due to their distinct pharmacological properties and potential involvement in brain injury. Zolpidem (ZPM), a widely used Z-drug, is known to induce paradoxical effects in patie...
Saved in:
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | en |
| Published: |
Japanese Association for Laboratory Animal Science
2025
|
| Subjects: | |
| Online Access: | http://irep.iium.edu.my/126749/13/126749_Exploring%20the%20role%20of%20zolpidem.pdf http://irep.iium.edu.my/126749/ https://www.jalas.jp/english/experimental/en_archive.html |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| Summary: | The ε-containing GABA(A) receptors (GABAARs), a lesser-studied subtype within the GABAAR family,
have garnered attention due to their distinct pharmacological properties and potential involvement in brain injury.
Zolpidem (ZPM), a widely used Z-drug, is known to induce paradoxical effects in patients with brain injury, although
the underlying molecular mechanisms remain unclear. In this study, a chronic cerebral hypoperfusion (CCH) rat
model was established using Permanent Bilateral Occlusion of the Common Carotid Arteries (PBOCCA), followed
by administration of ZPM at doses of 1.0, 2.0, and 4.0 mg/kg. Behavioral assessments demonstrated that the 1.0
mg/kg dose of ZPM significantly improved spatial learning and memory acquisition (P<0.01) and enhanced memory
retention (P<0.001), whereas higher doses resulted in sedation and cognitive impairment. Immunohistochemical
analysis revealed an upregulation of the ε subunit expression in the hippocampal CA1 and CA3 regions of CCH
rats (P<0.05), suggesting alterations in receptor composition in response to cerebral hypoperfusion. Further
investigation of ZPM’s interaction with ε-containing GABAARs (specifically the α1β2ε subtype) was conducted
using in silico techniques. Molecular docking identified the α1+/ε- binding interface as a favorable ZPM binding
site, with key residues being either conserved or suitably replaced. Molecular dynamics simulations demonstrated
that ZPM stabilizes the receptor while permitting conformational flexibility, consistent with its role as a positive
allosteric modulator. These findings provide evidence that ZPM interacts with ε-containing GABAARs, potentially
explaining its paradoxical effects observed in brain injury models |
|---|