Neuroprotective Effects of Platelet-Derived Exosomes in a Rat Model of Methamphetamine-Induced Neurotoxicity

Methamphetamine (METH) is a potent psychostimulant that induces severe neurotoxicity, leading to long-lasting cognitive and affective impairments. Despite its widespread abuse, effective therapeutic strategies for reversing METH-induced neural damage remain limited. Platelet-derived exosomes (pExos) have recently emerged as promising cell-free candidates for neurorestorative therapies. This study aimed to investigate the effect of pExos in a rat model of chronic methamphetamine addiction. Then, 36 male Wistar rats were divided into three experimental groups. The treatment group received METH coadministered with platelet exosomes. After 10 days, a series of behavioral tests were performed to evaluate the treatment's effect on memory, learning, depression, and anxiety-like behaviors. These tests included the Morris water maze, Novel object recognition, Elevated plus maze, and Forced swimming test. The rat hippocampus was evaluated by several methods including Nissl staining, Immunohistochemical assay for Caspase-3, Ki-67, Iba1, and qRT-PCR for Bax and Bcl2 gene expression analysis. Furthermore, the concentrations of IL-1β and TNF-α, as well as the levels of several oxidative stress markers were assessed. Treatment with pExos significantly improved learning, spatial memory retention, and recognition performance in METH-treated rats (P < 0.05). Also, pExos reduced depression and anxiety-like behaviors (P < 0.01). These behavioral enhancements were accompanied by reduced apoptosis, neuronal cell loss, and restoration of hippocampal cell proliferation. Additionally, a reduction in inflammatory cytokines and oxidative stress was demonstrated following exosome therapy (P < 0.01). These findings suggest that pExos offer a multifaceted neuroprotective effect against METH-induced brain injury by modulating apoptosis, inflammation, oxidative stress, and neuronal cell proliferation. Given their safety, accessibility, and efficacy, pExos could be a promising therapeutic platform to address substance-induced neurocognitive disorders.