MMP-9 inhibitors impair learning in spontaneously hypertensive rats

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 12(th) 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.