Hypoxia-induced neuroinflammatory white-matter injury reduced by minocycline in SHR/SP

Fakhreya Y. Jalal, Yi Yang, Jeffrey F. Thompson, Tamara Roitbak, Gary A. Rosenberg

Research output: Contribution to journalArticlepeer-review

59 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1145-1153
Number of pages9
JournalJournal of Cerebral Blood Flow and Metabolism
Volume35
Issue number7
DOIs
Publication statusPublished - Jul 1 2015

Keywords

  • MRI
  • blood-brain barrier
  • hypoxia inducible factor
  • matrix metalloproteinases
  • vascular cognitive impairment
  • white matter

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology
  • Cardiology and Cardiovascular Medicine

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