Unravelling neuroregenerative and neuroprotective roles of Wnt/β-catenin pathway in ischemic stroke: Insights into molecular mechanisms.

Stroke is a serious condition often resulting in mortality or long-term disability, causing cognitive, memory, and motor impairments. A reduction in cerebral blood flow below critical levels defines the ischemic core and penumbra: the core undergoes irreversible damage, while the penumbra remains viable but functionally impaired. This functional impairment activates complex cell signaling pathways that determine cell survival or death, making the penumbra a key target for therapeutic interventions to prevent further damage. The Wnt/β-catenin (WβC) signaling pathway has emerged as a potential neuroprotective mechanism, promoting neurogenesis, angiogenesis, neuronal connectivity, and maintaining blood-brain barrier integrity after stroke. Activation of the WβC pathway also mitigates oxidative stress, inflammation, and apoptosis in ischemic regions, enhancing its neuroprotective effects. However, the overexpression of GSK3β and DKK1, or the presence of their agonists, can counteract these benefits. This review explores the therapeutic potential of WβC signaling, highlighting the effects of pharmacological modulation through antagonists, agonists, synthetic chemicals, natural products, stem cells, and macromolecules in preclinical models of ischemic stroke. While preclinical evidence supports the benefits of WβC activation, its role in human stroke requires further investigation. Additionally, the review discusses the potential adverse effects of prolonged WβC activation and suggests strategies to mitigate them. Overall, WβC signaling holds promise as a therapeutic target, offering insights into stroke pathophysiology and informing the development of novel treatment strategies.