Department of Pharmacology, Post Graduate Institute of Medical Education & Research, 160012, Chandigarh, India.
Department of Pharmacology, Post Graduate Institute of Medical Education & Research, 160012, Chandigarh, India.
Brain Res Bull. 2019 Jan;144:233-245. doi: 10.1016/j.brainresbull.2018.11.013. Epub 2018 Nov 22.
Role of apoptosis and neuroinflammation have been well established in the pathogenesis of epilepsy. It has been reported that the activation of nuclear factor-erythroid 2-related factor-2 (Nrf2) contributes to the attenuation of inflammation by inhibiting nuclear factor-kB (NF-kB) pathway. Therefore, the present study was designed to evaluate anti-inflammatory and anti-apoptotic role of dimethyl fumarate (DMF), an activator of Nrf2, in chemical kindling model in rats.
Chemical kindling model was established in Wistar rats by intraperitoneal (i.p.) administration of pentylenetetrazole (PTZ). Animals were treated with DMF (60 mg/kg) to activate the Nrf2 antioxidant response element (ARE) pathway. The animals were assessed for seizure score, neuronal damage and inflammatory cytokines levels (IL-1β, IL-6 and TNF-α) in hippocampus. The mRNA levels of various genes (Nrf2, HO-1, NQO1, Bcl2, Bax, Caspase 3, NF-kB, IL-6, IL-1β and TNF-α) were quantified by real-time PCR. The expression of anti-oxidative (Nrf2), apoptotic (Bax, Bcl2) and inflammatory (NF-kB) proteins were analysed by western blot. Immunohistochemistry (Bax) and electron microscopy were done to assess apoptosis.
The results showed reduction in the seizure score, percentage of kindled rats and neurological damage score in DMF treated rats. Pro-inflammatory cytokines concentrations were also decreased by DMF treatment. DMF downregulated the expression of inflammatory (NF-kB) and apoptotic (Bax, Caspase-3) genes and protein. DMF treatment increased the gene expression of Nrf2, HO-1, NQO1, Bcl-2 and protein expression of Nrf2 and Bcl2.
DMF demonstrated anti-apoptotic, anti-inflammatory and anti-oxidative effect in hippocampus, which might be regulated by increased level of antioxidant response elements.
细胞凋亡和神经炎症在癫痫发病机制中的作用已得到充分证实。据报道，核因子-红细胞 2 相关因子 2（Nrf2）的激活通过抑制核因子-κB（NF-κB）途径有助于减轻炎症。因此，本研究旨在评估激活 Nrf2 的富马酸二甲酯（DMF）在大鼠化学点燃模型中的抗炎和抗凋亡作用。
通过腹腔内（i.p.）给予戊四氮（PTZ）在 Wistar 大鼠中建立化学点燃模型。用 DMF（60mg/kg）处理动物以激活 Nrf2 抗氧化反应元件（ARE）途径。评估动物的癫痫发作评分、海马神经元损伤和炎性细胞因子水平（IL-1β、IL-6 和 TNF-α）。通过实时 PCR 定量各种基因（Nrf2、HO-1、NQO1、Bcl2、Bax、Caspase 3、NF-kB、IL-6、IL-1β和 TNF-α）的 mRNA 水平。通过 Western blot 分析抗氧化（Nrf2）、凋亡（Bax、Bcl2）和炎症（NF-kB）蛋白的表达。进行免疫组织化学（Bax）和电子显微镜检查以评估细胞凋亡。
结果表明，DMF 治疗可降低癫痫发作评分、点燃大鼠的百分比和神经损伤评分。DMF 治疗还降低了促炎细胞因子的浓度。DMF 下调了炎症（NF-kB）和凋亡（Bax、Caspase-3）基因的表达以及 NF-kB、Bax、Caspase-3 蛋白的表达。DMF 治疗增加了 Nrf2、HO-1、NQO1、Bcl-2 的基因表达和 Nrf2 和 Bcl2 的蛋白表达。
DMF 在海马体中表现出抗凋亡、抗炎和抗氧化作用，这可能是通过增加抗氧化反应元件的水平来调节的。
