El-Sayed Rehab M, Abdelaziz Ahmed M, Zaki Hala F, Abdel Rasheed Nora O
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Sinai University, El-Arish, Egypt.
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Sinai University, El-Arish, Egypt.
Int Immunopharmacol. 2023 Apr;117:109986. doi: 10.1016/j.intimp.2023.109986. Epub 2023 Mar 9.
Neuroinflammation induced by activation of the high mobility group box 1/ toll-like receptor 4 (HMGB1/TLR4) axis is one of the principal mechanisms involved in dopaminergic neuronal loss in Parkinson's disease (PD), and its activation exacerbates oxidative stress augmenting neurodegeneration.
This study investigated the novel neuroprotective effect of cilostazol on rotenone-intoxicated rats focusing on the HMGB1/TLR4 axis, erythroid-related factor 2 (Nrf2)/hemeoxygenase-1 (HO-1), and phosphoinositide 3-kinase (PI3K)/Protein kinase B (Akt)/the mammalian target of rapamycin (mTOR) pathway. The aim is extended to correlate the Nrf2 expression with all assessed parameters as promising therapeutic targets for neuroprotection.
Our experiment was designed as follows: vehicle group, cilostazol group, rotenone group (1.5 mg/kg, s.c), and the rotenone pretreated with cilostazol (50 mg/kg, p.o.) group. Eleven rotenone injections were injected day after day, while cilostazol was administered daily for 21 days.
Cilostazol significantly improved the neurobehavioral analysis, the histopathological examination, and dopamine levels. Moreover, the immunoreactivity of tyrosine hydroxylase (TH) in substantia nigra pars compacta (SNpc) enhanced. These effects were associated with enhancement of the antioxidant expression of Nrf2 and HO-1 by 1.01 and 1.08-fold, respectively, and repression of HMGB1/TLR4 pathway by 50.2 % and 39.3 %, respectively. Upregulation of the neuro-survival PI3K and Akt expression by 2.26 and 2.69-fold, respectively, and readjusting mTOR overexpression.
Cilostazol exerts a novel neuroprotective strategy against rotenone-induced neurodegeneration via activation of Nrf2/HO-1, suppression of HMGB1/TLR4 axis, upregulation of PI3K/Akt besides mTOR inhibition that compels more investigations with different PD models to clarify its precise role.
高迁移率族蛋白B1/ Toll样受体4（HMGB1/TLR4）轴激活所诱导的神经炎症是帕金森病（PD）中多巴胺能神经元丢失的主要机制之一，其激活会加剧氧化应激，增强神经退行性变。
本研究聚焦于HMGB1/TLR4轴、红细胞相关因子2（Nrf2）/血红素加氧酶-1（HO-1）以及磷酸肌醇3激酶（PI3K）/蛋白激酶B（Akt）/雷帕霉素靶蛋白（mTOR）通路，研究西洛他唑对鱼藤酮中毒大鼠的新型神经保护作用。该目的还扩展到将Nrf2表达与所有评估参数相关联，作为有前景的神经保护治疗靶点。
我们的实验设计如下：溶剂组、西洛他唑组、鱼藤酮组（1.5毫克/千克，皮下注射）以及鱼藤酮预处理西洛他唑组（50毫克/千克，口服）。每天注射鱼藤酮11次，而西洛他唑每天给药，持续21天。
西洛他唑显著改善了神经行为分析、组织病理学检查以及多巴胺水平。此外，黑质致密部（SNpc）中酪氨酸羟化酶（TH）的免疫反应性增强。这些作用分别与Nrf2和HO-1的抗氧化表达增强1.01倍和1.08倍相关，以及HMGB1/TLR4通路分别被抑制50.2%和39.3%相关。神经存活PI3K和Akt表达分别上调2.26倍和2.69倍，并重新调整mTOR的过表达。
西洛他唑通过激活Nrf2/HO-1、抑制HMGB1/TLR4轴、上调PI3K/Akt以及抑制mTOR，对鱼藤酮诱导的神经退行性变发挥了一种新型神经保护策略，这促使对不同PD模型进行更多研究以阐明其确切作用。
