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

Figure 1. Experimental setup. (A) Dose finding study. (B) Assessment of infarct volume and (C) brain water content 24 h after MCAo. (D) Measurement of antioxidant enzyme activity 24 h after MCAo. (E) Evaluation of outcome as assessed by Neurological Deficit Score for 7 days after MCAo.

Figure 2. Dose finding. Mean arterial blood pressure is not affected by injection of increasing doses of Aliskiren; after a cumulative dose of 6 μg MAP tends to lower, therefore no higher concentration was used.

Figure 3. Effect of Aliskiren on post-ischemic brain damage 24 h after MCAo. (A) CBF after induction of MCAo. Cerebral blood flow drops to <20% of baseline immediately after filament occlusion of the MCA in all groups. (B–D) Infarct volumes 24 h after MCAo. (B) Total infarct volume is significantly reduced in the 0.6 and 2 μg Aliskiren treatment groups. (C) Subcortical infarct volume was also reduced in these groups while (D) cortical infarct volumes were only significantly smaller in the 2 μg group compared to vehicle treated animals. (E) Exemplary coronal Nissl sections 24 h after MCAo.

Figure 4. Brain edema formation and neurological outcome after renin inhibition. (A) Brain water content 24 h after MCAo. Brain water content in the non-ischemic right hemisphere of all MCAo groups was not altered compared to sham operated animals; all animals that underwent ischemia showed significant brain edema formation in the left, i.e., ischemic hemisphere. Brain water content was significantly reduced by application of 0.6 μg Aliskiren. (B) Neurological deficit score after renin inhibition. Twenty four hours after MCAo all animals had significant motor deficits; Aliskiren 0.6 μg significantly improved the neurological scores; higher doses tended to reduce the score but did not have a significant effect on the animals performance.

Figure 5. Effects of Aliskiren (2 μg) on lipid peroxidation and brain tissue antioxidant enzyme activities in brain tissue homogenate of studied groups 24 h after MCAO. MDA, malondialdehyde; SOD, superoxide dismutase; CAT, catalase; GPX, glutathione peroxidase (n = 7). Values are mean ± SEM. †p < 0.001, +p < 0.01, and #p < 0.05 compared with sham group; **p < 0.01 and *p < 0.05 compared with vehicle group.

Figure 6. Functional outcome up to 7 days after MCAo. (A) While mortality in the vehicle group was 50% over time all Aliskiren animals survived. (B) Treatment animals recovered significantly quicker from post-ischemic weight loss. (C) Starting 2 days after MCAo, Aliskiren treated mice achieved significantly better scores for motor function.