Abstract
Hypertensive
small vessel disease is a major cause of vascular cognitive impairment
(VCI). Spontaneously hypertensive/stroke prone rats (SHR/SP) with
unilateral carotid artery occlusion (UCAO) and a Japanese permissive
diet (JPD) have white-matter (WM) damage similar to that seen in VCI. We
hypothesized that WM injury was due to hypoxia-mediated, blood–brain
barrier (BBB) disruption. Twelve-week-old SHR/SP had UCAO/JPD and were
studied with immunohistochemistry, biochemistry, multimodal magnetic
resonance imaging (MRI), and Morris water maze (MWM) testing. One week
after UCAO/JPD, WM showed a significant increase in hypoxia inducible
factor-1α (HIF-1α), which increased further by 3 weeks. Prolyl
hydroxylase-2 (PHD2) expression decreased at 1 and 3 weeks. Infiltrating
T cells and neutrophils appeared around endothelial cells from 1 to 3
weeks after UCAO/JPD, and matrix metalloproteinase-9 (MMP-9) colocalized
with inflammatory cells. At 3 weeks, WM immunostained for IgG,
indicating BBB leakage. Minocycline (50 mg/kg intraperitoeally) was
given every other day from weeks 12 to 20. Multimodal MRI showed that
treatment with minocycline significantly reduced lesion size and
improved cerebral blood flow. Minocycline improved performance in the
MWM and prolonged survival. We propose that BBB disruption occurred
secondary to hypoxia, which induced an MMP-9-mediated infiltration of
leukocytes. Minocycline significantly reduced WM damage, improved
behavior, and prolonged life.
More at link.
No comments:
Post a Comment