Abstract
Minocycline (Mino) reduces reperfusion injury and inflammation after stroke in animals and humans, but the late effects on remodeling of the neurovascular unit are less well studied. Previously, we showed that tight junction proteins (TJPs) disappeared from microvessels after reperfusion injury, reappearing in newly formed vessels in peri-infarct regions (peri-I) at 3 weeks, and that MMPs are involved in BBB restoration during recovery. Prior studies of Mino investigated short-term neuroprotective effects with or without tPA. We hypothesized that early treatment with Mino would improve neurovascular remodeling during recovery. To test the hypothesis, we monitored the time course of neurovascular remodeling after spontaneous and Mino-induced stroke recovery. Adult spontaneously hypertensive rats had a 90 min transient MCAO with reperfusion. At the onset of reperfusion they received a single dose of Mino (3 mg/kg, i.v.) or vehicle. They were studied at multiple times up to 4 weeks with MRI, immunohistochemistry, and biochemistry. A single dose of Mino significantly reduced the infarct size and tissue loss in the ischemic hemispheres compared to vehicle-treated rats from 2 to 4 weeks as measured with anatomical T2 MRI and ADC. FA measured at 4 weeks showed improved white matter recovery. ASL showed that Mino improved cerebral blood flow in peri-I by 7 days after reperfusion. BBB permeability in peri-I was reduced with Mino at 4 weeks using dynamic contrast-enhanced MRI. By 4 weeks, Mino induced higher levels of TJPs (occludin, ZO-1, and claudin-5), and MMP-3. We found that active microglia/macrophages, surrounding and within the peri-I, expressed both pro-inflammatory factors (TNF-α and IL-1β) and anti-inflammatory factors (TGF-β and IL-10) at 4 weeks. Western blot analysis showed that treatment with Mino significantly reduced levels of TNF-α and IL-1β, and increased levels of TGF-β and IL-10. Our results suggest that the early treatment with Mino significantly promotes later neurovascular remodeling during stroke recovery by: 1) reducing brain tissue loss; 2) enhancing TJP formation in newly formed vessels; and 3) accelerating functional alteration of microglia activation from pro-inflammatory stage to anti-inflammatory stage.
Published Version
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