Impact of levetiracetam on cognitive impairment, neuroinflammation, oxidative stress, and neuronal apoptosis caused by lipopolysaccharides in rats

INTRODUCTION: Neuroinflammation is associated with the elevation of toxic proinflammatory mediators that promote neurodegeneration and subsequently affect cognition. Causes of inflammation in the neuronal cells are believed to initiate various neurodegenerative disorders, mainly Alzheimer’s disease. Levetiracetam is a second-generation antiepileptic drug. There is evidence supporting the memory-enhancing effect of levetiracetam from numerous experimental and clinical studies. Therefore, this research focused on finding its protective effects against lipopolysaccharides prompted cognitive impairment and exploring possible mechanisms underlining their neuroprotection. METHODOLOGY: Two doses (100 or 200 mg/kg) of levetiracetam were administrated orally for 30 days. Additionally, four doses (250 µg/kg) of lipopolysaccharide were injected peripherally to induce neurotoxicity. Behavioral tests were carried out using various maze models. At the end of the tests, brain tissues were collected for biochemical evaluations. Cholinergic, neuroinflammatory, apoptosis, and oxidative-related parameters were analyzed in the brain homogenate to explore the possible mechanisms of action of levetiracetam. RESULTS: In lipopolysaccharide-induced rats, levetiracetam indicated a reduction (p < 0.01) in transfer latency using the elevated plus-maze. An improvement (p < 0.01) in novel and familiar objects exploration time using novel object recognition test. A rise (p < 0.05) in novel arm entries and extended time spent in the novel arm using the Y-maze test. In extension, the levels of acetylcholine (p < 0.001), anti-inflammatory factors (transforming growth factor-β1; p < 0.01 and interleukin-10; p < 0.05), and an antioxidant (catalase; p < 0.01) were elevated in lipopolysaccharide-induced rats after the administration of levetiracetam. In contrast, inflammatory factors (cyclooxygenase-2; p < 0.05, nuclear factor kappa B; p < 0.05, tumor necrosis factor-α; p < 0.01, and interleukin-6 (p < 0.01), apoptosis inducers (BCL2-associated X protein; p < 0.05 and Caspase-3 (p < 0.001), and oxidative stress (malondialdehyde; p < 0.05) were considerably reduced with levetiracetam in lipopolysaccharide-induced rats. CONCLUSION: The collective results suggested that levetiracetam may be able to treat neuroinflammatory-related memory loss by enhancing cholinergic activity while reducing neuroinflammation, cellular apoptosis, and oxidative stress.