The mechanism of 5-lipoxygenase in the impairment of learning and memory in rats subjected to chronic unpredictable mild stress.

Objectives: To examine the mechanism of 5-lipoxygenase (5-LO) in the learning and memory dysfunction in rats subjected to chronic unpredictable mild stress (CUMS).

Methods: Eighty rats were divided into eight groups: the 0.5% sodium carboxymethyl cellulose solution (NaCMC)-treated group, empty vector (LV-Mock)-treated group, CUMS+NaCMC-treated group, CUMS+sertraline-treated group, CUMS+caffeic acid (10mg/kg)-treated group, CUMS+caffeic acid (30mg/kg)-treated group, CUMS+LV-Mock-treated group, and CUMS+5-LO-silencers lentiviral vectors (LV-si-5-LO)-treated group, n=10. Sucrose preference tests were performed to assess depression-like behavior. The Morris water maze and step-down tests were used to evaluate learning and memory performance. The levels of inflammatory cytokines, malondialdehyde, and the activity of superoxide dismutase (SOD) were detected to estimate inflammation and oxidative stress. Changes in 5-LO mRNA and protein were detected using reverse transcription polymerase chain reaction and Western blotting. The expression of synaptophysin, postsynaptic density-95 (PSD-95), and brain-derived neurotrophic factor (BDNF) in the hippocampus were measured using immunohistochemical staining.

Results: Treatment with caffeic acid or LV-si-5-LO increased sucrose consumption, decreased escape latency and increased the number of platform crosses in the Morris water maze test, and decreased the number of errors and prolonged the latency in the step-down test. We observed a decreased expression of 5-LO, and levels of malondialdehyde, leukotriene-B4, tumor necrosis factor-α, and interleukin-6, while the protein levels of synaptophysin, PSD-95, BDNF, and the activity of SOD were increased in the hippocampus of the CUMS-treated rats.

Conclusions: CUMS-induced impairment in learning and memory could be triggered by an inflammatory response in the rat hippocampus, which results in oxidative stress injury and impacts the synaptic plasticity of hippocampal neurons. Inhibition of the activity or expression of 5-LO could suppress hippocampal inflammation, enhance synaptic plasticity, and improve learning and memory function in depressed rats.