Alleviating sleep disturbances and modulating neuronal activity after ischemia: Evidence for the benefits of zolpidem in stroke recovery

Aims Sleep disorders are prevalent among stroke survivors and impede stroke recovery, yet they are still insufficiently considered in the management of stroke patients, and the mechanisms by which they occur remain unclear. There is evidence that boosting phasic GABA signaling with zolpidem during t...

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Published in:CNS neuroscience & therapeutics 2024-02, Vol.30 (2), p.e14637-n/a
Main Authors: Zhong, Zhi‐Gang, Tao, Gui‐Jin, Hao, Shu‐Mei, Ben, Hui, Qu, Wei‐Min, Sun, Feng‐Yan, Huang, Zhi‐Li, Qiu, Mei‐Hong
Format: Article
Language:English
Subjects:
Animals
Benzodiazepines
Brain damage
Brain injury
c-Fos protein
Carotid arteries
Cerebral blood flow
Circadian rhythm
Circadian rhythms
c‐Fos
EEG
Electromyography
Humans
Infarction, Middle Cerebral Artery - drug therapy
Ischemia
Ischemic Stroke - drug therapy
Male
MCAO
Melatonin
Neural plasticity
Original
Pyridines - pharmacology
Pyridines - therapeutic use
Rats
Rehabilitation
Sleep
sleep disorder
Sleep disorders
Sleep Wake Disorders - drug therapy
Sleep Wake Disorders - etiology
Stroke
Stroke - complications
Stroke - drug therapy
Suprachiasmatic nucleus
Traumatic brain injury
Veins & arteries
Zolpidem
Zolpidem - pharmacology
Zolpidem - therapeutic use
γ-Aminobutyric acid
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Summary:Aims Sleep disorders are prevalent among stroke survivors and impede stroke recovery, yet they are still insufficiently considered in the management of stroke patients, and the mechanisms by which they occur remain unclear. There is evidence that boosting phasic GABA signaling with zolpidem during the repair phase improves stroke recovery by enhancing neural plasticity; however, as a non‐benzodiazepine hypnotic, the effects of zolpidem on post‐stroke sleep disorders remain unclear. Method Transient ischemic stroke in male rats was induced with a 30‐minute middle cerebral artery occlusion. Zolpidem or vehicle was intraperitoneally delivered once daily from 2 to 7 days after the stroke, and the electroencephalogram and electromyogram were recorded simultaneously. At 24 h after ischemia, c‐Fos immunostaining was used to assess the effect of transient ischemic stroke and acute zolpidem treatment on neuronal activity. Results In addition to the effects on reducing brain damage and mitigating behavioral deficits, repeated zolpidem treatment during the subacute phase of stroke quickly ameliorated circadian rhythm disruption, alleviated sleep fragmentation, and increased sleep depth in ischemic rats. Immunohistochemical staining showed that in contrast to robust activation in para‐infarct and some remote areas by 24 h after the onset of focal ischemia, the activity of the ipsilateral suprachiasmatic nucleus, the biological rhythm center, was strongly suppressed. A single dose of zolpidem significantly upregulated c‐Fos expression in the ipsilateral suprachiasmatic nucleus to levels comparable to the contralateral side. Conclusion Stroke leads to suprachiasmatic nucleus dysfunction. Zolpidem restores suprachiasmatic nucleus activity and effectively alleviates post‐stroke sleep disturbances, indicating its potential to promote stroke recovery. Sleep disorders are prevalent among stroke survivors and impede stroke recovery, yet the mechanisms are unclear and no approved drugs in stroke care. We found stoke causes dysfunction of the suprachiasmatic nucleus (SCN). The hypnotic drug zolpidem restores SCN activity, and rapidly relieves post‐stroke sleep problems, implying its therapeutic promise.
ISSN:1755-5930
1755-5949
DOI:10.1111/cns.14637