Research Progress on the Role of AMPK Signaling Pathway in the Regulation of Neural Injury

Nerve Injury (NI) imposes a severe clinical burden involving energy failure, neuroinflammation, oxidative stress, and apoptosis. This review aims to systematically synthesize structural insights into AMP-activated protein kinase (AMPK), elucidate its multifaceted molecular mechanisms in NI, and evaluate AMPK-targeted pharmacological interventions.

A comprehensive literature search across major databases (PubMed, Web of Science, Scopus, and Google Scholar) identified peer-reviewed in vitro and in vivo studies focusing on AMPK mechanisms, structural pharmacology, signaling networks (e.g., AMPK/mTOR, AMPK/SIRT1), and drug targeting in various neural injury models.

Upon cellular energy deficit, AMPK induces neuroprotective autophagy via the AMPK/mTOR/ULK1 axis and combats oxidative stress and neuroinflammation by promoting PGC-1α-mediated mitochondrial biogenesis and suppressing NF-κB. Conversely, AMPK dysregulation exacerbates neuronal death. Pharmacological agents demonstrate robust preclinical neuroprotection, though clinical application is hindered by off-target systemic toxicity and poor Blood-Brain Barrier (BBB) permeability.

The findings highlight AMPK as a pivotal modulator of interconnected metabolic stress response cascades. While pharmacological agents demonstrate robust preclinical neuroprotection, their clinical application is currently hindered by off-target systemic toxicity, lack of isoform specificity, and poor blood-brain barrier (BBB) permeability.

AMPK represents a highly promising therapeutic target for mitigating NI. Translating preclinical successes into clinical practice demands rigorous Structure-Activity Relationship (SAR) optimization to develop CNS-penetrant, isoform-selective modulators, thereby maximizing targeted neuroprotection while minimizing adverse systemic effects.