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: 5.72). 02/2012; 43(4):1115-22. DOI: 10.1161/STROKEAHA.111.643080
Source: PubMed


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


Available from: Yi Yang, Apr 23, 2014
  • 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 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.
    Full-text · Article · Aug 2014 · Neuroscience
  • Source
    • "In humans, HHcy and increased BBB permeability are each independent risk factors for lacunar infarcts and leukoaraiosis [23], [28], [29]. There may also be a connection among BBB breakdown, myelin loss, and neuroinflammation in hypertension [30]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Hyperhomocysteinemia (HHcy) is a risk factor for cognitive impairment. The purpose of this study was to determine the temporal pattern of cerebral pathology in a mouse model of mild HHcy, because understanding this time course provides the basis for understanding the mechanisms involved. C57Bl/6 mice with heterozygous deletion cystathionine β-synthase (cbs+/−; Het) were used as a model of mild HHcy along with their wild-type littermates (cbs+/+; WT). Mice were ‘young’ (5.3±0.2 months of age) and ‘old’ (16.6±0.9 months of age). Blood-brain barrier (BBB) permeability was quantified from Evans blue and sodium fluorescein extravasation. Microvascular architecture was assessed by z-stack confocal microscopy. Leukoaraiosis was measured from Luxol fast blue stained slides of paraffin brain sections. Inflammation was quantified using standard antibody-based immunohistochemical techniques. Cognitive function was assessed using the Morris water maze. BBB permeability was significantly greater in Het vs. WT mice at all ages (p<0.05). There were no differences in microvascular architecture among the groups. Compared with all other groups, old Het mice had significantly greater leukoaraiosis, inflammation in the fornix, and cognitive impairment (p<0.05). In mild HHcy, increased permeability of the BBB precedes the onset of cerebral pathology. This new paradigm may play a role in the progression of disease in HHcy.
    Full-text · Article · May 2013 · PLoS ONE
  • Source
    • "The development of hypertension is accelerated when the animals are fed a high-fat, high-salt diet [46]. This model has been used to confirm white matter lesions and increased levels of MMP-9 following stroke [47]. MMP-9 breaks down the collagenase matrix near cerebral blood vessels following a stroke, which, in conjunction with elevated inflammatory markers, augments BBB disruption [48]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The translation of neuroprotective agents for ischemic stroke from bench-to-bedside has largely failed to produce improved treatments since the development of tissue plasminogen activator (tPA). One possible reason for lack of translation is the failure to acknowledge the greatest risk factor for stroke, age, and other common comorbidities such as hypertension, obesity, and diabetes that are associated with stroke. In this review, we highlight both mechanisms of studying these factors and results of those that have been addressed. We also discuss the potential role of other lifestyle factors associated with an increased stroke risk such as sleep fragmentation and/or deprivation. Furthermore, many proposed therapeutic agents have targeted molecular mechanisms occurring soon after the onset of ischemia despite data indicating delayed patient presentation following ischemic stroke. Modulating inflammation has been identified as a promising therapeutic avenue consistent with preliminary success of ongoing clinical trials for anti-inflammatory compounds such as minocycline. We review the role of inflammation in stroke and in particular, the role of inflammatory cell recruitment and macrophage phenotype in the inflammatory process. Emerging evidence indicates an increasing role of neuro-immune crosstalk, which has led to increased interest in identification of peripheral biomarkers indicative of neural injury. It is our hope that identification and investigation of factors influencing stroke pathophysiology may lead to improved therapeutics.
    Full-text · Article · Jan 2013 · International Journal of Molecular Sciences
Show more