Time-of-Day Effects of Platelet-Derived Exosomes on Cognitive-Emotional Functions in an Animal Model of Methamphetamine Addiction.

Methamphetamine addiction leads to profound cognitive and emotional impairments through persistent neuroinflammatory and neurodegenerative processes. Recent advances suggest that platelet-derived exosomes possess the potential to promote neurorepair and functional recovery. However, the therapeutic efficacy of exosomes may be influenced by time-of-day administration, given that neural plasticity, blood-brain barrier function, and exosomal dynamics are strongly modulated by diurnal rhythms. Understanding how treatment timing across the daily cycle modulates the neuroprotective and behavioral effects of platelet-derived exosomes is critical to optimizing their therapeutic potential in addiction-related neuropsychiatric disorders. Accordingly, the present study was designed and implemented to evaluate the impact of time-of-day administration in improving the effects of platelet-derived exosomes (pExo) on methamphetamine-induced neurotoxicity. In this study, sixty adult male Wistar rats were divided into five groups and subjected to chronic methamphetamine exposure and subsequent pExo treatment during either the active or the rest phase. Spatial learning and memory were assessed using the Morris water maze, whereas anxiety-like behavior was evaluated through the elevated plus maze and grooming behavior tests. Furthermore, hippocampal indices of cell death, apoptosis, neurogenesis, and neuroinflammation were analyzed. The results demonstrated time-of-day-dependent efficacy of pExo, with administration during the Rest-phase-onset significantly enhancing spatial memory performance (p<0.05), whereas treatment during the active-phase-onset more effectively attenuated anxiety-like behaviors. Moreover, pExo delivery in the Rest-phase-onset led to a greater reduction in apoptosis and a more pronounced induction of neurogenesis relative to the active-phase-onset. However, no significant difference was observed in the expression of Iba1, a marker of neuroinflammation, between the two groups (p=0.35). These findings reveal a time-of-day-dependent modulation of pExo therapy efficacy, suggesting that aligning treatment administration with the rest-activity cycle could optimize neurorestorative outcomes. This time-tailored therapeutic approach may open new avenues for enhancing neural recovery and reducing relapse risk in individuals with substance use disorders.