Abstract WMP118: Involvement of MMP-9 in Inflammation-induced White Matter Injury in a Novel Rat Model of Vascular Cognitive Impairment

Abstract

Objective: We have recently developed a rat model of white matter (WM) injury in stroke-prone spontaneously hypertensive rats (SHR-SP), which shows chronic oligodendrocyte death, blood-brain barrier (BBB) disruption, and cognitive impairment. In this study, we investigated the mechanisms of white matter damage secondary to chronic hypertensive disease. Methods: At 12 weeks of age, we subjected SHR-SP to permanent unilateral carotid artery occlusion (UCAO) followed by the Japanese permissive diet (JPD) and 1 % NaCl in drinking water. One group of UCAO/JPD rats received minocycline (50 mg/kg in DMSO, i.p. every other day for 9 weeks) and another had only UCAO/JPD with DMSO. WM lesions were characterized histologically, biochemically, and by MRI; cognitive impairment was tested by Morris water maze. Results: One to 3 weeks after UCAO/JPD, we found an increase in hypoxia inducible factor-1α (HIF-1α) in astrocytes, a fall in pyrol hydroxylase-2 (PHD-2), and an increase in matrix metalloproteinase-9 (MMP-9) expression. At week 1, there was infiltration of T-cells and MMP-9 co-localized with endothelial cells and neutrophils. By 3 weeks, we observed IgG leakage, indicating disruption of the BBB, with scattered hemorrhages. Long term treatment with minocycline prevented cognitive impairment along with reduction in T2-weighted image size, apparent diffusion coefficients, and fractional anisotropy compared to the vehicle-treated group. Relative cerebral blood flow was unaffected by minocycline treatment. Conclusion: Our results suggest that hypoxic hypoperfusion of the deep WM, which occurs secondary to hypertensive damage to blood vessels, initiates expression of MMP-9 and migration of T-cells, disrupting the BBB and damaging WM. The anti-inflammatory agent, minocycline, significantly protected the deep WM from injury.