Exploitation of rat models for cerebrovascular dementia and studies on the pathogenesis and prevention.

鉴于我们对岛根县养老院住院人员的流行病学调查显示，一半以上的老年性痴呆尸检病例为脑血管性痴呆，我们开始利用目前100%自发发生卒中的易卒中自发性高血压(SHRSP)与OM/N株杂交建立脑血管性痴呆动物模型，其中我们注意到从美国NIH引进的24株正常血压株中，ADP聚集性检测的血小板功能最快。从血压和血小板功能中等的F1代中，我们获得了血压和血小板聚集性差异较大的F2代。F3是从中度高血压和血小板功能加速的F2中进一步获得的，通过与高血压和接近SHRSP的F3和接近OM/N的血小板功能的杂交，我们获得了观察到多发性脑梗塞所致腔隙性卒中的F4代尸检时n较多。这些F4后代的病理与人类脑血管性痴呆相似，暂时被命名为SPOM大鼠。详细的电子显微镜检查显示，这些大鼠的穿通动脉最初在外中层出现病变，被认为是局灶性变性和坏死，后来扩展到整个中层。巨噬细胞附着于内皮细胞，通过破坏紧密连接，破坏血脑屏障，侵入内膜下，引起大量纤维蛋白的渗透和沉积，导致管腔狭窄、闭塞，形成血栓。另一方面，被动回避实验清楚地表明这些SPOM表现出明显的行为障碍。因此，从SHRSP与OM/N杂交中筛选出一株新的SPOM菌株，可以从病理学和行为学两个方面建立人类脑血管性痴呆的模型，并可在该模型中进行进一步的预防研究。较少

Since our epidemiological survey of inmates of old people's home in Shimane Prefecture indicated that more than a half of autopsied cases of senile dementia was cerebrovascular dementia, we started our present studies to establish animal models for cerebrovascular dementia by cross breeding between stroke-prone SHR (SHRSP) developing stroke spontaneously in 100% nowadays and OM/N strain in which we noted platelet function tested by ADP aggregation was most accelerated among 24 normotensive strains introduced from NIH of USA. From Fl hybrids with intermediate blood pressure and platelet function, we obtained F2 generation which showed a wide variation in blood pressure and platelet aggregation. F3 was further obtained from F2 with moderate hypertension and accelerated platelet function, and by cross breeding between F3 with hypertension close to SHRSP and with platelet function close to OM/N we obtained F4 generation in which we observed lacunar stroke due to multiple cerebral infarctio … More n at post mortem pathological examination. The pathology of these F4 offspring was close to cerebrovascular dementia in man and these were tentatively named SPOM rats. Detailed electron microscopic examination revealed that perforating arteries in these rats showed initially lesions in the outer media considered as focal degeneration and necrosis which were later extended to the whole media. Then macrophages attached on the endothelial cells and invaded into subintima by disrupting tight junction and damaging blood brain barrier to induce massive infiltration and deposition of fibrin which resulted in narrowing of lumen and occlusion with thrombosis. On the other hand, passive avoidance test clearly demonstrated these SPOM showed obvious behavioral disturbance. Therefore, a new SPOM strain established by selective breeding from the crosses between SHRSP and OM/N can be a model for cerebrovascular dementia in man both from pathological and behavioral aspects, and prevention can be further studies in this model. Less