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P4‐061: INCREASED UREA LEVELS IN THE BRAIN OF ENDOTHELIAL NITRIC OXIDE SYNTHASE DEFICIENT MICE
Author(s) -
Hariharan Ashwini,
Jing Yu,
Collie Nicola D.,
Zhang Hu,
Liu Ping
Publication year - 2018
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2018.06.2464
Subject(s) - enos , urea , medicine , endocrinology , nitric oxide , nitric oxide synthase , ammonia , endothelial nos , nitric oxide synthase type iii , pathogenesis , chemistry , biochemistry
causing significant impact in daily life. It is second common form of dementia after Alzheimer’s disease, occurring post stroke of large artery to small vessel disease affecting aged population. Understanding about different signaling pathways involved in synaptic plasticity affected during vascular damage leading to cognitive dysfunction will help in novel therapeutic strategies. Methods:Endothelin 1 (ET-1) is a 21 amino acid vasoconstrictor peptide acts through ETA and ETB, G protein coupled receptors expressed in vascular endothelial as well as smooth muscle cells to maintain vascular function. Stimulation of ETB receptor results in release of nitric oxide shifting towards vasoconstriction and inflammation. We injected ET-1 bilaterally into intracerebroventricular space in lateral ventricles of C57 mice to induce vasoconstriction while control micewere injected with saline. To confirm vasoconstriction and inflammation expression of CD31, a marker of endothelial cells as well as Iba1, a microglial marker was examined using immunohistochemistry. Further we performed contextual fear conditioning (cFc) to study learning deficit followed by western blot in hippocampal lysate for markers of Akt1-mechanistic target of rapamycin (mTOR) signaling. Results: Mice injected with ET-1 showed deceased expression of CD 31 at hippocampal region compared to control demonstrating vasoconstriction. Further there was microglial activation in the regions around lateral ventricles and hippocampus marking neuroinflammation after 3 days of ET-1 treatment. Reduced blood flow in hippocampal region caused deficit in recall after contextual fear conditioning (cFc) at 7 days of ET-1 treatment indicating associative learning is affected. We observed decreased phosphorylation of AKt-1 resulting in low Akt1-mTOR signaling and consequent decrease in GSK a/b signaling in hippocampus after 7 days indicating activity dependent protein translation is affected. Conclusions: There was prominent deficit in associative memory as a consequence of reduced blood flow after endothelin injection. ET-1 caused impairment of Akt1mTOR signaling indicates a possible molecular mechanism for synaptic plasticity during vasoconstriction. The present study is an attempt to understand molecular underpinnings of vascular pathology and behavior in small-scale stroke, in the large disease spectrum of vascular dementia.