Neuroprotective Effect of the Combined Extract of Mentha piperita and Cornus officinalis Against Neuronal Cell Death and Scopolamine-Induced Memory Impairment

Mild cognitive impairment (MCI) represents an intermediate stage between normal aging and Alzheimer's disease. This study investigated the neuroprotective effects of a combined extract of <i>Mentha piperita</i> (MP) and <i>Cornus officinalis</i> (CO) (MC) using in vitro and in vivo models. In SK-N-SH cells, pretreatment with MC (50-150 μg/mL) significantly attenuated H₂O₂-induced cellular injury, as evidenced by a reduction in Annexin V-positive cells and an increase in brain-derived neurotrophic factor (<i>BDNF</i>) mRNA expression. Rosmarinic acid and loganin, the marker compounds of MP and CO, alone or combined at a 6:4 ratio, mitigated H₂O₂-induced decreases in cell viability and <i>BDNF</i> mRNA. In the in vivo study, male Sprague-Dawley rats were orally administered MC (50, 100, or 200 mg/kg/day) for 28 days, with phosphatidylserine (50 mg/kg/day) serving as a positive control. MC administration significantly improved cognitive performance in rats with scopolamine-induced memory impairment, as demonstrated by increased step-through latency in the passive avoidance test and reduced escape latency in the Morris water maze. Furthermore, in the probe trial, MC-treated rats spent significantly more time in the target quadrant, indicating enhanced spatial memory retention. Mechanistically, MC restored hippocampal acetylcholine levels and reversed the scopolamine-induced decrease in BDNF and its downstream signaling. Specifically, MC upregulated hippocampal BDNF expression and enhanced the phosphorylation of extracellular signal-regulated kinase (ERK), protein kinase B (AKT), and cAMP response element-binding protein (CREB). In conclusion, these results demonstrate that the MC extract possesses potent neuroprotective and learning- and memory-enhancing effects, highlighting its potential as a therapeutic candidate for managing age-related cognitive decline and MCI.