Orexin dual receptor antagonist attenuates neurological deficits possibly via PI3K/Akt/mTOR pathway activation in sleep-deprived stroke rats

BACKGROUND: Post-stroke sleep disorders are frequent complications of ischemic stroke and contribute to poor neurological recovery. Dual orexin receptor antagonists (DORAs) promote sleep via mechanisms distinct from traditional hypnotics. This study investigated whether almorexant attenuates sleep deprivation (SD)-aggravated ischemic injury in rats and explored the its potential association with PI3K/Akt/mTOR signaling pathway. METHODS: Male Sprague-Dawley rats underwent permanent middle cerebral artery occlusion (MCAO), and were assigned to sham, MCAO, MCAO+SD, MCAO+SD+almorexant, or MCAO+SD+estazolam. Neurological function (Zea-Longa score, open-field test), infarct volume (TTC), histopathology (H&E), neuronal apoptosis (TUNEL), and PI3K/Akt/mTOR expression (Western blot, RT-qPCR) were assessed. RESULTS: SD exacerbated neurological deficits after MCAO, as reflected by higher Zea-Longa scores and impaired locomotor activity. Almorexant treatment was associated with improved behavioral performance and reduced histologic injury, neuronal apoptosis in sleep-deprived MCAO rats. At the molecular level, both almorexant and estazolam treatments were associated with upregulated PI3K, Akt, and mTOR expression at both protein and mRNA levels. CONCLUSION: Almorexant was associated with attenuation of SD-exacerbated ischemic brain injury in rats, accompanied by alterations in PI3K/Akt/mTOR signaling, suggesting DORAs may have potential relevance for the management of post-stroke insomnia.