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

Dec 16, 2024Neuroscience

Brain repair and protection roles of the Wnt/β-catenin pathway after stroke: Understanding the molecular processes

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Abstract

The Wnt/β-catenin signaling pathway may enhance neuroprotection in ischemic stroke.

Ischemic strokes result in irreversible damage to the ischemic core and functional impairment in the surrounding penumbra.
Activation of the Wnt/β-catenin pathway is associated with promoting cell survival and reducing damage in stroke-affected areas.
The pathway may support neurogenesis, angiogenesis, and neuronal connectivity while maintaining blood-brain barrier integrity.
Overexpression of certain proteins like GSK3β and DKK1 can counteract the neuroprotective effects of Wnt/β-catenin signaling.
Preclinical models suggest pharmacological modulation of Wnt/β-catenin could be beneficial, but further research is needed for human applications.
Potential adverse effects of prolonged Wnt/β-catenin activation warrant careful consideration in therapeutic strategies.

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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.

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