PSG College of Pharmacy, Peelamedu, Coimbatore, TN, 641004, India.
PSG College of Pharmacy, Peelamedu, Coimbatore, TN, 641004, India.
Biomed Pharmacother. 2018 Jun;102:947-958. doi: 10.1016/j.biopha.2018.03.164. Epub 2018 Apr 5.
In the present study, we investigated the effects of angiotensin (Ang II) receptor blockers in cerebral ischemia by administration of telmisartan (AT blocker) and/or PD123319 (AT blocker) in global ischemic mice model. The neuroprotective effect of AT antagonists was evaluated through monitoring muscle co-ordination and cerebral blood perfusion in ischemic mice. Gene expression studies (NF-κB, GSK-3β, EAAT-2, AT & AT receptors) and staining of brain regions with cresyl violet, GFAP, synaptophysin and NSE methods were carried out in to understand the molecular mechanisms. Further, the brain glutamate, cytokines, and Ang II peptide levels were evaluated and their correlation with EAAT-2 mRNA expression was performed. Our results indicate that the induction of ischemia elevates brain Ang II, cytokines, and glutamate levels and reduced muscle co-ordination and cerebral blood perfusion. The expressions of NF-κB, GSK-3β and AT were significantly increased, whereas, EAAT-2 expression was decreased. Blocking of AT receptors by telmisartan (TM) reversed the detrimental responses of cerebral ischemia and restored the cerebral blood flow denoting blockade of Ang II/AT pathway is beneficial in ischemia, whereas, blockade of AT receptors by PD123319 (PD) increased the ischemic injury in mice. This vulnerable effect of PD may be attributed through augmenting the Ang II/AT dependent cytokines mediated glutamate transporter (EAAT-2) dysfunction. Interestingly, the beneficial effects of AT blocker was remarkably antagonized by AT blocker in most of the parameters studied in ischemic conditions. Also, the expression of AT receptors was significantly increased compared to that of AT receptors upon ischemic induction. It denotes that the endogenous Ang II predominantly acts on AT receptor, thereby promoting its own mRNA transcription. Hence, the increased expression of AT receptors in ischemic condition could be used as target protein for therapeutic benefit.
在本研究中，我们通过给予替米沙坦（AT 阻滞剂）和/或 PD123319（AT 阻滞剂）在全脑缺血小鼠模型中，研究了血管紧张素（Ang II）受体阻滞剂对脑缺血的影响。通过监测缺血小鼠的肌肉协调性和脑血流灌注来评估 AT 拮抗剂的神经保护作用。进行了基因表达研究（NF-κB、GSK-3β、EAAT-2、AT 和 AT 受体）以及用 Cresyl 紫、GFAP、突触小体和 NSE 方法对脑区进行染色，以了解分子机制。此外，还评估了脑内谷氨酸、细胞因子和 Ang II 肽水平，并对其与 EAAT-2 mRNA 表达的相关性进行了分析。我们的结果表明，缺血诱导会升高大脑 Ang II、细胞因子和谷氨酸水平，降低肌肉协调性和脑血流灌注。NF-κB、GSK-3β 和 AT 的表达显著增加，而 EAAT-2 的表达减少。替米沙坦（TM）阻断 AT 受体逆转了脑缺血的不良反应，恢复了脑血流，表明阻断 Ang II/AT 途径对缺血有益，而 PD123319（PD）阻断 AT 受体则增加了小鼠的缺血损伤。PD 的这种脆弱作用可能归因于增强了 Ang II/AT 依赖性细胞因子介导的谷氨酸转运体（EAAT-2）功能障碍。有趣的是，在缺血条件下，大多数研究参数中 AT 阻滞剂的有益作用都被 AT 阻滞剂显著拮抗。此外，与缺血诱导时的 AT 受体相比，AT 受体的表达显著增加。这表明内源性 Ang II 主要作用于 AT 受体，从而促进其自身的 mRNA 转录。因此，缺血状态下 AT 受体的表达增加可作为治疗受益的靶蛋白。
