Resatorvid as a promising neuroprotective agent in pentylenetetrazol-kindling rat model: Suppressing neuroinflammation and enhancing cognitive and motor functions

IF 4.7 3区医学 Q1 PHARMACOLOGY & PHARMACY

European journal of pharmacology Pub Date : 2025-09-15 DOI:10.1016/j.ejphar.2025.178160

Mennatallah H. Zidan, Hanan S. El-Abhar, Samira Saleh , Nesrine S. El Sayed, Suzan M. Mansour

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Abstract

Toll-like receptor 4 (TLR4) plays a key role in promoting seizure susceptibility, neuronal damage, and network dysfunction in epilepsy through its downstream inflammatory pathways. However, the therapeutic potential of resatorvid, a TLR4 inhibitor remains underexplored. This study investigated the neuroprotective effects of resatorvid (0.25 mg/kg) in a pentylenetetrazole (PTZ)-induced kindling model in rats. Seizures were induced by PTZ (35 mg/kg, every other day, i.p), and once full kindling was established, animals received either resatorvid or the standard antiepileptic drug carbamazepine for 14 days.

Resatorvid significantly reduced seizure severity, duration, and latency, mirroring the effects of carbamazepine. Using the Morris water maze and open field tests demonstrated improvements in locomotor activity, spatial memory, and cognitive performance. These behavioral gains correlated with hippocampal histopathological improvements, including reduced neuronal damage in the CA1 and CA3 regions as observed via H&E staining.

At the molecular level, resatorvid treatment downregulated hippocampal protein expression of high mobility group box 1 (HMGB1), TLR4, and its downstream inflammatory signal, phosphorylated-nuclear factor kappa (NF-κ)B p65, and proinflammatory cytokines interleukin (IL)-1β and IL-8, while restoring that of the inhibitory kappa (Iκ)B. In addition, resatorvid reduced glial activation, as evidenced by decreased expression of the astrocytic marker GFAP and microglial marker Iba1 in the cytoplasm. These findings suggest that resatorvid exerts a multimodal neuroprotective effect by attenuating neuroinflammation and glial reactivity, preserving hippocampal structure, and improving cognitive and motor functions. Altogether, the results highlight resatorvid as a promising therapeutic candidate for epilepsy, warranting further exploration in preclinical and clinical settings.

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雷伐托维作为一种有前途的神经保护剂在戊四唑点燃大鼠模型中：抑制神经炎症和增强认知和运动功能。

toll样受体4 （TLR4）通过其下游炎症通路在癫痫发作易感性、神经元损伤和网络功能障碍中起关键作用。然而，一种TLR4抑制剂resatorvid的治疗潜力仍未被充分发掘。研究瑞托维（0.25 mg/kg）对戊四唑（PTZ）致大鼠点火模型的神经保护作用。PTZ （35 mg/kg，每隔一天，ig）诱导癫痫发作，一旦完全点燃，给予雷托维或标准抗癫痫药物卡马西平14天。瑞托维显著降低癫痫发作的严重程度、持续时间和潜伏期，与卡马西平的作用相似。使用Morris水迷宫和开放场地测试显示运动活动，空间记忆和认知表现的改善。这些行为的改善与海马组织病理学的改善相关，包括通过H&E染色观察到的CA1和CA3区域神经元损伤的减少。在分子水平上，resatorvid治疗下调海马高迁移率组盒1 （HMGB1）、TLR4及其下游炎症信号、磷酸化核因子κ B (NF-κ) p65、促炎细胞因子白介素(IL)-1β和IL-8的表达，同时恢复抑制性κ B的表达。此外，resatorvid降低了胶质细胞的激活，这可以通过细胞质中星形胶质细胞标记物GFAP和小胶质细胞标记物Iba1的表达降低来证明。这些发现表明，resatorvid通过减轻神经炎症和神经胶质反应性，保护海马结构，改善认知和运动功能，发挥多模式神经保护作用。总之，这些结果突出了resatorvid作为一种有希望的癫痫治疗候选药物，值得在临床前和临床环境中进一步探索。

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来源期刊

European journal of pharmacology 医学-药学

CiteScore

9.00

自引率

0.00%

发文量

572

审稿时长

34 days

期刊介绍： The European Journal of Pharmacology publishes research papers covering all aspects of experimental pharmacology with focus on the mechanism of action of structurally identified compounds affecting biological systems. The scope includes: Behavioural pharmacology Neuropharmacology and analgesia Cardiovascular pharmacology Pulmonary, gastrointestinal and urogenital pharmacology Endocrine pharmacology Immunopharmacology and inflammation Molecular and cellular pharmacology Regenerative pharmacology Biologicals and biotherapeutics Translational pharmacology Nutriceutical pharmacology.