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Query: UMLS:C0917798 (cerebral ischemia)
 17,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This study describes local immune responses in cerebral ischemia induced by permanent occlusion of the middle cerebral artery (MCAO) in the rat. The temporal and spatial pattern of leukocyte infiltration was characterized immunocytochemically using monoclonal antibodies against CD5, a pan T cell marker, against CD4 and CD8 for subtyping of T lymphocytes, and ED1, a marker for macrophages. CD5+ T cells were present in some animals on the pial surface at day 1 and with increasing numbers mainly at the edges of the infarcts at days 3 and 7. By day 14 their number had significantly decreased. Subtyping of T lymphocytes revealed that CD4+ helper/inducer T cells were rare, while CD8+ lymphocytes were abundant. Moreover, CD8+ lymphocytes outnumbered CD5+ T cells indicating the presence of CD5-/CD8+ natural killer (NK) cells. ED1+ macrophages primarily infiltrated the core of the infarct starting on day 1. Infiltrating leukocytes expressed leukocyte function associated antigen-1 and MHC class I and II antigens. Early after infarction, increased expression of the intercellular adhesion molecule-1 was found on vessels and leukocytes. In conclusion, this study shows that lymphocytes enter the nervous system not only in autoimmune diseases, but also in response to primarily 'non-immune' neuronal damage such as stroke.
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PMID:Local immune responses in the rat cerebral cortex after middle cerebral artery occlusion. 753 Feb 60

In order to evaluate the involvement of inflammatory reactions following focal cerebral ischemia in the rat, we immunohistochemically visualized microglial cells and blood-borne leukocytes (neutrophils and monocytes) using various antibodies directed against immunomolecules expressed on these cells. Focal cerebral ischemia was produced by intraluminal occlusion of the right middle cerebral artery for 1 h. The brains were perfusion-fixed at 4 h, 1 day, 3 days, 7 days and 14 days after ischemia. Frozen brain sections were prepared and stained with monoclonal antibodies to complement receptor type 3 (OX42), major histocompatibility complex (MHC) class I and class II antigens (OX18 and OX6, respectively), a pan-macrophage/monocyte marker (ED1), intercellular adhesion molecule-1 (ICAM-1), LFA-1 alpha chain (CD11a) and beta chain (CD18), and T cells (CD5). In ischemic areas where infarction developed later, microglial cells were destroyed (beginning at 4 h), neutrophils migrated (1-3 days), and then monocytes/macrophages infiltrated and covered the entire lesions (3-14 days). The invading leukocytes expressed CD11 and CD18 adhesion molecules on their cell surface while ICAM-1 was expressed on endothelial cells. In surrounding areas, in contrast, there was a rapid activation of microglia showing morphological changes and upregulation of OX42 immunoreactivity (4 h-7 days), especially in the transitional rim of the infarct (7 days). ED1 and MHC antigens were expressed on both activated microglia and invading leukocytes. Thus, developing infarction was accompanied by accumulation of inflammatory cells of both intrinsic (microglia) and extrinsic (leukocytes) origins. Thus, results suggest that the relative importance of each source is determined by the time after ischemia and the site within the lesion, and that the expression of immunological molecules plays an important role in eliciting such inflammatory reactions.
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PMID:Progressive expression of immunomolecules on activated microglia and invading leukocytes following focal cerebral ischemia in the rat. 889 26

The potentially neurotrophic cytokine transforming growth factor-beta1 (TGF-beta1) is locally expressed following human stroke and experimental ischemic lesions, but the cellular source(s) and profile of induction have so far not been established in experimental focal cerebral ischemia. This study presents the time course and a cellular localization of TGF-beta1 mRNA, visualized by in situ hybridization combined with immunohistochemical staining for microglia, macrophages, or astrocytes, on brain sections from adult spontaneously hypertensive rats subjected to transient proximal occlusion of their middle cerebral artery. Six hours after ischemia, an early and transient neuronal and microglial expression of TGF-beta1 mRNA was observed in the extraischemic cingulate and frontal cortices. Both early and protracted expression of TGF-beta1 mRNA in the caudate-putamen and neocortical infarcts and in the caudate-putamen penumbra colocalized with OX42/ED1-immunoreactive microglia and macrophages, whereas TGF-beta1 mRNA in the neocortical penumbra colocalized with OX42/ED1-immunoreactive cells of a microglial morphology. No astrocytes were double-labeled. The number of TGF-beta1 mRNA-expressing microglia and macrophages increased strongly during the first week. Thereafter, TGF-beta1 mRNA became increasingly restricted to the neocortical penumbra (3 weeks), and after 3 months it was confined to activated microglia in the anterior commissure. Our data establish activated microglia and macrophages as the major source of TGF-beta1 mRNA following experimental focal cerebral ischemia. Consequently, TGF-beta1-mediated functions may be exerted by microglia both in the early degenerative phase, and later in combination with blood-borne macrophages, in the remodeling and healing phase after focal cerebral ischemia.
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PMID:Microglia and macrophages are major sources of locally produced transforming growth factor-beta1 after transient middle cerebral artery occlusion in rats. 981 24

Although interleukin-6 (IL-6) has various neuroprotective effects against cerebral ischemia, the topographic distribution and cellular source of IL-6 after cerebral ischemia remain unclear. In the current study, the localization of IL-6 protein was immunohistochemically examined in rats after 3.5, 12, 24, and 48 hours of reperfusion after 1.5 hours of middle cerebral artery occlusion. Middle cerebral artery occlusion was induced by the intraluminal suture method. The specificity of the anti-IL-6 antibody used in the current study was confirmed by Western blot analysis and an immunoabsorption test. To identify the cellular source, lectin histochemical study and immunohistochemical study with microtubule-associated protein-2, ED1, and glial fibrillary acidic protein also were carried out. The sham group did not show any clear IL-6 immunoreactivity. After 3.5 hours of reperfusion, IL-6 immunoreactivity was first detected on the reperfused side, and it was upregulated, especially in the periinfarct region, after 24 hours of reperfusion. Also, IL-6 was expressed after 3.5 hours of reperfusion in the contralateral cerebral cortex and bilateral hippocampi. Double staining showed that the cells containing IL-6 were neurons and round-type microglia, not astrocytes. The current findings suggest that IL-6 expression in ischemically threatened neurons and reactive microglia is closely associated with brain tissue neuroprotective mechanisms against cerebral ischemia.
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PMID:Temporal profile and cellular localization of interleukin-6 protein after focal cerebral ischemia in rats. 1056 72

The left and right neocortex of the brain has been shown to exert asymmetrical effects on the immune system. In the present study, we used a middle cerebral artery (MCA) occlusion model in Wistar rats to analyze the influence of unilateral CNS ischemia on spleen cell number and function. The occlusion time was 1 h, followed by reperfusion with survival for 0, 2, 7, 14, and 28 days. Changes in plasma norepinephrine levels were used as an index of peripheral sympathetic activity. Results showed that the total number of spleen cells significantly decreased after 2-28 days of survival in animals with cerebral ischemia compared to sham-operated controls. There was no change in the percentage of CD5(+)-CD4(+) T cells, MHC class II(+) cells, or ED1(+) macrophages. However, the percentage of CD5(+)-CD8(+) T cells decreased at 2 days, resulting in an increased CD4/CD8 ratio, and both parameters returned to control levels after 7 days. Mitogen-induced T and B lymphocyte proliferation increased after 0-28 days post-ischemia independently of the mitogen used. There was no difference in immune response or norepinephrine levels between left and right MCA occlusions. These results are consistent with the notion that cerebral ischemia induces mobilization of certain immune cells from the periphery to the brain, where they may contribute to the local inflammatory response. Additionally, the data indicate that cerebral ischemia is followed by a systemic activation of T and B lymphocytes. Absence of asymmetric effects of left versus right stroke, and failure to demonstrate any suppressive effects of left-sided lesions on lymphocyte proliferation, probably reflects the fact that these large cerebral ischemic lesions affect both cortical and subcortical areas.
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PMID:Temporal effects of left versus right middle cerebral artery occlusion on spleen lymphocyte subsets and mitogenic response in Wistar rats. 1241 24

This study was aimed to ascertain the effect of sleep deprivation on subsequent cerebral ischemia in the rat hippocampal formation. Seven days after transient global cerebral ischemia induced by four-vessel occlusion method, most of the pyramidal cells in the hippocampal CA1 subfield underwent disruption and pyknosis as detected by cresyl violet staining. With OX-42, OX-18, OX-6 and ED1 immunohistochemistry, robust microglia/macrophage reactions were observed in the CA1 and dentate hilus. The majority of reactive microglia was rod-shaped, bushy or amoeboidic cells bearing hypertrophic processes. Astrocytes also displayed hypertrophic processes, whose immunostaining for glial fibrillary acidic protein was markedly enhanced. The ischemia-induced neuronal damage and glial reactions, however, were noticeably attenuated in rats subjected to pretreatment with sleep deprivation for five consecutive days. The most drastic effect was the diminution of OX-18, OX-6 and ED1 immunoreactivities, suggesting that the immune potentiality and/or phagocytosis of these cells was suppressed by prolonged sleep deprivation prior to ischemic insult. It is postulated that sleep deprivation may have a preconditioning influence on subsequent lethal cerebral ischemia. Hence, sleep deprivation may be considered as a therapeutic strategy in brain ischemic damage.
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PMID:Sleep deprivation prior to transient global cerebral ischemia attenuates glial reaction in the rat hippocampal formation. 1293 51

Blood-brain barrier (BBB) breakdown is a feature of cerebral ischaemia, multiple sclerosis, and other neurodegenerative diseases, yet the relationship between astrocytes and the BBB integrity remains unclear. We present a simple in vivo model in which primary astrocyte loss is followed by microvascular damage, using the metabolic toxin 3-chloropropanediol (S-alpha-chlorohydrin). This model is uncomplicated by trauma, ischaemia, or primary immune involvement, permitting the study of the role of astrocytes in vascular endothelium integrity, maintenance of the BBB, and neuronal function. Male Fisher F344 rats given 3-chloropropanediol show astrocytic damage and death at 4-24 h in symmetrical brainstem and midbrain nuclear lesions, while neurons show morphological changes at 24-48 h. Fluorescent 10 kDa dextran tracers show the BBB leaking from 24 h, progressing to petechial haemorrhage after 48-72 h, with apparent repair after 6 days. BBB breakdown, but not the earlier astrocytic death, is accompanied by a delayed increase in blood flow in the inferior colliculus. An ED1 inflammatory response develops well after astrocyte loss, suggesting that inflammation may not be a factor in starting BBB breakdown. This model demonstrates that the BBB can self-repair despite the apparent absence of direct astrocytic-endothelial contact. The temporal separation of pathological events allows pharmacological intervention, and the mild reversible ataxia permits long-term survival studies of repair mechanisms.
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PMID:Focal astrocyte loss is followed by microvascular damage, with subsequent repair of the blood-brain barrier in the apparent absence of direct astrocytic contact. 1496 64

Free radicals and inflammatory mediators are involved in transient focal cerebral ischemia (FCI). Preadministration of N-acetylcysteine (NAC) has been found to attenuate the cerebral ischemia-reperfusion injury in a rat model of experimental stroke. This study was undertaken to investigate the neuroprotective potential of NAC administered after ischemic events in experimental stroke. FCI was induced for 30 min by occluding the middle cerebral artery (MCA). NAC (150 mg/kg) was administered intraperitoneally at the time of reperfusion followed by another dose 6 hr later. Animals were sacrificed after 24 hr of reperfusion. The cerebral infarct consistently involved the cortex and striatum. Infarction was assessed by staining the brain sections with 2,3,5-triphenyltetrazolium chloride. Animals treated with NAC showed a significant reduction in infarct area and infarct volume and an improvement in neurologic scores and glutathione level. Reduction in infarction was significant even when a single dose of NAC was administered at 6 hr of reperfusion. Immunohistochemical and quantitative real-time PCR studies demonstrated a reduction in the expression of proinflammatory cytokines such as tumor necrosis factor alpha (TNFalpha) and interleukin 1beta (IL-1beta) and inducible nitric oxide synthase (iNOS) in NAC compared to that in vehicle-treated animals. The expression of activated macrophage/microglia (ED1) and apoptotic cell death in ischemic brain was also reduced by NAC treatment. These results indicate that in a rat model of experimental stroke, administration of NAC even after ischemia onset protected the brain from free radical injury, apoptosis, and inflammation, with a wide treatment window.
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PMID:Administration of N-acetylcysteine after focal cerebral ischemia protects brain and reduces inflammation in a rat model of experimental stroke. 1511 24

Preservation of endothelial functions with low-dose nitric oxide (NO) and inhibition of excessive production of NO from inducible NO synthase (iNOS) is a potential therapeutic approach for acute stroke. Based on this hypothesis, an NO modulator, S-nitrosoglutathione (GSNO) was used, which provided neuroprotection in a rat model of focal cerebral ischemia. Administration of GSNO after the onset of ischemia reduced infarction and improved cerebral blood flow. To understand the mechanism of protection, the involvement of inflammation in ischemic brain injury was examined. Treatment with GSNO reduced the expression of tumor necrosis factor-alpha, interleukin-1beta, and iNOS; inhibited the activation of microglia/macrophage (ED1, CD11-b); and downregulated the expression of leukocyte function-associated antigen-1 and intercellular adhesion molecule-1 in the ischemic brain. The number of apoptotic cells (including neurons) and the activity of caspase-3 were also decreased after GSNO treatment. Further, the antiinflammatory effect of GSNO on expression of iNOS and activation of NF-kappaB machinery in rat primary astrocytes and in the murine microglial cell line BV2 was tested. Cytokine-mediated expression of iNOS and activation of NF-kappaB were inhibited by GSNO treatment. That GSNO protects the brain against ischemia/reperfusion injury by modulating NO systems, resulting in a reduction in inflammation and neuronal cell death was documented by the results.
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PMID:S-Nitrosoglutathione reduces inflammation and protects brain against focal cerebral ischemia in a rat model of experimental stroke. 1564 46

Cerebral ischemia triggers an inflammatory process involving the infiltration of leukocytes to the parenchyma. Circulating leukocytes adhere to the vascular wall through adhesion molecules. Here we quantified the in vivo expression of vascular cell adhesion molecule-1 (VCAM-1) in the brain, heart and lungs from 6 to 48 h after transient middle cerebral artery (MCA) occlusion in rats, by intravenous injection of a tracer radiolabelled anti-VCAM-1 antibody. The vascular localization of VCAM-1 was verified by immunohistochemistry after in vivo injection of the antibody. Vascular cell adhesion molecule-1 was strongly induced (4-fold at 24 h) in the microvasculature of the ischemic area, and, to a lesser extent, in the contralateral hemisphere and in a remote organ, the heart, but not in the lungs, indicating that the inflammatory process propagates beyond the injured brain. We injected intravenously either blocking doses of anti-VCAM-1 antibodies or control antibodies after MCA occlusion in rats and mice. We evaluated the neurological score in rats, and infarct volume at 2 days in rats and at 4 days in mice. Anti-VCAM-1 did not protect against ischemic damage either in rats or in mice. Vascular cell adhesion molecule-1 blockade significantly decreased the number of ED1 (labeling monocytes /macrophages/reactive microglia)-positive cells in the ischemic rat brain. However, it did not reduce the numbers of infiltrating neutrophils and lymphocytes, and total leukocytes (CD45 positive), which showed a trend to increase. The results show vascular upregulation of VCAM-1 after transient focal ischemia, but no benefits of blocking VCAM-1, suggesting that this is not a therapeutical strategy for stroke treatment.
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PMID:Anti-VCAM-1 antibodies did not protect against ischemic damage either in rats or in mice. 1607 86


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