Abstract
Cerebral ischemia-reperfusion (I/R) injury leads to neuronal loss through oxidative stress, inflammation, and apoptosis. Curcumin, memantine, and caffeic acid possess antioxidant and neuroprotective properties. This study compared their efficacy in a rat model of transient cerebral ischemia. Forty male Wistar albino rats were initially allocated into six experimental groups; however, the vehicle control group was excluded from statistical analyses, and data are presented for five groups (n = 8 per group): sham, ischemia-reperfusion (I/R), I/R + curcumin (300 mg/kg/day), I/R + memantine (10 mg/kg/day), and I/R + caffeic acid (10 μmol/kg/day). Transient ischemia was induced by bilateral carotid artery occlusion for 30 min followed by 72 h reperfusion. Treatments were administered intraperitoneally beginning 30 min after reperfusion and continued once daily for five consecutive days. Histopathological and immunohistochemical analyses of the frontoparietal cortex demonstrated that I/R induced severe neuronal degeneration, necrosis, gliosis, vascular hyperemia, and marked inflammatory and apoptotic activation, with severity scores reaching the highest grade (3) (p < 0.001 vs. sham). Memantine and caffeic acid significantly reduced all degenerative, inflammatory, and apoptotic parameters (p < 0.001), restoring histopathological morphology to levels not statistically different from the sham group (p > 0.05). In particular, caspase-3, IL-1β, TNF-α, and TUNEL positivity were markedly suppressed in both treatment groups. In contrast, curcumin treatment resulted in only partial attenuation of neuronal degeneration and inflammatory infiltration, without achieving statistical significance in most parameters (p > 0.05 vs. I/R). Correlation analyses revealed strong negative associations between antioxidant enzyme activities (GR and GST) and histopathological damage scores (r = -0.71 to -0.82, p < 0.001), as well as strong positive correlations between apoptotic/inflammatory markers and neuronal injury severity (r = 0.68 to 0.79, p < 0.001). These findings demonstrate that memantine and caffeic acid exert robust histopathological neuroprotection against cerebral ischemia-reperfusion injury, whereas curcumin shows limited efficacy under the applied experimental conditions.