This Is MS Multiple Sclerosis Knowledge & Support Community

3. Hypoperfusion and reduced cerebral blood flow cause neurodegeneration in a mouse model characterizing vascular cognitive impairment and white matter changes.

Introduction: Reduced cerebral blood flow is associated with neurodegenerative disorders and dementia, in particular. Experimental evidence has demonstrated the initiating role of chronic cerebral hypoperfusion in neuronal damage to the hippocampus, the cerebral cortex, the white matter areas and the visual system. Permanent, bilateral occlusion of the common carotid arteries of rats (two vessel occlusion - 2VO) has been introduced for the reproduction of chronic cerebral hypoperfusion as it occurs in Alzheimer’s disease and human aging. Increased generation of free radicals through lipid peroxidation can damage neuronal cell membrane. Markers of lipid peroxidation have been found to be elevated in brain tissues and body fluids in neurodegenerative diseases, including Alzheimer’s disease, Parkinson disease and amyotrophic lateral sclerosis. [8]

J Neurol Sci. 2010 Dec 15;299(1-2):72-80. doi: 10.1016/j.jns.2010.08.035. Epub 2010 Sep 17.
Is endothelial dysfunction of cerebral small vessel responsible for white matter lesions after chronic cerebral hypoperfusion in rats?
Huang Y1, Zhang W, Lin L, Feng J, Chen F, Wei W, Zhao X, Guo W, Li J, Yin W, Li L.
Author information
Department of Neurology, Beijing Military General Hospital, Beijing, China.

Abstract

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.

Copyright © 2010 Elsevier B.V. All rights reserved.

PMID: 20850139 [PubMed - indexed for MEDLINE]

“Our latest finding gives us a new way of thinking about brain disease—that some conditions assumed to be caused by faulty neurons could actually be problems with faulty blood vessels,” Hillman adds. “This gives us a new target to focus on to explore treatments for a wide range of disorders that have, until now, been thought of as impossible to treat. The brain’s vasculature is a critical partner in normal brain function. We hope that we are slowly getting closer to untangling some of the mysteries of the human brain.”