Lamotrigine Attenuates Lipopolysaccharide-Induced Working-Memory Impairment and Is Associated with Changes in Neuroinflammatory, Oxidative-Stress, and Apoptosis-Related Markers

Abstract

Highlights What are the main findings? Lamotrigine (LTG) ameliorated lipopolysaccharide (LPS)-induced working-memory impairment and suppressed neuroinflammatory responses in the prefrontal cortex. LTG reduced oxidative stress and pro-apoptotic signaling while restoring endogenous antioxidant and anti-apoptotic defenses. What are the implications of the main findings? LTG may exert neuroprotective effects through coordinated regulation of inflammatory, oxidative, and apoptotic pathways. These findings support further investigation of LTG as a potential therapeutic strategy for inflammation-associated working-memory impairment. Abstract Background/Objectives: Persistent neuroinflammation, oxidative imbalance, and neuronal apoptosis are key mechanisms underlying memory loss and working-memory impairment in many neurodegenerative conditions. LTG, an established anticonvulsant recognized for its glutamate-modulating and immune-dampening actions, has been reported to exert neuroprotective actions beyond seizure control. This study investigated whether LTG can counteract LPS-induced deficits in cognition and neuroinflammatory responses in rats by modulating oxidative stress- and apoptosis-related markers. Methods: A total of twenty-four rats were allocated into four different groups: Control, LPS, LTG, and LTG + LPS. LTG (30 mg/kg, orally) was administered for 15 days, whereas LPS (1 mg/kg, intraperitoneally) was administered during the final four days to provoke neuroinflammation. Working memory abilities were assessed utilizing the Y-maze spontaneous alternation test. Subsequently, brain tissues were analyzed for inflammatory mediators (COX-2, TNF-α, IL-6), apoptotic markers (Caspase-3, Bcl-2, BAX), and oxidative stress indicators (MDA, GSH, catalase). Results: LPS exposure produced significant memory deterioration, accompanied by elevated COX-2, TNF-α, IL-6, and MDA levels, along with reduced GSH and catalase activity, indicating oxidative and inflammatory stress. BAX and Caspase-3 expression were markedly enhanced, whereas Bcl-2 expression was significantly reduced. Pretreatment with LTG markedly attenuated the LPS-induced decline in Y-maze performance, cytokine elevation, and alterations in redox and apoptotic parameters. Conclusions: LTG effectively attenuated LPS-induced cognitive impairment and neuroinflammatory responses, accompanied by improvements in oxidative stress- and apoptosis-related markers. These findings support further investigation of the potential preventive or neuroprotective effects of LTG against neuroinflammation-associated working-memory impairment.