Neuroprotective effects of agomelatine in a D-galactose-induced hippocampal aging model

Low melatonin levels are common features of both aging and depression, conditions associated with hippocampal degeneration resulting from neuronal damage, as well as a decline in the survival of various hippocampal cell types, including neural stem cells (NSCs) that generate new neurons. The novel antidepressant agomelatine (Ago), a melatonin (MT) receptor agonist, may enhance hippocampal cell survival. Male Wistar rats were intraperitoneally injected with D-galactose (D-gal, 100 mg/kg) for 14 weeks to induce aging. During the last 4 weeks, they received either Ago (40 mg/kg) or melatonin (10 mg/kg) as a positive control. Our results showed that D-gal-induced hippocampal aging led to increased expression of hypoxia-inducible factor 1 alpha (HIF-1α), which was consistent with elevated vascular endothelial growth factor (VEGF) levels. Treatment with either Ago or melatonin decreased HIF-1α and VEGF levels. Furthermore, Ago and melatonin treatment stimulated phosphorylation of VEGFR2 in the hippocampus, which contains NSCs. This activation is associated with stimulation of the phosphatidylinositol 3-kinase/AKT (PI3K/AKT) survival pathway and increased production of brain-derived neurotrophic factor (BDNF). The NSC population (nestin-positive cells) increased, as did the population of immature neurons (doublecortin (DCX)- and Tuj1-positive cells. Ago and melatonin treatments also enhanced synaptic function, as indicated by elevated postsynaptic density protein 95 (PSD95) and synaptophysin, both of which are associated with spatial memory measured using the Morris water maze (MWM) test. Our findings demonstrate that Ago improves memory function in aging rats, potentially through enhanced hippocampal survival, mediated by increased pVEGFR2, which is correlated with the PI3K/AKT signaling pathway.