Department of Neurology, Beijing Military General Hospital, Beijing, China.
J Neurol Sci. 2010 Dec 15;299(1-2):72-80. doi: 10.1016/j.jns.2010.08.035. Epub 2010 Sep 17.
Cerebral white matter (WM) lesions contribute to cognitive impairment and motor dysfunction in the elderly. Intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) are two important adhesion molecules that are upregulated during endothelial activation. Data from recent studies have suggested that ICAM-1 levels are related to progression of white matter hyperintensities (WMH) on MRI. In the present study, we hypothesized that ICAM-1 and VCAM-1 are involved in the endothelial dysfunction and the subsequent WM lesions after chronic cerebral hypoperfusion. Rats underwent bilateral common carotid artery ligation. They were divided into the lipoic acid group and the saline (vehicle) group. RT-PCR and double immunofluorescence for ICAM-1, VCAM-1, endothelial cells (staining positive for von Willebrand factor, vWF), reactive astrocytes (GFAP staining) and activated microglia/macrophages/(CD11b/c staining) were analyzed at baseline and at 1, 3, 7, 14 and 28 days after hypoperfusion. The severity of the WM lesions in the corpus callosum, internal capsule, and external capsule of both hemispheres was graded by luxol fast blue staining. RT-PCR and double immunofluorescence analysis of white matter from rats that had received lipoic acid (100mg/kg/day) for 28 days exhibited markedly reduced expression of ICAM-1 and VCAM-1 over endothelial cells compared with that of rats receiving saline. In the rats treated with lipoic acid, the WM lesions after chronic cerebral hypoperfusion were significantly less severe, and the number of reactive astrocytes and activated microglia/macrophages (CD11b/c staining) were also significantly lower as compared with the saline-treated rats. These findings indicate that endothelial dysfunction plays a critical role in overexpression of ICAM-1 and VCAM-1, glial cell activation and WM lesions after chronic cerebral hypoperfusion and suggest the potential value of lipoic acid as a therapeutic tool in cerebrovascular WM lesions. Our results also provide support for endothelial activation being involved in early pathogenesis of WM lesions and suggest that therapies that stabilize the endothelium may have a role in preventing WM lesions progression.
脑白质（WM）病变导致老年人认知障碍和运动功能障碍。细胞间黏附分子-1（ICAM-1）和血管细胞黏附分子-1（VCAM-1）是两种重要的黏附分子，在血管内皮细胞激活时上调。最近的研究数据表明，ICAM-1 水平与 MRI 上的白质高信号（WMH）进展有关。在本研究中，我们假设 ICAM-1 和 VCAM-1 参与了慢性脑低灌注后的内皮功能障碍和随后的 WM 病变。大鼠进行双侧颈总动脉结扎。它们被分为硫辛酸组和生理盐水（载体）组。在低灌注后 1、3、7、14 和 28 天，通过 RT-PCR 和 ICAM-1、VCAM-1、内皮细胞（von Willebrand 因子染色阳性，vWF）、反应性星形胶质细胞（GFAP 染色）和活化的小胶质细胞/巨噬细胞/（CD11b/c 染色）的双重免疫荧光进行分析。通过洛索夫快速蓝染色对双侧半球胼胝体、内囊和外囊的 WM 病变严重程度进行分级。用硫辛酸（100mg/kg/天）治疗 28 天的大鼠的 WM 组织的 RT-PCR 和双重免疫荧光分析显示，与接受生理盐水的大鼠相比，ICAM-1 和 VCAM-1 在血管内皮细胞上的表达明显减少。在接受硫辛酸治疗的大鼠中，慢性脑低灌注后的 WM 病变明显较轻，反应性星形胶质细胞和活化的小胶质细胞/巨噬细胞（CD11b/c 染色）的数量也明显低于接受生理盐水治疗的大鼠。这些发现表明，内皮功能障碍在慢性脑低灌注后 ICAM-1 和 VCAM-1 的过度表达、神经胶质细胞的激活和 WM 病变中起着关键作用，并表明硫辛酸作为一种治疗工具在脑血管 WM 病变中的潜在价值。我们的结果还为内皮激活参与 WM 病变的早期发病机制提供了支持，并表明稳定内皮的治疗可能在防止 WM 病变进展方面发挥作用。
