Myelin Loss Associated With Neuroinflammation in Hypertensive Rats (original) (raw)
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Acta Neuropathologica Communications
The major vascular cause of dementia is cerebral small vessel disease (SVD), including white matter hyperintensities (WMH) amongst others. While the underlying pathology of SVD remains unclear, chronic hypertension and neuroinflammation are recognized as important risk factors for SVD and for the conversion of normal-appearing white matter (NAWM) to WMH. Unfortunately, most studies investigating the role of neuroinflammation in WMH relied on peripheral blood markers, e.g., markers for systemic or vascular inflammation, as a proxy for inflammation in the brain itself. However, it is unknown whether such markers accurately capture inflammatory changes within the cerebral white matter. Therefore, we aimed to comprehensively investigate the impact of hypertension on perivascular- and neuroinflammation in both WMH and NAWM. We conducted high field brain magnetic resonance imaging (MRI), followed by (immuno-)histopathological staining of neuroinflammatory markers on human post-mortem brai...
Neurodegeneration, Myelin Loss and Glial Response in the Three-Vessel Global Ischemia Model in Rat
International Journal of Molecular Sciences, 2020
(1) Background: Although myelin disruption is an integral part of ischemic brain injury, it is rarely the subject of research, particularly in animal models. This study assessed for the first time, myelin and oligodendrocyte loss in a three-vessel model of global cerebral ischemia (GCI), which causes hippocampal damage. In addition, we investigated the relationships between demyelination and changes in microglia and astrocytes, as well as oligodendrogenesis in the hippocampus; (2) Methods: Adult male Wistar rats (n = 15) underwent complete interruption of cerebral blood flow for 7 min by ligation of the major arteries supplying the brain or sham-operation. At 10 and 30 days after the surgery, brain slices were stained for neurodegeneration with Fluoro-Jade C and immunohistochemically to assess myelin content (MBP+ percentage of total area), oligodendrocyte (CNP+ cells) and neuronal (NeuN+ cells) loss, neuroinflammation (Iba1+ cells), astrogliosis (GFAP+ cells) and oligodendrogenesis (NG2+ cells); (3) Results: 10 days after GCI significant myelin and oligodendrocyte loss was found only in the stratum oriens and stratum pyramidale. By the 30th day, demyelination in these hippocampal layers intensified and affected the substratum radiatum. In addition to myelin damage, activation and an increase in the number of microglia and astrocytes in the corresponding layers, a loss of the CA1 pyramidal neurons, and neurodegeneration in the neocortex and thalamus was observed. At a 10-day time point, we observed rod-shaped microglia in the substratum radiatum. Parallel with ongoing myelin loss on the 30th day after ischemia, we found significant oligodendrogenesis in demyelinated hippocampal layers; (4) Conclusions: Our study showed that GCI-simulating cardiac arrest in humans-causes not only the loss of pyramidal neurons in the CA1 field, but also the myelin loss of adjacent layers of the hippocampus.
Journal of Stroke and Cerebrovascular Diseases, 2014
Background: White matter hyperintensity (WMH), a common radiographic finding associated with stroke risk and outcome, has been linked to matrix metalloproteinase (MMP) activity and increased levels of oxidative stress in nonstroke populations. We sought to determine whether WMH severity is associated with plasma levels of MMPs and oxidative stress (F2-isoprostane) in subjects with acute ischemic stroke (AIS). Methods: We measured plasma biomarker levels at baseline and 48 hours in consecutive AIS subjects. White matter hyperintensity volume (WMHv) was quantified on admission magnetic resonance imaging using a validated semiautomated protocol, and Spearman correlation coefficients were derived for all measured biomarkers. Results: We enrolled 405 AIS subjects (mean age 70 6 15 years; 58% male; median WMHv 3.4 cm 3 , interquartile range 1.4-9.5). WMHv and age were strongly correlated (r 5 .57, P , .0001). WMHv and MMP-2 levels were correlated at baseline (r 5 .23, P , .0001) and at 48 hours poststroke (r 5 .19, P 5 .002). In multivariate analysis, 48-hour MMP-2 levels were independently associated with WMHv (b 5 .12, P 5 .04). MMP-9 and F2-isioprostane levels did not correlate with WMHv. Conclusions: In AIS patients, MMP-2 levels are associated with the pre-existing burden of WMH. If validated, these findings may further elucidate the role of MMP-2 in pathophysiology of chronic cerebrovascular injury, such as WMH, and in brain susceptibility to acute ischemia. Key Words: Leukoaraiosis-white matter hyperintensity-stroke-F2-isoprostane(s)-matrix metalloproteinase 2-oxidative stress.
Stroke, 2011
Background and Purpose-Subcortical ischemic vascular disease (SIVD) is a major form of vascular cognitive impairment (VCI) due to small vessel disease. Matrix metalloproteinases (MMPs) are neutral proteases that disrupt the blood-brain barrier and degrade myelin basic protein under conditions of neuroinflammation. Brain tissues and cerebrospinal fluid (CSF) of patients with VCI have increased levels of MMPs. We hypothesized that patients with SIVD have increased MMPs in the CSF, which are associated with increased CSF albumin. Methods-We studied 60 patients with suspected VCI. Twenty-five were classified as SIVD, whereas other groups included mixed Alzheimer disease and VCI, multiple strokes, and leukoaraiosis when white matter lesions were present and the diagnosis of VCI was uncertain. MMP-2 and MMP-9 in CSF and plasma were measured by gel zymography and indexed to CSF and plasma albumin. MMP-3 activity was measured by fluorescent assay. Results-We found reduced MMP-2 index (PϽ0.001) in the CSF for the full group of patients (SIVD, multiple strokes, mixed Alzheimer disease and VCI, and leukoaraiosis) compared with control subjects, whose CSF was obtained during spinal anesthesia. MMP-3 activity was increased in VCI compared with control subjects (PϽ0.01). In SIVD, MMP-2 index showed a negative correlation with albumin index, which was absent with the MMP-9 index. Combining MMP-2 index and MMP-3 activity separated the patients with SIVD from the control subjects with high specificity (PϽ0.0005). Conclusions-Our results support the hypothesis that MMPs are associated with increased CSF albumin and suggest that they may contribute to the pathophysiology of SIVD. (Stroke. 2011;42:1345-1350.)
Neuroinflammatory Markers in Spontaneously Hypertensive Rat Brain: An Immunohistochemical Study
Cns & Neurological Disorders-drug Targets, 2016
Background: Spontaneously hypertensive rats (SHR) represent a model of hypertension and vascular injury. In the past decade, SHR were also considered as a model of vascular dementia. Several studies have shown that cerebrovascular changes in SHR may mimic brain vascular diseases of hypertensive individuals. Vascular and cerebrovascular changes during hypertension are often linked to inflammatory processes. Inflammation frequently affects vascular endothelium, perivascular astrocytes that form blood brain barrier. This inflammatory reaction may lead to neuro-inflammation with consequent damage of brain tissue. A significant brain atrophy, a reduction of white matter volumes, and BBB dysfunction were found in SHR. Micro-and macrogliosis in deep cortical regions were also observed. Based on these findings, this study was designed to define neuroinflammation entity in SHR, using immunohistochemistry technique for different inflammatory markers. Methods: Thirty-two-week-old SHR and age-matched Wistar Kyoto rats were used. Brain was processed for immunohistochemistry. Astrogliosis markers for astrocytes (glial fibrillary acidic protein) and microglia (isolectin IB4) were used. The pro-inflammatory interleukins (IL-1b, IL-6) and tumor necrosis factor alpha (TNFa) expression were also evaluated. Results: In SHR brain, an obvious glial reaction was found both for GFAP-immunoreactive astrocytes and for microglia. The pro-inflammatory IL-1b was significantly increased in CA1 sub-field of SHR hippocampus. The TNFa expression was higher in frontal cortex of SHR compared to WKY. Conclusion: The above neuromorphological evidences indicate that SHR are predictive animal models for vascular brain disorders and neuroinflammation. Furthermore, this model may be useful to evaluate anti-inflammatory and neuroprotective effects of different molecules.
Brain Research, 2011
Although the white matter lesions, so called leuko-araiosis, often seen in elderly people have been gaining attention due to their association with cognitive dysfunction (CD) and high risk of incident stroke, the pathological significance of these lesions still remains controversial. Therefore, in the present study, we investigated the alterations in oligodendrocytes (OLG), including oligodendrocytes progenitor cells (OPCs), myelin, and CD following chronic cerebral ischemia in rats. SD rats were subjected to bilateral common carotid artery occlusion. Immunohistochemical staining was performed at 2, 4, 6, 8, and 12 weeks after the induction of ischemia with anti-NG2 (OPCs), anti-GST-π (OLG), and anti-MBP antibodies in paramedian corpus callosum (CC). CD was assessed by the Morris water maze test. There was a significant decrease in the number of GST-π positive cells at 2 weeks after the start of ischemia compared with that seen in the sham group. There was a significant increase of the number of NG2 positive cells at 4 weeks in the ischemia group compared with the sham group. In the ischemic group, the amount of MBP was observed to have decreased significantly at each time point compared with the sham group. CD was observed in the ischemic group than that in the sham group at all time points. Our results indicate that remyelination is strongly correlated with the recovery of cognitive dysfunction following chronic cerebral ischemia.
Glia, 2012
After stroke and brain injury, cortical gray matter recovery involves mechanisms of neurovascular matrix remodeling. In white matter however, the mechanisms of recovery remain unclear. In this present study, we demonstrate that oligodendrocytes secrete matrix metalloproteinase-9 (MMP-9), which accelerates the angiogenic response after white matter injury. In primary oligodendrocyte cultures, treatment with the pro-inflammatory cytokine interleukin-1β (IL-1β) induced an upregulation and secretion of MMP-9. Conditioned media from IL-1β-stimulated oligodendrocytes significantly amplified matrigel tube formation in brain endothelial cells, indicating that MMP-9 from oligodendrocytes can promote angiogenesis in vitro. Next we asked whether similar signals and substrates operate after white matter injury in vivo. Focal white matter injury and demyelination was induced in mice via stereotactic injection of lysophosphatidylcholine (LPC) into corpus callosum. Western blot analysis showed that IL-1β expression was increased in damaged white matter. Immunostaining demonstrated MMP-9 signals in MOBP (myelin-associated oligodendrocytic basic protein)-positive oligodendrocytes. Treatment with an IL-1β-neutralizing antibody suppressed the MMP-9 response in oligodendrocytes. Finally, we confirmed that the broad spectrum MMP inhibitor GM6001 inhibited angiogenesis around the injury area in this white matter injury model. In gray matter, a neurovascular niche promotes cortical recovery after brain injury. Our study suggests that an analogous oligovascular niche may mediate recovery in white matter.
Characterization of White Matter Injury in a Rat Model of Chronic Cerebral Hypoperfusion
Stroke, 2015
Background and Purpose— Chronic cerebral hypoperfusion can lead to ischemic white matter injury resulting in vascular dementia. To characterize white matter injury in vascular dementia, we investigated disintegration of diverse white matter components using a rat model of chronic cerebral hypoperfusion. Methods— Chronic cerebral hypoperfusion was modeled in Wistar rats by permanent occlusion of the bilateral common carotid arteries. We performed cognitive behavioral tests, including the water maze task, odor discrimination task, and novel object test; histological investigation of neuroinflammation, oligodendrocytes, myelin basic protein, and nodal or paranodal proteins at the nodes of Ranvier; and serial diffusion tensor imaging. Cilostazol was administered to protect against white matter injury. Results— Diverse cognitive impairments were induced by chronic cerebral hypoperfusion. Disintegration of white matter was characterized by neuroinflammation, loss of oligodendrocytes, atte...
Neuroreport, 2001
There have been few studies on the white matter lesions of spontaneously hypertensive rats (SHR). From the point of view of hypertension and arteriosclerosis, white matter lesions were examined in SHR and stroke-prone SHR (SHRSP), and were then compared with Wistar-Kyoto (WKY) rats. The vasculopathy was analyzed by morphometric immunohistochemistry for collagen and smooth muscle actin. Both SHR and SHRSP had hypertension at > 12 weeks of age, and the latter developed severe white matter lesions at 20 weeks. Immuno-histochemistry revealed proliferation of microglia in the white matter and an increase in smooth muscle actin in the vessels of SHRSP compared with the WKY rats and SHR, but there were no changes in the collagen. These results indicate a role of hypertension in the pathogenesis of white matter lesions.