IGF-II: a neuroprotective agent against Cocaine-induced oxidative stress and apoptosis

Abstract

Excessive cocaine (benzoylmethylecgonine) consumption has been associated with neurodegenerative diseases affecting dopaminergic neurons, such as Parkinson’s disease (PD). Insulin-like growth factor II (IGF-II) has demonstrated protective effects against oxidative stress induced by neuropathologies and drug exposure. This study evaluates the impact of cocaine on neuronal morphology and viability and investigates IGF-II’s potential neuroprotective role using SN4741 dopaminergic cells. Cells were exposed for 24 hours to either cocaine alone or cocaine with IGF-II. Cell death (LDH assay) and morphological alterations (Giemsa staining) were assessed, alongside mitochondrial integrity and function (OCR, Seahorse), membrane potential (JC-1), and ROS production (DHE) after 6-hour treatments. An optimal cocaine concentration (2 mM) was measured, inducing 39.75% neuronal death. IGF-II (1.5 ng/mL), established as effective in previous studies, significantly reduced cocaine-induced cell death (280% increase vs. control). Morphological changes induced by cocaine, including globular shape, membrane thinning, loss of neurites, and cell aggregation, were prevented by IGF-II co-treatment. Cocaine significantly increased ROS levels (173.6%) and reduced mitochondrial membrane potential (20%), both indicative of apoptosis induction. IGF-II effectively reversed these effects, preventing oxidative stress and preserving mitochondrial function. Furthermore, IGF-II mitigated a 60% reduction in mitochondrial oxygen consumption induced by cocaine. In conclusion, IGF-II exhibits potent antioxidant and neuroprotective properties, counteracting cocaine-induced oxidative stress, mitochondrial dysfunction, and neuronal degeneration. These findings support IGF-II as a potential therapeutic agent against cocaine-related neurotoxicity.