Cerebral ischemia induced inflammatory response and altered glutaminergic function mediated through brain AT₁ and not...

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.