Li_2025_Transl.Neurosci_16_20250379

OBJECTIVE: Acute sleep deprivation (ASD) is prevalent in contemporary society. This study explored the mechanism of melatonin affecting cognitive dysfunction (CD) in ASD mice through the nuclear factor kappaB (NF-kappaB) pathway and oxidative stress. METHODS: The ASD mouse model was established and treated with low-dose and high-dose melatonin, a NF-kappaB inhibitor PDTC, or lipopolysaccharide (LPS), with their spatial memory, spontaneous activity, and anxiety assessed. Hippocampal morphology and neuronal status were observed via HE and Nissl staining. Superoxide dismutase (SOD) activity and levels of hippocampal CA1 region postsynaptic density protein 95 (PSD95), phosphorylated (p)-p65, and p-IkappaB proteins; acetylcholinesterase (AChE), acetylcholine (ACh), malondialdehyde (MDA), and reactive oxygen species (ROS); and IL-4, IL-10, tumor necrosis factor [TNF]-alpha, and IL-1beta levels were determined by western blot and ELISA kits. RESULTS: ASD mice exhibited reduced learning and memory abilities and spontaneous activities, loosely-arranged cells in the hippocampal CA1 region, unclear cell body boundaries, enlarged gaps, severe neuronal damage, and reduced PSD95 protein level. There were increases in AChE, p-p65, p-IkappaB, TNF-alpha, IL-1beta, MDA, and ROS levels, decrements in ACh, IL-4, and IL-10 levels and SOD activity in the hippocampal CA1 region of ASD mice. Melatonin or PDTC inhibited the NF-kappaB pathway, down-regulated TNF-alpha, IL-1beta, MDA, and ROS and up-regulated IL-4 and IL-10 and SOD activity in the hippocampal CA1 region of ASD mice, and improved the learning and memory abilities. LPS-induced NF-kappaB pathway activation partially averted melatonin's beneficial effects on ASD mice. CONCLUSION: Melatonin ameliorated ASD-induced CD in mice by modulating the NF-kappaB pathway and oxidative stress.