Li Yumei, Zhang Ting, Zhang Xiaojie, Zou Wenying, Gong Xian, Fu Jianliang
Department of Neurology, Shanghai Jiaotong University Affiliated Sixth People's Hospital.
Biol Pharm Bull. 2017 Mar 1;40(3):249-255. doi: 10.1248/bpb.b16-00567. Epub 2016 Dec 17.
To determine the combined effect of type 2 diabetes (T2D) and chronic cerebral hypoperfusion (CCH) on learning and spatial memory, we developed a rat model of CCH by permanent occlusion of bilateral common carotid arteries (2-vessel occlusion (2VO)) in high-fat diet (HFD)-fed rats injected with low-dose streptozotocin (STZ). Furthermore, we examined the effect of cinepazide maleate (CM) on cognitive deficits and brain damage in this rat model. Rats were maintained on HFD for 6 weeks and then injected with 35 mg/kg STZ to induce T2D. Sham or 2VO surgery was performed in non-diabetic or diabetic (DM) rats to obtain four groups: blank, DM, CCH, and DM-CCH groups. Cognitive function was tested by the Morris water maze (MWM) test. To determine the effects of the vasodilator cinepazide maleate (CM) on cognitive deficits and brain damage, DM-CCH rats were administered with 10 mg/kg CM or saline daily for 14 d. Neuronal damage in DM-CCH rats was associated with increased expression of glial fibrillary acidic protein (GFAP) and β-secretase 1 (BACE1), but decreased expression of choline acetyltransferase (ChAT). Moreover, the levels of all these proteins were significantly alleviated by CM treatment. These results suggest that T2D exacerbated CCH-induced brain damage and cognitive impairment, and CM ameliorated these effects.
为了确定2型糖尿病（T2D）和慢性脑灌注不足（CCH）对学习和空间记忆的联合影响，我们通过在高脂饮食（HFD）喂养的大鼠中注射低剂量链脲佐菌素（STZ）后永久性结扎双侧颈总动脉（双血管闭塞（2VO））建立了CCH大鼠模型。此外，我们研究了马来酸桂哌齐特（CM）对该大鼠模型认知缺陷和脑损伤的影响。大鼠维持高脂饮食6周，然后注射35mg/kg STZ以诱导T2D。在非糖尿病或糖尿病（DM）大鼠中进行假手术或2VO手术，以获得四组：空白组、DM组、CCH组和DM-CCH组。通过莫里斯水迷宫（MWM）试验测试认知功能。为了确定血管扩张剂马来酸桂哌齐特（CM）对认知缺陷和脑损伤的影响，DM-CCH大鼠每天给予10mg/kg CM或生理盐水，持续14天。DM-CCH大鼠的神经元损伤与胶质纤维酸性蛋白（GFAP）和β-分泌酶1（BACE1）表达增加有关，但胆碱乙酰转移酶（ChAT）表达降低。此外，CM治疗可显著减轻所有这些蛋白质的水平。这些结果表明，T2D加剧了CCH诱导的脑损伤和认知障碍，而CM改善了这些影响。
