Department of Pharmacology and Toxicology, Heliopolis University, Cairo, Egypt.
Department of Pharmacology and Toxicology, Ain Shams University, Cairo, Egypt.
Eur J Pharmacol. 2022 Oct 15;932:175204. doi: 10.1016/j.ejphar.2022.175204. Epub 2022 Aug 12.
Current treatments for Parkinson's Disease (PD) only provide symptomatic relief; however, they don't delay the disease progression, hence new treatment options should be considered. Carvedilol is a nonselective β & α1 blocker with additional effects as an antioxidant, anti-inflammatory and neuro protective properties. In this research, an insilico study was conducted to primarily evaluate carvedilol as an anti-parkinsonian and anti-tau protein target. PASS prediction was performed followed by a docking study of carvedilol. Carvedilol yielded promising results and forward guided this study onto its in vivo evaluation. The in vivo study aimed to assess the neuro-protective effects of carvedilol in rotenone-induced rat model of PD and investigate the potential underlying mechanisms. The effects of carvedilol (2.5, 5, and 10 mg/kg) on the measured parameters of open field, catalepsy, Y-maze tests as well as brain histology, and tyrosine hydroxylase (TH) were evaluated. The effective doses (5 and 10 mg/kg) were further tested for their potential anti-tau protein effects. Carvedilol (5 and 10 mg/kg) prevented rotenone-induced motor deficits, spatial memory dysfunction, and histological damage. Additionally, carvedilol significantly inhibited rotenone-induced decrease in TH expression in the striata of the rats. These effects were associated with reduction of rotenone-induced neuro-inflammation, microglial activation and release of glial fibrillary acidic protein (GFAP), along with reduction in N-methyl-D-aspartate receptors activation, alpha-synculein and phospho-Tau (P-Tau) protein expression. Carvedilol also reduced tau protein hyper-phosphosrylation by Glycogen synthase 3β (GSK 3β) inhibition and Phosphoinositide 3-kinase (PI3K) stimulation. Collectively, these results suggest that carvedilol might be a possible candidate for management of PD.
目前治疗帕金森病（PD）的方法仅能提供症状缓解，不能延缓疾病进展，因此需要考虑新的治疗方法。卡维地洛是一种非选择性β和α1阻断剂，具有抗氧化、抗炎和神经保护作用。在这项研究中，我们进行了一项计算机模拟研究，主要评估卡维地洛作为抗帕金森病和抗tau 蛋白靶点的作用。我们进行了 PASS 预测，然后对卡维地洛进行了对接研究。卡维地洛的研究结果非常有前景，因此我们将其进一步进行了体内评估。这项体内研究旨在评估卡维地洛在鱼藤酮诱导的 PD 大鼠模型中的神经保护作用，并探讨其潜在的作用机制。我们评估了卡维地洛（2.5、5 和 10mg/kg）对旷场试验、僵住试验、Y 迷宫试验以及大脑组织学和酪氨酸羟化酶（TH）的影响。我们进一步测试了有效剂量（5 和 10mg/kg）对 tau 蛋白的潜在作用。卡维地洛（5 和 10mg/kg）可预防鱼藤酮引起的运动功能障碍、空间记忆功能障碍和组织学损伤。此外，卡维地洛可显著抑制鱼藤酮诱导的大鼠纹状体 TH 表达下降。这些作用与减少鱼藤酮诱导的神经炎症、小胶质细胞激活和胶质纤维酸性蛋白（GFAP）释放以及减少 N-甲基-D-天冬氨酸受体激活、α-突触核蛋白和磷酸化 Tau（P-Tau）蛋白表达有关。卡维地洛还通过抑制糖原合酶 3β（GSK 3β）和刺激磷酸肌醇 3-激酶（PI3K）减少 tau 蛋白过度磷酸化。综上所述，这些结果表明卡维地洛可能是治疗 PD 的一种候选药物。
