Melatonin Effects on PI3K/Akt Pathway and Cognitive Function in Hypoxic Rat Hippocampal Neurons

This study aims to investigate whether melatonin improves cognitive dysfunction in rats, induced by intermittent hypoxia, by modulating the PI3K/Akt signaling pathway, using an intermittent hypoxia animal model.

Sixty-four male Wistar rats were randomly assigned to the following groups: normoxic control (UC), intermittent hypoxia (IH), PI3K inhibitor (PI3K-i), and melatonin intervention (MT), with n = 16 per group. Subgroups were distributed across 2-, 4-, 6-, and 8-week time points. Except for the UC group, all other groups underwent daily 7-hour IH exposure. The MT group and PI3K-i group received intraperitoneal injections of melatonin (10 mg/kg) or PI3K inhibitor GDC-0084 (20 mg/kg), respectively, prior to exposure. Cognitive function was assessed using the Morris water maze. Immunohistochemistry examined expression of p-PI3K, p-Akt, Nrf2, and HO-1 in the hippocampal CA1 region. Statistical analysis employed two-way ANOVA with Tukey's post hoc test; partial η² was reported.

Behavioral data showed that the escape latency in the IH group significantly increased with prolonged exposure duration (2W: 21.30 ± 1.23 seconds, 8W: 55.61 ± 1.49 seconds), while the percentage of time spent in the target quadrant decreased (2W: 76.25 ± 1.72%, 8W: 22.76 ± 2.73%). The MT group demonstrated superior cognitive performance at all time points compared to the IH group (e.g., escape latency at 4 weeks: 28.74 ± 0.85 seconds vs. 32.24 ± 1.03 seconds, p < 0.05). Protein expression analysis revealed that p-PI3K, p-Akt, Nrf2, and HO-1 expression in both IH and MT groups exhibited an initial increase followed by a decrease, peaking at 4 weeks (e.g., IH group p-PI3K: 2.25 ± 0.09; MT group: 2.73 ± 0.05). Protein expression in the MT group was significantly higher than in the IH group (all p < 0.05), while expression in the PI3K-i group showed no significant difference from the UC group. Both treatment and time interactions were significant (e.g., p-PI3K: F(9,48) = 189.18, p < 0.001, η² = 0.86).

Melatonin may alleviate oxidative stress induced by intermittent hypoxia by regulating the PI3K/ AKT signaling pathway and related antioxidant protein expression, thereby improving cognitive function in rats. PI3K inhibitors effectively blocked the upregulation of these proteins, whose expression levels showed no significant difference overall compared to the untreated group.