Mani Vasudevan, Rashed Almutairi Salem
Department of Pharmacology and Toxicology, College of Pharmacy, Qassim University, Buraydah, Saudi Arabia.
Saudi Pharm J. 2023 Sep;31(9):101728. doi: 10.1016/j.jsps.2023.101728. Epub 2023 Aug 3.
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.
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.
In lipopolysaccharide-induced rats, levetiracetam indicated a reduction ( < 0.01) in transfer latency using the elevated plus-maze. An improvement ( < 0.01) in novel and familiar objects exploration time using novel object recognition test. A rise ( < 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 ( < 0.001), anti-inflammatory factors (transforming growth factor-β1; < 0.01 and interleukin-10; < 0.05), and an antioxidant (catalase; < 0.01) were elevated in lipopolysaccharide-induced rats after the administration of levetiracetam. In contrast, inflammatory factors (cyclooxygenase-2; < 0.05, nuclear factor kappa B; < 0.05, tumor necrosis factor-α; < 0.01, and interleukin-6 ( < 0.01), apoptosis inducers (BCL2-associated X protein; < 0.05 and Caspase-3 ( < 0.001), and oxidative stress (malondialdehyde; < 0.05) were considerably reduced with levetiracetam in lipopolysaccharide-induced rats.
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.
神经炎症与毒性促炎介质的升高有关，这些介质会促进神经退行性变并随后影响认知。据信，神经元细胞中的炎症原因会引发各种神经退行性疾病，主要是阿尔茨海默病。左乙拉西坦是一种第二代抗癫痫药物。大量实验和临床研究有证据支持左乙拉西坦的记忆增强作用。因此，本研究着重于发现其对脂多糖引发的认知障碍的保护作用，并探索其神经保护作用的潜在机制。
口服给予两剂（100或200毫克/千克）左乙拉西坦，持续30天。此外，外周注射四剂（250微克/千克）脂多糖以诱导神经毒性。使用各种迷宫模型进行行为测试。在测试结束时，收集脑组织进行生化评估。分析脑匀浆中的胆碱能、神经炎症、细胞凋亡和氧化相关参数，以探索左乙拉西坦可能的作用机制。
在脂多糖诱导的大鼠中，左乙拉西坦使用高架十字迷宫时的转移潜伏期缩短（<0.01）。使用新物体识别测试时，新物体和熟悉物体探索时间有所改善（<0.01）。使用Y迷宫测试时，新臂进入次数增加（<0.05），在新臂中花费的时间延长。此外，在给予左乙拉西坦后，脂多糖诱导的大鼠中乙酰胆碱水平（<0.001）、抗炎因子（转化生长因子-β1；<0.01和白细胞介素-10；<0.05）以及抗氧化剂（过氧化氢酶；<0.01）升高。相反，脂多糖诱导的大鼠中，左乙拉西坦可使炎症因子（环氧化酶-2；<0.05、核因子κB；<0.05、肿瘤坏死因子-α；<0.01和白细胞介素-6（<0.01）、细胞凋亡诱导剂（BCL2相关X蛋白；<0.05和半胱天冬酶-3（<0.001）以及氧化应激（丙二醛；<0.05）显著降低。
综合结果表明，左乙拉西坦可能通过增强胆碱能活性、同时减少神经炎症、细胞凋亡和氧化应激来治疗与神经炎症相关的记忆丧失。
