title: Myelin loss associated with neuroinflammation in hypertensive rats.
abstract: OBJECTIVE
  Small vessel disease is the major cause of white matter injury in patients with vascular cognitive impairment. Matrix metalloproteinase (MMP)-mediated inflammation may be involved in the white matter damage with oligodendrocyte (Ol) death. Therefore, we used spontaneously hypertensive stroke-prone rats to study the role of neuroinflammation in white matter damage.
  
  
  METHODS
  Permanent unilateral carotid artery occlusion was performed at 12 weeks of age in spontaneously hypertensive stroke-prone rats. Following surgery, rats were placed on a Japanese permissive diet and received 1% NaCl in drinking water. MRI, histology, biochemistry, and ELISA characterized white matter lesions, and cognitive impairment was tested by Morris water maze.
  
  
  RESULTS
  White matter damage was observed 4 to 5 weeks following permanent unilateral carotid artery occlusion/Japanese permissive diet. Immunoblotting showed marked reduction in myelin basic protein and upregulation of immature Ols. Mature Ols underwent caspase-3-mediated apoptosis. Morris water maze showed cognitive impairment. Abnormally appearing vessels were observed and surrounded by inflammatory-like cells. IgG extravasation and hemorrhage, indicating blood-brain barrier (BBB) disruption, was closely associated with MMP-9 expression. Lesions in white matter showed reactive astrocytosis and activated microglia that expressed tumor necrosis factor-α. MMP-3 and MMP-9 were significantly increased, and MMP-2 was reduced in both astrocytes and Ol.
  
  
  CONCLUSIONS
  We found apoptosis of mature Ols with an increase in immature Ols. Increased MMP-3, MMP-9, and tumor necrosis factor-α were associated with myelin breakdown and BBB disruption. Neuroinflammation is an important factor in white matter damage and Ol death, and studies using this new model can be performed to assess agents to block inflammation.
authors.affiliation: Department of Neurology, MSC10 5620, 1 University of New Mexico, Albuquerque, NM 87131, USA.
authors.forename: Fakhreya Y
authors.initials: FY
authors.lastname: Jalal
authors.forename: Yi
authors.initials: Y
authors.lastname: Yang
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Thompson
authors.forename: Anita C
authors.initials: AC
authors.lastname: Lopez
authors.forename: Gary A
authors.initials: GA
authors.lastname: Rosenberg
mesh_terms: D000818:Animals; D017209:Apoptosis; D001253:Astrocytes / Q000378:metabolism / Q000473:pathology; D001812:Blood-Brain Barrier / Q000378:metabolism / Q000473:pathology; D053148:Caspase 3 / Q000096:biosynthesis; D002540:Cerebral Cortex / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis; D019278:Matrix Metalloproteinase 3 / Q000096:biosynthesis; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis; D017628:Microglia / Q000378:metabolism / Q000473:pathology; D004676:Myelin Basic Protein / Q000378:metabolism*; D009186:Myelin Sheath / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D011918:Rats, Inbred SHR; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D004676:Myelin Basic Protein; D014409:Tumor Necrosis Factor-alpha; C505410:Casp3 protein, rat; D053148:Caspase 3; D019278:Matrix Metalloproteinase 3; D020778:Matrix Metalloproteinase 2; C522363:Mmp2 protein, rat; D020780:Matrix Metalloproteinase 9