Article

Myelin Loss Associated With Neuroinflammation in Hypertensive Rats

Department of Neurology, MSC10 5620, 1 University of New Mexico, Albuquerque, NM 87131, USA.
Stroke (Impact Factor: 6.02). 02/2012; 43(4):1115-22. DOI: 10.1161/STROKEAHA.111.643080
Source: PubMed

ABSTRACT 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.
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.
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.
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.

Download full-text

Full-text

Available from: Yi Yang, Apr 23, 2014
0 Followers
 · 
112 Views
  • Source
    • "These MMPs can cause damage to the extracellular matrix and to the blood–brain barrier (BBB), exacerbating brain edema, hemorrhage, and ultimately neuronal and glial cell death (Asahi et al., 2001; Yang et al., 2007; Del Zoppo, 2010; Seo et al., 2012; Lakhan et al., 2013). Additional detrimental effects of gelatinases during ischemia include myelin loss (Jalal et al., 2012), degradation of neurotrophic factor receptors (Navaratna et al., 2013), chemoattractant shedding from adhesion molecules (Ahn et al., 2012), processing and activation of http://dx.doi.org/10.1016/j.neuroscience.2014.07.064 0306-4522/Ó 2014 IBRO. Published by Elsevier Ltd. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The pathophysiological processes implicated in ischemic brain damage are strongly affected by an inflammatory reaction characterised by activation of immune cells and release of soluble mediators, including cytokines and chemokines. The pro-inflammatory cytokine interleukin (IL)-1β has been implicated in ischemic brain injury, however, to date, the mechanisms involved in the maturation of this cytokine in the ischemic brain have not been completely elucidated. We have previously suggested that matrix metalloproteases (MMPs) may be implicated in cytokine production under pathological conditions. Here, we demonstrate that significant elevation of IL-1β occurs in the cortex as early as 1h after the beginning of reperfusion in rats subjected to 2h middle cerebral artery occlusion (MCAo). At this early stage, we observe increased expression of IL-1β in pericallosal astroglial cells and in cortical neurons and this latter signal colocalizes with elevated gelatinolytic activity. By gel zymography, we demonstrate that the increased gelatinolytic signal at 1h reperfusion is mainly ascribed to MMP2. Thus, MMP2 seems to contribute to early brain elevation of IL-β after transient ischemia and this mechanism may promote damage since pharmacological inhibition of gelatinases by the selective MMP2/MMP9 inhibitor V provides neuroprotection in rats subjected to transient MCAo.
    Neuroscience 08/2014; 277. DOI:10.1016/j.neuroscience.2014.07.064 · 3.33 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Small vessel disease (SVD) is a frequent cause of vascular cognitive impairment (VCI), encompassing vascular dementia. SVD is characterised by vasculopathy in deep penetrating arteries, diffuse white matter lesions (seen radiologically as leukoaraiosis) and focal, lacunar infarcts. Risk factors are age and hypertension but the pathogenic mechanism is unknown. Recent systematic reviews assessed experimental models of SVD or VCI. Chronically hypertensive animals (e.g. stroke-prone spontaneously hypertensive rats) display some features of SVD vasculopathy, such as vessel wall thickening. White matter lesions are seen in chronic hypoperfusion states (e.g. carotid occlusion/stenosis models). Small focal infarcts are induced by targeted ischemic challenge (surgical occlusion of a small artery, or stereotaxic endothelin-1 injection). Some degree of cognitive impairment is detectable in most cerebrovascular models, probably reflecting the broad neuroanatomical mapping of cognitive function. Important confounds to be considered in animal models of VCI are somatosensory impairment and hippocampal damage. Advances in clinical understanding will come from targeting specific questions on some aspect of SVD (e.g. vasculopathy, white matter damage) to the appropriate model in vivo. In vivo models of SVD are likely to benefit experimental studies of pathological processes, interactions with other brain disease states (such as Alzheimer disease), and therapeutic strategies.
    Journal of the neurological sciences 06/2012; 322(1-2):237-40. DOI:10.1016/j.jns.2012.05.046 · 2.26 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Antibodies to brain antigens are present in stroke survivors. In this study, we assessed autoantibody responses to white matter antigens, their correlation to white matter disease and stroke outcome. Antibody titers (immunoglobulin G [igG]) to myelin basic protein (MBP), proteolipid protein (PLP) and tetanus toxoid (TT) were available at one or more time points for 112 subjects with ischemic stroke. In comparison to the control subjects (N=40), there was a global decrease in IgG titers to TT early after stroke. Patients with white matter disease on magnetic resonance imaging had elevated titers of antibodies to both MBP and PLP at 30days after stroke, and anti-MBP antibodies were associated with worse outcome. The potential pathologic consequences of antibodies to white matter, especially MBP, is deserving of further investigation.
    Journal of neuroimmunology 08/2012; 252(1-2):106-12. DOI:10.1016/j.jneuroim.2012.08.006 · 2.79 Impact Factor
Show more