Neuroprotective effects of spermidine in stroke and other neurological disorders: mechanisms and translational challenges

Objective (background) Spermidine (SPD), an endogenous polyamine, has garnered increasing interest for its pleiotropic biological activities and potential benefits for neurological health. This review aims to evaluates the evidence for SPD’s neuroprotective effects in neurological disorders, with particular emphasis on its emerging role in intracerebral hemorrhage (ICH), and to delineate its multifaceted mechanisms of actions Methods We systematically reviewed and synthesized the available preclinical literature on SPD in models of stroke, Alzheimer’s disease (AD), Parkinson’s disease (PD), depression, anxiety, and epilepsy, with a focused analysis on ICH. Key mechanistic studies were examined to identify the core pathways underlying SPD’s neuroprotective actions. Results A core mechanism underlying SPD’s neuroprotective effects is the induction of protective autophagy, primarily through inhibition of the mechanistic target of rapamycin pathway. Additionally, SPD also demonstrates potent anti-neuroinflammatory effects, which consequently reduces the production of pro-inflammatory cytokines such as interleukin-1β, interleukin-6, and tumor necrosis factor-α. Furthermore, SPD alleviates oxidative stress by enhancing antioxidant defenses and helps preserve blood–brain barrier integrity through upregulating tight junction proteins like Zonula Occludens-1. Conclusion Clinical translation of SPD faces key challenges, including limited human pharmacokinetic data and unclear context-dependent mechanisms. Nonetheless, its robust preclinical efficacy and favorable safety profile support SPD as a promising candidate for future neuroprotective strategies.