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Stroke is a leading cause of death throughout the world, and angiotensin II (Ang II) acting via its type 1 receptors (AT1R) is well known to exert harmful effects in both the ischemic and hemorrhagic forms of this disease. In several cardiovascular diseases, the angiotensin converting enzyme 2/angiotensin-(1-7)/Mas (ACE2/Ang-(1-7)/Mas) axis of the renin-angiotensin system exerts beneficial actions, often in opposition to the deleterious actions of Ang II/AT1R. Therefore we have investigated the potential beneficial actions of the ACE2/Ang-(1-7)/Mas axis in both ischemic and hemorrhagic stroke. Ischemic stroke was induced in Sprague-Dawley (SD) normotensive rats by intracranial injection of endothelin-1 (ET-1; 3 ul of 80 uM) to elicit middle cerebral artery occlusion (MCAO). For this and all other surgical procedures anesthesia was induced using a mixture of oxygen and isoflurane (4%), and was maintained during the procedure with oxygen/isoflurane (2%). Following the surgeries, before waking, rats were administered the analgesic buprenorphine (0.05 mg/kg). Intracerebroventricular (icv) infusion of Ang-(1-7) [1.1 nM; 0.5 ul/h] via osmotic minipumps prior to and during ET-1 induced MCAO elicited significant neuroroprotection, as indicated by a >50% reduction in infarct size and improved performance on behavioral tests. Similar neuroprotection was elicited by icv infusion of the ACE2 activator diminazine aceturate (DIZE; 5 ug/0.5 ul/h) as above. These beneficial effects of Ang-(1-7) and DIZE were abolished by central infusion of the Mas receptor blocker A-779 (1.14 nM; 0.5 ul/h). Importantly, DIZE exerted similar neuroprotective actions when administered systemically postischemic stroke. For example, intraperitoneal (IP) injection of DIZE (0.75-7.5 mg/kg) at 4, 24 and 48 h post ET-1-induced MCAO produced significant (~40%) decreases in cerebral infarct size and behavioral deficits, effects that were reversed by icv administered A-779 (1.14 nM; 0.5 ul/h). In stroke prone spontaneously hypertensive rats (spSHR), an animal model of hemorrhagic stroke, icv infusion of Ang-(1-7) as above elicited a significant reduction in the number of striatal hemorrhages and increased the lifespan of these rats. With respect to mechanism, these protective actions of Ang-(1-7)/DIZE were not associated with either altered blood pressure, cerebral blood flow or (in the case of ischemic stroke) attenuation of ET-1 action. However, Ang-(1-7) administered icv as above exerts anti-inflammatory effects, reducing the increased levels of pro-inflammatory cytokines and microglial activation within cerebral infarct zone following ischemic stroke, and reducing the numbers of microglia within the striatum of spSHR. In vitro studies using microglia isolated from rat cerebral cortex and striatum indicate that Ang-(1-7) (100 nM) decreases activation of these cells and reduces the levels of pro-inflammatory cytokines, confirming an anti-inflammatory action of this peptide. In summary our data indicate that induction of the ACE2/Ang-(1-7)/Mas axis produces powerful anti-stroke actions, and may represent a novel therapeutic avenue for both ischemic and hemorrhagic stroke [ABSTRACT FROM AUTHOR]