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Cerebral ischemia induced inflammatory response and altered glutaminergic function mediated through brain AT 1 and not AT 2 receptor.
Biomedicine & Pharmacotherapy 2018 June
In the present study, we investigated the effects of angiotensin (Ang II) receptor blockers in cerebral ischemia by administration of telmisartan (AT1 blocker) and/or PD123319 (AT2 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, AT1 & AT2 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 AT1 were significantly increased, whereas, EAAT-2 expression was decreased. Blocking of AT1 receptors by telmisartan (TM) reversed the detrimental responses of cerebral ischemia and restored the cerebral blood flow denoting blockade of Ang II/AT1 pathway is beneficial in ischemia, whereas, blockade of AT2 receptors by PD123319 (PD) increased the ischemic injury in mice. This vulnerable effect of PD may be attributed through augmenting the Ang II/AT1 dependent cytokines mediated glutamate transporter (EAAT-2) dysfunction. Interestingly, the beneficial effects of AT1 blocker was remarkably antagonized by AT2 blocker in most of the parameters studied in ischemic conditions. Also, the expression of AT2 receptors was significantly increased compared to that of AT1 receptors upon ischemic induction. It denotes that the endogenous Ang II predominantly acts on AT2 receptor, thereby promoting its own mRNA transcription. Hence, the increased expression of AT2 receptors in ischemic condition could be used as target protein for therapeutic benefit.
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