Efficacy of Alpha-Lipoic Acid in Mitigating Neuropathic Pain: Mechanistic Insights and Therapeutic Implications

Neuropathic pain (NP), affecting 7–10% of the general population, results from damage to the somatosensory nervous system and leads to persistent discomfort, functional limitations, and psychological distress. This study investigates the analgesic effects of alpha-lipoic acid (ALA) on neuropathic pain management and elucidates the underlying biological mechanisms. A neuropathic pain model was induced via spinal nerve ligation (SNL), and pain behaviors were evaluated following intraperitoneal ALA injections at doses of 50, 100, and 200 mg/kg. Immunofluorescence assessed the activation of IBA1 and GFAP in the spinal L4 segment and dorsal root ganglia, while cytokine levels were measured to evaluate inflammatory responses. Mitochondrial integrity was analyzed with Transmission Electron Microscopy, and oxidative stress indicators were assessed through western blotting. Results showed that SNL mice exhibited heightened pain sensitivity, which was significantly reduced with ALA administration, improving both mechanical and thermal hyperalgesia. ALA treatment suppressed pro-inflammatory mediators, enhanced mitochondrial integrity, and decreased mitochondrial fission. Elevated oxidative stress markers were reduced, with ALA mitigating caspase-9, caspase-3, and Bax activity while promoting Bcl-2 expression. Additionally, ALA enhanced the level of PPARγ, facilitated the nuclear translocation of Nrf2 and inhibited NF-κB activation, leading to increased antioxidant levels and reduced inflammation. Thus, ALA effectively alleviated pain sensitivity and oxidative stress, improved mitochondrial structure, and decreased apoptosis, highlighting its potential as a promising therapeutic strategy for neuropathic pain management.