Preliminary exploration of the mechanism of melatonin in ischemic brain injury: A comprehensive systematic review and meta-analysis

Melatonin is an endogenous neurohormone with potent antioxidant, anti-inflammatory, and anti-apoptotic properties. Acting as a free radical scavenger, it demonstrates significant neuroprotective potential in experimental models of ischemic stroke. To systematically evaluate the therapeutic efficacy and underlying molecular mechanisms of exogenous melatonin in rodent models of focal cerebral ischemia. A comprehensive literature search was conducted across PubMed, EMBASE, and Scopus for studies published between 1995 and July 2024. Risk of bias was assessed using the SYRCLE tool. Meta-analyses were conducted using CMA software, and the GRADE approach was used to rate evidence certainty. The protocol was registered with PROSPERO (CRD42023461295). A total of 48 preclinical studies were included. Compared to controls, melatonin significantly reduced infarct volume (SMD = 2.26, 95% CI: 1.86–2.66), neurological deficits (SMD = 4.22), brain edema (Hedges' g = 0.51), and cleaved caspase-3 expression (SMD = 3.06). Melatonin administration also suppressed pro-apoptotic markers (BAX), oxidative stress indicators (ROS, cytochrome C), pro-inflammatory cytokines (TNF-α, IL-1β, IL-6), and glial activation markers (GFAP, iNOS), while upregulating AKT signaling and enhancing neuronal survival. While melatonin appears to offer multi-target neuroprotection, small-study effects may have led to overestimation of its efficacy.