DHYZ modulates hippocampal cholinergic pathway acetylation to ameliorate cognitive deficits post-ischemic stroke in rats

Ischemic stroke is a serious cerebrovascular disease that is often accompanied by debilitating sensorimotor deficits and persistent cognitive deficits, which seriously affect patients’ quality of life. DHYZ, a traditional Chinese herbal formula, has shown significant efficacy in restoring neurological function in ischemic regions of the brain, but its potential for improving poststroke cognitive impairment remains underdeveloped. In this study, the middle cerebral artery occlusion/reperfusion (MCAO/R) model was used to reproduce the pathological process of ischemic stroke in humans. We systematically investigated the therapeutic effect of DHYZ on poststroke cognitive dysfunction and the underlying mechanisms through a combination of behavioral assessment (Morris water maze), histopathological evaluation, molecular analysis (quantitative PCR, immunofluorescence, and Western blotting), and acetylcholine (ACh) content detection. The experimental data revealed that DHYZ treatment significantly reduced the volume of cerebral infarction, improved neurological recovery, and enhanced spatial learning/memory ability in MCAO/R rats. DHYZ enhanced the activation of hippocampal cholinergic circuits in MCAO/R rats, promoted the upregulation of CREB-binding protein (CBP) expression by increasing CREB phosphorylation and further increased the acetylation levels of the promoters of the acetylcholine transferase (ChAT) and acetylcholinesterase (AChE) genes in the hippocampus. This cascade enhances acetylation of the choline acetyltransferase (ChAT) and acetylcholinesterase (AChE) gene promoters in the hippocampal pathway. The effects of ChAT and AChE on ACh balance each other and promote cognitive function. Our findings elucidate a novel mechanism involving the regulation of cholinergic signaling pathways and provide new insights for the development of effective interventions targeting ischemic stroke-related cognitive dysfunction.