Central Application of Aliskiren, a Renin Inhibitor, Improves Outcome After Experimental Stroke Independent of Its Blood Pressure Lowering Effect

Cool results, now if we just get followup human studies. But that won't occur with our fucking failures of stroke associations.  We need as much oxygen rich blood flowing thru the brain as possible post stroke and lowering blood pressure to me seems to be the wrong thing to do, at least for ischemic strokes. But I'm not medically trained so I know nothing. 

Central Application of Aliskiren, a Renin Inhibitor, Improves Outcome After Experimental Stroke Independent of Its Blood Pressure Lowering Effect 

Hamdollah Panahpour^1,2†, Nicole A. Terpolilli^1,3,4†, David Schaffert⁵, Carsten Culmsee⁶ and Nikolaus Plesnila^1,4*

• ¹Laboratory of Experimental Stroke Research, Institute for Stroke and Dementia Research (ISD), Munich University Hospital, Munich, Germany
• ²Department of Physiology, Medical School, Ardabil University of Medical Sciences, Ardabil, Iran
• ³Department of Neurosurgery, Munich University Hospital, Munich, Germany
• ⁴Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
• ⁵Pharmaceutical Biotechnology, Department of Pharmacy, Ludwig-Maximilians University, Munich, Germany
• ⁶Institute for Pharmacology and Clinical Pharmacy, University of Marburg, Marburg, Germany

Epidemiological studies suggest that pharmacological reduction of systemic hypertension lowers incidence and severity of stroke. However, whether the reduction of blood pressure per se or the compounds used to reduce hypertension are responsible for this effect received little attention. In the current study we therefore aimed to investigate whether Aliskiren, a renin-inhibitor used to treat arterial hypertension, may improve outcome in a mouse model of ischemic stroke when applied centrally and in a dose not affecting blood pressure. Male C57BL/6 mice received 0.6, 2.0, or 6.0 μg Aliskiren or vehicle by intracerebroventricular injection as a pretreatment and were then subjected to 60 min of middle cerebral artery occlusion (MCAo). Infarct volume, brain edema formation, mortality, antioxidant effects, and functional outcome were assessed up to seven days after MCAo. Central administration of Aliskiren (0.6 or 2.0 μg) had no effect on systemic blood pressure but significantly reduced infarct volume and brain edema formation, blunted mortality, and improved neurological outcome up to 1 week after MCAo. Due to the central and prophylactic administration of the compound, we cannot make any conclusions about the potency of Aliskiren for acute stroke treatment, however, our study clearly demonstrates, that in addition to lowering blood pressure Aliskiren seems to have a direct neuroprotective effect. Hence, renin-inhibitors may be an effective addition to prophylactic treatment regimens in stroke patients.

Introduction

Epidemiological studies suggest that treating arterial hypertension reduces the incidence and the severity of ischemic and hemorrhagic stroke (1, 2). This effect is attributed to the reduction of hypertension, however, an alternative explanation could be that pharmacological compounds used to reduce systemic blood pressure may in addition also have neuroprotective effects.

One pathway that has been implicated in the pathophysiology of hypertension and ischemic stroke, is the renin-angiotensin-system (RAS) (3). The RAS plays a crucial role in the maintenance of blood pressure and blood volume. Drops in blood pressure or blood volume lead to secretion of renin, a protease, which hydrolyses angiotensinogen to angiotensin I (Ang I). Ang I is converted to Angiotensin II (Ang II), a strong vasoconstrictor, by angiotensin converting enzyme (ACE). Ang II activates Angiotensin 1 receptors (AT₁R), which induce vasoconstriction, inflammatory changes and oxidative stress, and Angiotensin 2 receptors (AT₂R) which mediate vasodilation via Angiotensin 1-7 (Ang1-7) and MAS receptors, the so called “alternative axis” (4).

Accordingly, the RAS reduces blood pressure via inhibition of AT₁ receptors and/or activation of AT₂ receptors, but may well deteriorate ischemic damage thorough vasoconstriction and the other actions of AT₁ receptors (4). In fact, inhibition of ACE or angiotensin type 1 receptors were shown to reduce arterial hypertension and to effectively prevent cerebro-vascular events (5, 6), while also being protective after cerebral ischemia. Further, activation of the AT₂ axis inferred neuroprotection after experimental stroke (7–9).

Despite this elegant work on the downstream members of the RAS, relatively little is known about the role of renin after stroke, the first step of the RAS-cascade, which is the rate-limiting enzyme of the whole system (10–12). The activity of renin can be inhibited by the small molecule Aliskiren, a clinically frequently used compound, which was shown to effectively reduce arterial hypertension (13–16), and its sequels, that is nephropathy (17, 18) and myocardial infarction (19, 20). With regard to cerebral ischemia, however, it is not known whether Aliskiren prevents stroke only by its blood pressure lowering effect or possibly also by a direct neuroprotective effect on the brain. To investigate this hypothesis we applied not blood pressure lowering doses of Aliskiren by intracerebroventricular injection to mice, subjected them to experimental stroke, and investigated infarct volume, brain edema formation, and neurological function for up to seven days thereafter.