Reperfusion Injury after Focal Cerebral Ischemia: The Role of Inflammation and the Therapeutic Horizon

Jean, Walter C.; Spellman, Stephen R.; Nussbaum, Eric S.; Low, Walter C.

doi:10.1227/00006123-199812000-00076

Cited by 125 publications

(153 citation statements)

References 171 publications

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“…This effect may have resulted indirectly from a Slit-induced decrease in leukocyte chemotaxis and recruitment, and/or directly from a Slitinduced change in the neuronal response to ischemia. Although not a universal finding (Hayward et al, 1996;Emerich et al, 2002), considerable evidence supports the notion that adherent and infiltrating leukocytes contribute to ischemic damage following focal ischemia (see Jean et al, 1998 andWang et al, 2005 for reviews). In particular, the degree of leukocyte infiltration following focal stroke correlates with the severity of neuronal injury and neurological deficits in animals Clark et al, 1994;del Zoppo et al, 1991) and humans (Akopov et al, 1996).…”

Section: Discussionmentioning

confidence: 96%

Slit modulates cerebrovascular inflammation and mediates neuroprotection against global cerebral ischemia

Altay

McLaughlin

et al. 2007

Experimental Neurology

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Cerebrovascular inflammation contributes to secondary brain injury following ischemia. Recent in vitro studies of cell migration and molecular guidance mechanisms have indicated that the Slit family of secreted proteins can exert repellant effects on leukocyte recruitment in response to chemoattractants. Utilizing intravital microscopy, we addressed the role of Slit in modulating leukocyte dynamics in the mouse cortical venular microcirculation in vivo following TNFα application or global cerebral ischemia. We also studied whether Slit affected neuronal survival in the mouse global ischemia model as well as in mixed neuronal-glial cultures subjected to oxygenglucose deprivation. We found that systemically administered Slit significantly attenuated cerebral microvessel leukocyte-endothelial adherence occurring 4 h after TNFα and 24 h after global cerebral ischemia. Administration of RoboN, the soluble receptor for Slit, exacerbated the acute chemotactic response to TNFα. These findings are indicative of a tonic repellant effect of endogenous Slit in brain under acute proinflammatory conditions. Three days of continuous systemic administration of Slit following global ischemia significantly attenuated the delayed neuronal death of hippocampal CA1 pyramidal cells. Moreover, Slit abrogated neuronal death in mixed neuronal-glial cultures exposed to oxygen-glucose deprivation. The ability of Slit to reduce the recruitment of immune cells to ischemic brain and to provide cytoprotective effects suggests that this protein may serve as a novel anti-inflammatory and neuroprotective target for stroke therapy.

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Section: Discussionmentioning

confidence: 96%

Slit modulates cerebrovascular inflammation and mediates neuroprotection against global cerebral ischemia

Altay

McLaughlin

et al. 2007

Experimental Neurology

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“…Clinical studies demonstrate highly inhomogeneous vascular findings in patients suffering from acute territorial stroke, ranging from early recanalization and delayed or drug-induced recanalization to permanent vessel occlusion. 19 -21 Since the underlying pathophysiology of brain damage therefore is likewise heterogeneous, depending on the presence (and time point) of additional reperfusion injury, 22,23 it has been suggested that neuroprotective therapies should be evaluated in both transient and permanent vessel occlusion models. 24,25 In the suture MCAO model, hypothalamic damage and hyperthermia seem to occur only if reperfusion is performed later than 90 minutes after MCAO.…”

Section: Relevance For Future Preclinical Studiesmentioning

confidence: 99%

Neuroprotective Effects of MK-801 in Different Rat Stroke Models for Permanent Middle Cerebral Artery Occlusion

Gerriets

Stolz

Walberer

et al. 2003

Stroke

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Background and Purpose-Permanent middle cerebral artery occlusion (MCAO) with the use of the suture technique causes hypothalamic damage with subsequent hyperthermia, which can confound neuroprotective drug studies. In the present study the neuroprotective effects of dizocilpine (MK-801) were compared in different permanent MCAO models with and without hypothalamic damage and hyperthermia. Methods-Sixty Sprague-Dawley rats were treated with MK-801 or placebo, beginning 15 minutes before MCAO, and assigned to the following groups: suture MCAO (group I), macrosphere MCAO without hypothalamic damage (group II), or macrosphere MCAO with intentionally induced hypothalamic infarction (group III). Body temperature was measured at 3, 6, and 24 hours. Lesion size was determined after 24 hours (2,3,5-triphenyltetrazolium chloride staining). Results-Hypothalamic damage was present in animals in group I and was intentionally induced in group III with the use of a modified macrosphere MCAO technique. Body temperature was significantly increased 3, 6, and 24 hours after MCAO in these 2 groups of animals. Hypothalamic damage and subsequent hyperthermia could be avoided effectively by limiting the number of macrospheres (group II). MK-801 provided a highly significant neuroprotective effect in group II but not in groups I and III. Conclusions-Hypothalamic damage with subsequent hyperthermia masked the neuroprotective effect of MK-801. This side effect can be avoided by using the macrosphere MCAO technique with a limited number of spheres. This model therefore may be more appropriate to study the effects of neuroprotective drugs in permanent focal cerebral ischemia than the suture method.

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“…Neutrophils play a central role in ischemia-reperfusion injury (1). Additionally, many neurological insults are accompanied by an acute inflammatory reaction due to neutrophil infiltration, the latter contributing to neuronal damage (2)(3)(4)(5)(6). Neutrophil functions such as chemotaxis, exocytosis, or superoxide burst are initiated in activated neutrophils.…”

mentioning

confidence: 99%

γ-Amino Butyric Acid Type B Receptors Stimulate Neutrophil Chemotaxis during Ischemia-Reperfusion

Rane

Gozal

Butt

et al. 2005

The Journal of Immunology

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Serine/threonine kinase Akt, or protein kinase B, has been shown to regulate a number of neutrophil functions. We sought to identify Akt binding proteins in neutrophils to provide further insights into understanding the mechanism by which Akt regulates various neutrophil functions. Proteomic and immunoprecipitation studies identified γ-amino butyric acid (GABA) type B receptor 2 (GABABR2) as an Akt binding protein in human neutrophils. Neutrophil lysates subjected to Akt immunoprecipitation followed by immunoblotting with anti-GABABR2 demonstrated Akt association with the intact GABABR. Similar results were obtained when reciprocal immunoprecipitations were performed with anti-GABABR2 Ab. Additionally, GABABR2 and Akt colocalization was demonstrated by confocal microscopy. A GABABR agonist, baclofen, activated Akt and stimulated neutrophil-directed migration in a PI3K-dependent manner, whereas CGP52432, a GABABR antagonist blocked such effects. Baclofen, stimulated neutrophil chemotaxis and tubulin reorganization in a PI3K-dependent manner. Additionally, a GABABR agonist failed to stimulate neutrophil superoxide burst. We are unaware of the association of GABABR with Akt in any cell type. The present study shows for the first time that a brain-specific receptor, GABABR2 is present in human neutrophils and that it is functionally associated with Akt. Intraventricular baclofen pretreatment in rats subjected to a stroke model showed increased migration of neutrophils to the ischemic lesion. Thus, the GABABR is functionally expressed in neutrophils, and acts as a chemoattractant receptor via an Akt-dependent pathway. The GABABR potentially plays a significant role in the inflammatory response and neutrophil-dependent ischemia-reperfusion injury such as stroke.

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Reperfusion Injury after Focal Cerebral Ischemia: The Role of Inflammation and the Therapeutic Horizon

Cited by 125 publications

References 171 publications

Slit modulates cerebrovascular inflammation and mediates neuroprotection against global cerebral ischemia

Slit modulates cerebrovascular inflammation and mediates neuroprotection against global cerebral ischemia

Neuroprotective Effects of MK-801 in Different Rat Stroke Models for Permanent Middle Cerebral Artery Occlusion

γ-Amino Butyric Acid Type B Receptors Stimulate Neutrophil Chemotaxis during Ischemia-Reperfusion

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