The serotonergic 5-HT7 receptor: A therapeutic target for mitigating acute stress-induced cognitive, neuroinflammatory, and oxidative damage in the hippocampus.

This study investigates the role of 5-HT7 receptors in mediating repeated acute stress-induced impairments on memory, hippocampal neuronal health, neuroinflammation, and oxidative stress in mice. By elucidating these mechanisms, we aim to identify novel therapeutic targets to mitigate cognitive deficits resulting from acute stress. Mice were randomly assigned to four groups: control, stress, 5-HT7 receptor agonist (AS19, 5 mg/kg, i.p.) + stress, and 5-HT7 receptor antagonist (SB-269970, 2.5 mg/kg, i.p.) + stress. Cognitive and avoidance memory were assessed using the novel object recognition (NOR) and passive avoidance (PA) tests, respectively. Hippocampus tissue was analyzed for BDNF levels via ELISA, neuronal density through hematoxylin staining, and TNFα inflammatory marker via immunofluorescence. Additionally, oxidative stress markers including total oxidant status (TOS), malondialdehyde (MDA), total antioxidant capacity (TAC), superoxide dismutase (SOD), total thiol groups (TTG), and glutathione (GSH) were measured. Our findings demonstrate that repeated acute stress significantly impairs memory, reduces hippocampal BDNF levels and neuronal density, and increases neuroinflammation and oxidative stress. Crucially, administration of the 5-HT7 receptor agonist, AS19, effectively ameliorated these stress-induced deficits, while the antagonist, SB-269970, had no protective effect. These results highlight the 5-HT7 receptor as a promising therapeutic target for combating the detrimental effects of acute stress on brain health and cognitive function.