Abstract
Vascular cognitive impairment dementia (VCID) is a major cause of cognitive loss in the elderly. Matrix metalloproteinases (MMPs) are a family of proteases involved in remodeling the extracellular matrix in development, injury and repair. Blood-brain barrier (BBB) disruption due to inflammation mediated by MMPs is a mechanism of white matter injury. Currently there are no treatments besides the control of vascular risk factors. We tested two MMP-9 inhibitors that improved outcome in acute stroke: DP-460 and SB-3CT. We hypothesized that these inhibitors would have a beneficial effect in chronic stroke by reducing edema in white matter and improving behavioral outcomes. Spontaneously hypertensive stroke-prone rats (SHRSPs) with unilateral carotid artery occlusion (UCAO) fed a Japanese Permissive Diet (JPD) were used as a model of VCID. JPD was begun in the 12th week of life. Rats were treated with DP-460 (500 mg/kg) for 4 weeks, or SB-3CT (10 mg/kg) for 8 weeks, beginning at the UCAO/JPD onset. Rats treated with a dextrose or DMSO solution served as vehicle controls. Naïve SHRSPs on a standard diet served as sham control. Magnetic resonance imaging (MRI) analyses of the corpus callosum, external capsule, hippocampus and Morris water maze behavioral tests were conducted. We found an increase in body weight (p = 0.004) and blood pressure (p = 0.007) at 15 weeks with the DP-460 drug. SB-3CT increased body weight at 14 weeks (p = 0.015) and had significant but variable effects on blood pressure. Neither drug affected imaging parameters. Behavioral studies showed an impaired ability to learn with DP-460 (p<0.001) and no effect on learning with SB-3CT. Unchanged MMP-9 levels were detected in DP-460-treated rats via gel zymography. Our findings suggest that MMPs are not major factors in white matter damage in the SHRSP model of VCID and that drugs that are relatively selective for MMP-9 can interfere with learning.
Highlights
We have shown that spontaneously hypertensive stroke-prone rats (SHRSPs) subjected to unilateral carotid artery occlusion (UCAO) and Japanese permissive diet (JPD), underwent white matter injury that is associated with Bloodbrain barrier (BBB) disruption.[9]
This BBB disruption occurred secondary to increased hypoxia-inducible factor-1α (HIF-1α), a transcriptional regulator elevated during hypoxia, which induced an matrix metalloproteinases (MMPs)-9-mediated infiltration of leukocytes.[7]
DP-460 had a detrimental effect on learning, while SB-3CT had no effect
Summary
Vascular cognitive impairment dementia (VCID) is an important cause of dementia and an accelerator of cognitive decline in Alzheimer’s disease (AD).[1, 2] Neuroinflammation is a major contributor to progressive injury to the white matter.[3, 4] Earlier, we showed that minocycline blocks the damage to the white matter and improves cognition in spontaneously hypertensive stroke-prone rats (SHRSPs), which is an animal model of VCID.[5, 6] Bloodbrain barrier (BBB) disruption mediated by pro-inflammatory matrix metalloproteinases (MMPs) is a major factor in the mechanism of white matter injury.[7, 8] Previously, we have shown that SHRSPs subjected to unilateral carotid artery occlusion (UCAO) and Japanese permissive diet (JPD), underwent white matter injury that is associated with BBB disruption.[9] This BBB disruption occurred secondary to increased hypoxia-inducible factor-1α (HIF-1α), a transcriptional regulator elevated during hypoxia, which induced an MMP-9-mediated infiltration of leukocytes.[7] The observed improvements in brain structure and function with minocycline could have been due to an indirect reduction in inflammation by blocking microglia activity or by directly blocking the action of MMP-9
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