Neuroprotective Effect of Fisetin Through Suppression of IL-1R/TLR Axis and Apoptosis in Pentylenetetrazole-Induced Kindling in Mice.
Neuroprotective Effect of Fisetin Through Suppression of IL-1R/TLR Axis and Apoptosis in Pentylenetetrazole-Induced Kindling in Mice.
复制标题
DOI：
10.3389/fneur.2021.689069
复制
发表时间：
2021
影响因子：
3.4
通讯作者：
Alam O
中科院分区：
文献类型：
--
作者：
Khatoon S;Agarwal NB;Samim M;Alam O
癫痫是一种复杂的神经系统疾病，其特征是大脑区域频繁的电活动。炎症和细胞凋亡级联激活是癫痫发作期间严重的神经系统后遗症。 Fisetin（3, 3',4',7-四羟基黄酮）是一种类黄酮分子，被认为具有有效的抗炎和抗凋亡特性。本研究调查了非瑟酮对实验性癫痫的神经保护作用。对于急性研究，进行了增加电流电击（ICES）和戊四唑（PTZ）诱导的癫痫试验来评估非瑟酮的抗癫痫活性。对于慢性研究，通过给予亚惊厥剂量的 PTZ（25 mg/kg，腹腔注射）建立点燃模型。小鼠接受非瑟酮（5、10 和 20 毫克/千克，口服）治疗，以研究其可能的抗癫痫机制。对点燃的小鼠进行癫痫评分评估。对他们的海马体和皮层的神经元损伤、炎症和细胞凋亡进行了评估。在实验小鼠的海马体中观察到组织学改变。通过 ELISA 评估海马和皮质中高迁移率族蛋白 1 (HMGB1)、Toll 样受体 4 (TLR-4)、白细胞介素 1 受体 1 (IL-1R1)、白细胞介素 1β (IL-1β)、白细胞介素 6 (IL-6) 和肿瘤坏死因子 α (TNF-α) 的水平。通过免疫组织化学分析和实时 PCR 定量核因子-κB (NF-κB)、环氧合酶-2 (COX-2)、细胞色素 C 和 caspase-3 的免疫反应性和 mRNA 表达。采用磷酸化 ELISA 来评估点燃小鼠海马体和皮质中的 AkT/mTOR（雷帕霉素的哺乳动物靶标）激活情况。结果表明，非瑟酮给药增加了 ICES 测试中的癫痫阈值电流（STC）。在 PTZ 诱发的癫痫发作中，使用非瑟酮会增加肌阵挛性抽搐 (MJ) 和全身性癫痫发作 (GS) 的潜伏期。在 PTZ 诱导的点燃模型中，给予非瑟酮剂量依赖性地抑制实验小鼠中点燃的发展和相关的神经元损伤。此外，非瑟酮的施用改善了点燃引起的神经炎症，从点燃小鼠海马和皮质中 HMGB1、TLR-4、IL-1R1、IL-1β、IL-6 和 TNF-α 水平的降低可以明显看出。此外，给予点燃的动物中非瑟酮后，炎症分子、NF-κB 和 COX-2 的免疫反应性和 mRNA 表达降低。据报道，在点燃小鼠的海马和皮层中施用非瑟酮后，AkT/mTOR 通路的磷酸化减少。使用非瑟汀后，细胞凋亡分子、细胞色素 C 和 caspase-3 的免疫反应性和 mRNA 表达减弱。研究结果表明，非瑟酮通过抑制炎症和凋亡分子的释放并减弱实验性癫痫期间的组织学改变而显示出神经保护作用。
Epilepsy is a complex neurological disorder, characterized by frequent electrical activity in brain regions. Inflammation and apoptosis cascade activation are serious neurological sequelae during seizures. Fisetin (3, 3′,4′,7-tetrahydroxyflavone), a flavonoid molecule, is considered for its effective anti-inflammatory and anti-apoptotic properties. This study investigated the neuroprotective effect of fisetin on experimental epilepsy. For acute studies, increasing current electroshock (ICES) and pentylenetetrazole (PTZ)-induced seizure tests were performed to evaluate the antiseizure activity of fisetin. For the chronic study, the kindling model was established by the administration of PTZ in subconvulsive dose (25 mg/kg, i.p.). Mice were treated with fisetin (5, 10, and 20 mg/kg, p.o.) to study its probable antiseizure mechanism. The kindled mice were evaluated for seizure scores. Their hippocampus and cortex were assessed for neuronal damage, inflammation, and apoptosis. Histological alterations were observed in the hippocampus of the experimental mice. Levels of high mobility group box 1 (HMGB1), Toll-like receptor-4 (TLR-4), interleukin-1 receptor 1 (IL-1R1), interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) were assessed in the hippocampus and cortex by ELISA. The immunoreactivity and mRNA expressions of nuclear factor-κB (NF-κB), cyclooxygenase-2 (COX-2), cytochrome C, and caspase-3 were quantified by immunohistochemical analysis and real-time PCR. Phosphorylation ELISA was performed to evaluate AkT/mTOR (mammalian target of rapamycin) activation in the hippocampus and cortex of the kindled mice. The results showed that fisetin administration increased the seizure threshold current (STC) in the ICES test. In PTZ-induced seizures, fisetin administration increased the latency for myoclonic jerks (MJs) and generalized seizures (GSs). In the PTZ-induced kindling model, fisetin administration dose-dependently suppressed the development of kindling and the associated neuronal damage in the experimental mice. Further, fisetin administration ameliorated kindling-induced neuroinflammation as evident from decreased levels of HMGB1, TLR-4, IL-1R1, IL-1β, IL-6, and TNF-α in the hippocampus and cortex of the kindled mice. Also, the immunoreactivity and mRNA expressions of inflammatory molecules, NF-κB, and COX-2 were decreased with fisetin administration in the kindled animals. Decreased phosphorylation of the AkT/mTOR pathway was reported with fisetin administration in the hippocampus and cortex of the kindled mice. The immunoreactivity and mRNA expressions of apoptotic molecules, cytochrome C, and caspase-3 were attenuated upon fisetin administration. The findings suggest that fisetin shows a neuroprotective effect by suppressing the release of inflammatory and apoptosis molecules and attenuating histological alterations during experimental epilepsy.
登录
查看更多内容
影响因子：
6.1
作者：
Iori, Valentina;Iyer, Anand M.;Vezzani, Annamaria
通讯作者：
Vezzani, Annamaria
影响因子：
6.3
作者：
Bartsch, Thorsten;Doehring, Juliane;Jansen, Olav
通讯作者：
Jansen, Olav
影响因子：
5.1
作者：
Ahmad, Ashfaq;Ali, Tahir;Kim, Myeong Ok
通讯作者：
Kim, Myeong Ok
影响因子：
3
作者：
Ishikawa, Nobustune;Kobayashi, Yoshiyuki;Kobayashi, Masao
通讯作者：
Kobayashi, Masao
影响因子：
3.6
作者：
Hoda, Ubedul;Agarwal, Nidhi Bharal;Raisuddin, Sheikh
通讯作者：
Raisuddin, Sheikh