Unraveling Shared Molecular Mechanisms in Alzheimer's, Parkinson's, and Neuropathic Pain: Targeting p38 MAPK and Wnt/beta-Catenin Pathways
CNS Neurol Disord Drug Targets. 2026 Oct 6. doi: 10.2174/0118715273492918261001111401. Online ahead of print.
ABSTRACT
Neurodegenerative disorders, including Alzheimer's Disease (AD), Parkinson's Disease (PD), and Neuropathic Pain (NP), share overlapping molecular and cellular mechanisms that contribute to progressive neuronal dysfunction, neuroinflammation, and impaired neural repair. Although these conditions present with distinct clinical manifestations, accumulating evidence indicates that dysregulation of the p38 mitogen-activated protein kinase (p38 MAPK) and Wnt/β-catenin signaling pathways represents a common pathogenic axis underlying disease initiation and progression. Activation of p38 MAPK amplifies inflammatory signaling, mitochondrial dysfunction, oxidative stress, neuronal apoptosis, and glial activation, whereas suppression of Wnt/β-catenin signaling disrupts synaptic plasticity, blood-brain barrier integrity, neurogenesis, and neuronal survival. The reciprocal interaction between these pathways further exacerbates amyloid-β accumulation, dopaminergic neuronal degeneration, tau hyperphosphorylation, central sensitization, and persistent neuroimmune activation, thereby linking cognitive decline, motor impairment, and chronic pain. This review comprehensively examines the molecular crosstalk between p38 MAPK and Wnt/β-catenin signaling across AD, PD, and NP, highlighting their roles in regulating neuroinflammation, oxidative stress, mitochondrial homeostasis, and neuronal resilience. In addition, it summarizes emerging pharmacological agents, natural bioactive compounds, and targeted therapeutic strategies designed to inhibit p38 MAPK activation or restore Wnt/β-catenin signaling to promote neuroprotection and functional recovery. Particular emphasis is placed on the translational potential of dual-pathway modulation as a disease-modifying approach that addresses shared pathological mechanisms rather than isolated disease- specific manifestations. By integrating current experimental and clinical evidence, this review provides a unified mechanistic perspective, identifies promising therapeutic opportunities for developing more effective interventions against neurodegenerative disorders and neuropathic pain, and outlines the remaining challenges for future translational research.
PMID:42864926 | DOI:10.2174/0118715273492918261001111401