Pterostilbene Orchestrates Synaptic Remodeling and Mitochondrial Functional Reconstitution to Attenuate Ischemic Vascular Dementia.

Vascular dementia (VaD), a major contributor to cognitive decline, arises primarily from impaired regulation of cerebral circulation. Pterostilbene (PTE), a natural stilbene, exhibits potent neuroprotective properties, including antioxidative, anti-apoptotic, and cognition-enhancing effects; however, the molecular basis of its protective action in VaD remains poorly defined. Here, we integrated network pharmacology with in-vitro and in-vivo validation to delineate the mechanistic underpinnings of PTE. An ischemic injury model was established in SH-SY5Y cells using oxygen-glucose deprivation/reoxygenation (OGD/R), while VaD was induced in rats by bilateral common carotid artery occlusion. Cognitive function was assessed by behavioural paradigms, and neuronal integrity, vascular architecture, mitochondrial function, respiratory complex activities, and synaptic plasticity via the cAMP/PKA/CREB signalling cascade were evaluated using histological, biochemical, and molecular assays. Network pharmacology identified the cAMP pathway as a principal mediator of PTE activity. In ischemia injured SH-SY5Y cells, PTE improved viability, reduced oxidative stress, stabilized mitochondrial membrane potential, and elevated ATP production. In VaD rats, PTE enhanced spatial learning and memory, preserved cortical and hippocampal structures, and promoted mitochondrial health, evidenced by upregulation of PGC-1α and TFAM, restoration of respiratory complex activities, and preservation of mitochondrial ultrastructure. PTE also increased expression of synaptic proteins (PSD95, Synaptophysin). Consistently across both models, PTE activated the cAMP/PKA/CREB signalling axis. Collectively, these findings demonstrate that PTE mitigates ischemia-induced cognitive impairment by reversing mitochondrial dysfunction while sustaining synaptic plasticity through cAMP/PKA/CREB activation, highlighting its translational potential as a therapeutic candidate for VaD.