Lead-induced neurotoxicity: molecular mechanisms, oxidative stress and emerging pharmacological neuroprotective strategies

Lead (Pb) is a persistent environmental toxicant that poses a significant threat to human health, particularly because of its adverse effects on the central nervous system (CNS). Both acute and chronic lead exposure can interfere with normal neuronal function, while exposure during prenatal and early postnatal development may produce long-lasting neurological and cognitive abnormalities. Lead-induced neurotoxicity involves multiple interconnected molecular mechanisms, including disruption of calcium homeostasis, altered neurotransmitter signalling, mitochondrial dysfunction, oxidative stress, neuroinflammation and neuronal apoptosis. Among these mechanisms, oxidative stress plays a central role by increasing reactive oxygen species (ROS), reducing endogenous antioxidant defence, promoting lipid peroxidation and damaging cellular proteins and DNA. Lead also interferes with antioxidant enzymes, including superoxide dismutase, catalase and glutathione peroxidase, thereby weakening neuronal resistance to oxidative injury. Conventional management of lead poisoning involves eliminating the exposure source, supportive care and chelation therapy in appropriately selected patients. However, chelation does not reliably reverse established neurological damage. Consequently, increasing attention has been directed towards pharmacological neuroprotective agents, including N-acetylcysteine, vitamins C and E, curcumin, resveratrol, melatonin, alpha-lipoic acid and mitochondria-targeted antioxidants. These compounds have demonstrated antioxidant, anti-inflammatory or antiapoptotic properties in experimental models. Furthermore, modulation of Nrf2/ARE, NF-κB, SIRT1/AMPK and mitochondrial apoptotic pathways represents a promising direction for future drug development. This review critically discusses the molecular mechanisms of lead-induced neurotoxicity, the importance of oxidative stress and the potential of emerging pharmacological interventions. It also identifies limitations in current research and highlights the need for controlled clinical investigations to establish the safety and therapeutic efficacy of experimental neuroprotective agents