A novel pharmacodynamic model in rats for preventing vascular dementia from maintaining neurovascular coupling sensitivity

作者:Zhao, Xin; Liu, Jinyu; Yang, Shijun; Song, Dandan; Wang, Chen; Chen, Chen; Wang, Chengcheng; Pu, Feifei; Yang, Runmei; Li, Xiaoya; Wang, Qiuting; Ge, Shasha; Lin, Yulin; Liu, Xiuhua*; Cai, Dayong*
来源:European Journal of Pharmacology, 2018, 827: 149-158.
DOI:10.1016/j.ejphar.2018.03.010

摘要

Vascular dementia (VaD) is the common cognitive disorder derived mainly from lacunar stroke. The neurovascular coupling (NVC) dysfunction involves in its pathogenesis. VaD lacks suitable animal models for developing preventive therapies. This study aimed to confirm a model for preventing VaD via maintaining NVC sensitivity in rats. The model was replicated with autologous microthrombi against the background of hypercholesterolemia. A phosphodiesterase inhibitor (pentoxyfylline) was preventively administrated to confirm the role of NVC sensitivity. Cognitive function was evaluated as exploratory, learning and memorizing abilities. NVC sensitivity was defined as the ratio of microcirculative cerebral blood flow (Delta CBF) to the quantitative electroencephalograph (Delta qEEG) before and after penicillin stimulation. The pathogenesis of NVC dysfunction was explored as expressions of neuronal (nNOS), inducible (iNOS) and endothelial nitric oxide synthase (eNOS) in cerebral cortex. The model rats showed cognitive impairment, microvascular edema (2.54 +/- 0.30%, P < 0.01), neuronal edema (1.24 +/- 0.48%, P < 0.01) and nissl body loss (0.03 +/- 0.003%, P < 0.01) in cerebral cortex, and neuronal necrosis in hippocampal CA1 region (neuronal cell number 41.76 +/- 10.04 cells, P < 0.01) compared with sham group. The NVC dullness in model rats was confirmed as significantly decreased ratio of Delta CBF/Delta qEEG (0.05 +/- 0.02%, P < 0.01) compared with sham group (0.20 +/- 0.06%). The underlying mechanism of NVC dysfunction was found as imbalanced NOS expressions (decreased nNOS and eNOS, while increased iNOS levels in cerebral cortex). The NVC dullness was significantly relieved in pentoxyfylline administrated rats (0.12 +/- 0.06%, P < 0.01). It indicated that this model was suitable to evaluate candidates for preventing VaD via maintaining NVC sensitivity.