Cilostazol alleviates cerebral small-vessel pathology and white-matter lesions in stroke-prone spontaneously hypertensive rats

Small-vessel pathology is believed to have a critical role in cerebrovascular white-matter (WM) lesions. However, the cellular aspect of vascular pathology, including the phenotypic modulation of smooth-muscle cells (SMCs) and its role in the small-vessel disease, remains undefined. The involvement or otherwise of the phenotypic modulation of SMCs in cerebral small-vessel pathology has been investigated, and the effect of cilostazol on both the small vessels and the WM lesions has been determined in stroke-prone spontaneously hypertensive rats (SHRSP). Male SHRSP and Wistar Kyoto rats were used. SHRSP were divided into two groups: the cilostazol- treated (20-week treatment) and vehicle-treated groups. Small-vessel pathology was analyzed using both histopathology and immunohistochemistry for smooth-muscle actin and nonmuscle myosin heavy chain (SMemb, a marker for the synthetic phenotype of SMC). The pathological changes in the WM were quantified in terms of the numerical density of activated microglia and the degree of WM lesions. Vascular wall thickening and perivascular fibrosis, determined by the wall area/lumen area ratio and the Collagen area/total vessel area ratio, respectively, showed an increase in the vehicle-treated SHRSP, and this increase was significantly attenuated by cilostazol treatment. The percentage of small vessels immunopositive for SMemb was also reduced by cilostazol treatment. In the cilostazol- treated SHRSP, microglial activation and the degree of WM lesions were attenuated compared with the vehicle-treated SHRSP. The results indicated that cilostazol attenuates the phenotypic modulation of SMC associated with cerebral small-vessel pathology and WM lesions without causing changes in the blood pressure. (c) 2008 Elsevier B.V. All rights reserved.