Alpha-Lipoic Acid Derivatives: A Multifunctional Neuroprotective Agent with Potential for Treating Ischemic Stroke

Abstract Ischemic stroke (IS) is a major public health burden due to its high mortality and disability rates. Neuroinflammation and ferroptosis are two key drivers of IS progression. α-Lipoic acid (ALA) exhibits both anti-ferroptosis and anti-inflammatory activities; however, its anti-ferroptosis efficacy is suboptimal. In this study, we designed and synthesized 23 ALA derivatives. Among them, D14 exhibited the most potent anti-ferroptosis activity, with an EC50 value of 0.00247 μM, an approximately 16,000-fold improvement over ALA, while retaining comparable anti-inflammatory activity (IC50 = 13.6 μM). Mechanistically, D14 scavenged free radicals and activated the Nrf2/GPX4 pathway to restore GSH levels and reduce MDA, Fe2+, and ROS accumulation, thereby inhibiting ferroptosis. D14 also suppressed NF-κB activation by preventing IκBα degradation and p65 phosphorylation, and it reduced IL-1β, IL-6, and TNF-α secretion. In a rat middle cerebral artery occlusion (MCAO) model, D14 reduced cerebral infarct volume and ameliorated neurological deficits, surpassing ALA and the clinically used drug edaravone. Preliminary toxicity evaluation of D14 indicated a favorable safety profile. Overall, D14 is a promising multi-target lead compound for the treatment of IS.