Division of Neuroscience and Ageing Biology, CSIR-Central Drug Research Institute, Lucknow 226031, U.P., India.
Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, U.P., India.
ACS Chem Neurosci. 2022 May 18;13(10):1491-1504. doi: 10.1021/acschemneuro.1c00797. Epub 2022 May 9.
Hypertension is reported to cause major brain disorders including Parkinson's disease (PD), apart from cardiovascular and chronic kidney disorders. Considering this, for the first time, we explored the effect of modulation of the ACE2/Ang (1-7)/MasR axis using diminazene aceturate (DIZE), an ACE2 activator, in 6-hydroxydopamine (6-OHDA) induced PD model. We found that DIZE treatment improved neuromuscular coordination and locomotor deficits in the 6-OHDA induced PD rat model. Further, the DIZE-mediated activation of ACE2 led to increased tyrosine hydroxylase (TH) and dopamine transporters (DAT) expression in the rat brain, indicating the protection of dopaminergic (DAergic) neurons from 6-OHDA induced neurotoxicity. Moreover, 6-OHDA induced activation of glial cells (astrocytes and microglia) and release of neuroinflammatory mediators were attenuated by DIZE treatment in both as well as models of PD. DIZE exerted its effect by activating ACE2 that produced Ang (1-7), a neuroprotective peptide. Ang (1-7) conferred its neuroprotective effect upon binding with the G-protein-coupled MAS receptor that led to the upregulation of cell survival proteins while downregulating apoptotic proteins. Importantly, these findings were further validated by using A-779, a MasR antagonist. The result showed that treatment with A-779 reversed the antioxidative and anti-inflammatory effects of DIZE by decreasing glial activation and neuroinflammatory markers. Although the role of ACE2 in PD pathology needs to be additionally confirmed using transgenic models in either ACE2 overexpressing or knockout mice, still, our study demonstrates that enhancing ACE2 activity could be a novel approach for ameliorating PD pathology.
高血压被报道会导致主要的大脑紊乱，包括帕金森病（PD），除此之外还有心血管和慢性肾病紊乱。考虑到这一点，我们首次探索了使用二氮嗪（DIZE），一种 ACE2 激活剂，调节 ACE2/Ang（1-7）/MasR 轴对 6-羟多巴胺（6-OHDA）诱导的 PD 模型的影响。我们发现 DIZE 治疗改善了 6-OHDA 诱导的 PD 大鼠模型的神经肌肉协调性和运动缺陷。此外，DIZE 介导的 ACE2 激活导致大鼠脑中酪氨酸羟化酶（TH）和多巴胺转运体（DAT）表达增加，表明多巴胺能（DAergic）神经元免受 6-OHDA 诱导的神经毒性。此外，6-OHDA 诱导的神经胶质细胞（星形胶质细胞和小胶质细胞）激活和神经炎症介质释放被 DIZE 治疗在 PD 的 和 模型中减弱。DIZE 通过激活 ACE2 发挥作用，ACE2 产生神经保护肽 Ang（1-7）。Ang（1-7）与 G 蛋白偶联的 MAS 受体结合发挥其神经保护作用，导致细胞存活蛋白上调，同时下调凋亡蛋白。重要的是，这些发现通过使用 MasR 拮抗剂 A-779 得到进一步验证。结果表明，用 A-779 治疗会通过减少神经胶质细胞激活和神经炎症标志物来逆转 DIZE 的抗氧化和抗炎作用。尽管 ACE2 在 PD 发病机制中的作用需要使用 ACE2 过表达或敲除小鼠的转基因模型进一步确认，但我们的研究表明，增强 ACE2 活性可能是改善 PD 病理的一种新方法。
