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Angiotensin II Peptide Vaccine Protects Ischemic Brain Through Reducing Oxidative Stress
Kouji Wakayama1, Munehisa Shimamura2, Jun-Ichi Suzuki1
1From the Department of Advanced Clinical Science and Therapeutics (K.W., J.-i.S.) and Department of Cardiovascular Medicine (H.A.), Graduate School of Medicine, The University of Tokyo, Japan; Department of Neurology (M.S., H.M.), Department of Health Development and Medicine (M.S., H.K., H.N.), and Department of Clinical Gene Therapy (R.M.), Graduate School of Medicine, Osaka University, Japan; and Department of Human Genetics and Disease Diversity (R.W.) and Department of Cardiovascular Medicine (R.W., M.I.), Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Japan.
Background And Purpose:
Medication nonadherence is one of major risk factors for the poor outcome in ischemic stroke. Vaccination is expected to solve such a problem because of its long-lasting effects, but its effect on ischemic brain damage is still unknown. Here, we focused on vaccination for renin-angiotensin system and examined the effects of angiotensin II (Ang II) peptide vaccine in permanent middle cerebral artery occlusion model in rats.
Methods:
Male Wistar rats were exposed to permanent middle cerebral artery occlusion after 3× injections of Ang II peptide vaccine, and the serum or brain level of anti-Ang II antibody was examined. The effects of the vaccine were evaluated by differences in infarction volume, brain renin-angiotensin system components, and markers for neurodegeneration and oxidative stress.
Results:
Ang II vaccination successfully produced anti-Ang II antibodies in serum without concomitant change in blood pressure. Sufficient production of serum anti-Ang II antibody led to reduction of infarct volume and induced the penetration of anti-Ang II antibody in ischemic hemisphere, with suppressed expression of Ang II type 1 receptor mRNA. Vaccinated rats with sufficient antibody production showed the reduction of Fluoro-Jade B-positive cells, spectrin fragmentation, 4-hydroxynonenal-positive cells, and Nox 2 mRNA expression.
Conclusions:
Our findings indicate that Ang II vaccination exerts neuroprotective and antioxidative effects in cerebral ischemia, with renin-angiotensin system blockade by penetration of anti-Ang II antibodies into ischemic brain lesion. Ang II peptide vaccination could be a promising approach to treat ischemic stroke.