H2 S、NO 和 BDNF-TrkB 信号通路参与辛伐他汀对戊四唑诱导的点燃和认知障碍的保护作用。,Basic & Clinical Pharmacology & Toxicology

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H2 S、NO 和 BDNF-TrkB 信号通路参与辛伐他汀对戊四唑诱导的点燃和认知障碍的保护作用。
Basic & Clinical Pharmacology & Toxicology ( IF 2.7 ) Pub Date : 2020-06-20 , DOI: 10.1111/bcpt.13457
Marwa A Ahmed ₁ , Esam O Kamel ₂

Affiliation

在戊四唑 (PTZ) 点燃的小鼠中观察到认知功能障碍。评估了辛伐他汀 (SIM) 对 PTZ 诱导的小鼠点燃和认知障碍的潜在有效性。还研究了 SIM 对硫化氢 (H ₂ S)、一氧化氮 (NO)、活性醛和脑源性神经营养因子/酪氨酸受体激酶 B (BDNF-TrkB) 信号的影响。小鼠的点燃和认知障碍是通过每隔一天 12 次 ip 注射 PTZ (35 mg/kg) 引起的。活性醛和亚硝酸盐的含量增加，而 H ₂S 在 PTZ 处理的小鼠中降低。这些结果伴随着醛脱氢酶 2、胱硫醚 β-合酶、BDNF 和 TrkB 基因表达的减少。在 PTZ 点燃的小鼠中，观察到与组织病理学变化相关的脑诱导型一氧化氮合酶蛋白表达增加。SIM 给药（1、5 和 10 mg/kg，每天口服）以及隔天 PTZ（35 mg/kg）导致 PTZ 诱导的点燃减少，认知功能出现剂量依赖性改善。SIM (10 mg/kg) 在不同程度上预防了与 PTZ 点燃小鼠相关的紊乱，并改善了皮质、小脑和海马结构。这些结果表明 SIM 触发了多种机制，通过调节氧化应激、H₂ S、NO 和 BDNF-TrkB 信号通路。

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Involvement of H2 S, NO and BDNF-TrkB signalling pathway in the protective effects of simvastatin against pentylenetetrazole-induced kindling and cognitive impairments.

Cognitive dysfunction was observed in pentylenetetrazole (PTZ)‐kindled mice. The potential effectiveness of simvastatin (SIM) on PTZ‐induced kindling and cognitive impairments in mice was evaluated. The influence of SIM on hydrogen sulphide (H₂S), nitric oxide (NO), reactive aldehydes and brain‐derived neurotrophic factor/tyrosine receptor kinase B (BDNF‐TrkB) signalling was also investigated. Kindling and cognitive impairments in mice were induced by 12 ip injections of PTZ (35 mg/kg) once every alternate day. The levels of reactive aldehydes and nitrite were increased while H₂S was decreased in PTZ‐treated mice. These results were accompanied by a reduction in the gene expression of aldehyde dehydrogenase 2, cystathionine β‐synthase, BDNF and TrkB. In PTZ‐kindled mice, a rise in brain inducible nitric oxide synthase protein expression associated with histopathological changes was observed. SIM administration (1, 5 and 10 mg/kg, daily orally) along with alternate day of PTZ (35 mg/kg) resulted in a decrease in PTZ‐induced kindling with a dose‐dependent improvement in cognitive function. SIM (10 mg/kg) prevented, to variable extent, the disturbances associated with PTZ‐kindled mice with cortical, cerebellar and hippocampal structural improvement. These results suggested that SIM triggers multiple mechanisms that improve cognitive function in PTZ‐kindled mice through modulation of oxidative stress, H₂S, NO and BDNF‐TrkB signalling pathway.

更新日期：2020-06-20

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