Combined and Separate Pretreatments with L-Theanine and Aerobic Exercise Modulate Cognitive Decline Following Chronic Neuroinflammation in Rats Exposed to Lipopolysaccharide

Chronic neuroinflammation is a prominent feature of several central nervous system disorders and contributes significantly to cognitive impairment. The present study aimed to investigate the effects of pretreatment with L-theanine (LT), aerobic exercise (ex), and their combination on cognitive deficits induced by subchronic lipopolysaccharide (LPS) administration in rats. Male Wistar rats were assigned to the following groups: control; veh-sed-LPS, sedentary (sed) rats treated with vehicle (veh) and LPS; LT-sed-LPS; veh-ex-LPS; and LT-ex-LPS. L-theanine treatment and/or treadmill running were administered for 5 weeks. Following these interventions, neuroinflammation was induced by LPS injections for 7 days, while the control group received veh treatment. Cognitive function was assessed using Y-maze, object recognition, and object location tests. Hippocampal cAMP response element-binding protein (CREB) phosphorylation status, β-amyloid (Aβ_1-42) accumulation, and pro-inflammatory cytokines (TNF-α, IL-1β) were measured by ELISA. Pretreatment with LT, ex, or their combination improved Y-maze performance and recognition memory, partly restoring the LPS-induced reduction in the pCREB/CREB ratio. Exercise, but not LT, reduced Aβ_1-42 levels and neuroinflammatory cytokine expression. Combined treatment produced additive benefits for some cognitive measures but not for spatial memory. These findings suggest that the prophylactic combination of LT and ex can partially attenuate cognitive impairments associated with subchronic neuroinflammation in this model.