Astrocyte-Mediated Ischemic Tolerance

Hirayama, Yuri; Ikeda‐Matsuo, Yuri; Notomi, Shoji; Enaida, Hiroshi; Kinouchi, Hiroyuki; Koizumi, Schuichi

doi:10.1523/jneurosci.4218-14.2015

Cited by 102 publications

(101 citation statements)

References 50 publications

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“…It is also conceivable that P2X7-dependent mechanisms occur downstream of GFAP-related astroglial activation, as has been shown in a recent study comparing WT and P2X7 −/− mice subjected to cerebral ischemia. In case of preconditioning to ischemic insults, astrocytic P2X7 was shown to mediate ischemic tolerance and to provide neuroprotection even though no differences between the two genetic phenotypes were found in GFAP immunofluorescence [40]. Similar to our results, infarct sizes analyzed by post mortem 2,3,5, triphenyltetrazolium chloride (TTC) staining were not different between the genotypes in this study.…”

Section: Discussionsupporting

confidence: 86%

Lack of functional P2X7 receptor aggravates brain edema development after middle cerebral artery occlusion

Kaiser

Penk

Franke

et al. 2016

Purinergic Signalling

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Effective therapeutic measures against the development of brain edema, a life-threatening complication of cerebral ischemia, are necessary to improve the functional outcome for the patient. Here, we identified a beneficial role of purinergic receptor P2X7 activation in acute ischemic stroke. Involvement of P2X7 in the development of neurological deficits, infarct size, brain edema, and glial responses after ischemic cerebral infarction has been analyzed. Neurologic evaluation, magnetic resonance imaging, and immunofluorescence assays were used to characterize the receptor's effect on the disease progress during 72 h after transient middle cerebral artery occlusion (tMCAO). Sham-operated animals were included in all experiments for control purposes. We found P2X7-deficient mice to develop a more prominent brain edema with a trend towards more severe neurological deficits 24 h after tMCAO. Infarct sizes, T2 times, and apparent diffusion coefficients did not differ significantly between wild-type and P2X7 −/− animals.Our results show a characteristic spatial distribution of reactive glia cells with strongly attenuated microglia activation in P2X7 −/− mice 72 h after tMCAO. Our data indicate that P2X7 exerts a role in limiting the early edema formation, possibly by modulating glial responses, and supports later microglia activation.

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Section: Discussionsupporting

confidence: 86%

Lack of functional P2X7 receptor aggravates brain edema development after middle cerebral artery occlusion

Kaiser

Penk

Franke

et al. 2016

Purinergic Signalling

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show abstract

“…To determine whether reactive astrocytes become phagocytic under pathological conditions, we employed a transient middle cerebral artery occlusion (MCAO) mouse model 21, 22 . The mice were subjected to right-sided ligature MCAO for 15 min followed by various periods of reperfusion.…”

Section: Resultsmentioning

confidence: 99%

Reactive astrocytes function as phagocytes after brain ischemia via ABCA1-mediated pathway

et al. 2017

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Astrocytes become reactive following various brain insults; however, the functions of reactive astrocytes are poorly understood. Here, we show that reactive astrocytes function as phagocytes after transient ischemic injury and appear in a limited spatiotemporal pattern. Following transient brain ischemia, phagocytic astrocytes are observed within the ischemic penumbra region during the later stage of ischemia. However, phagocytic microglia are mainly observed within the ischemic core region during the earlier stage of ischemia. Phagocytic astrocytes upregulate ABCA1 and its pathway molecules, MEGF10 and GULP1, which are required for phagocytosis, and upregulation of ABCA1 alone is sufficient for enhancement of phagocytosis in vitro. Disrupting ABCA1 in reactive astrocytes result in fewer phagocytic inclusions after ischemia. Together, these findings suggest that astrocytes are transformed into a phagocytic phenotype as a result of increase in ABCA1 and its pathway molecules and contribute to remodeling of damaged tissues and penumbra networks.

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“…P2X7R has been shown to have a role in ischemic preconditioning as well. Ischemic preconditioning fails to be neuroprotective in P2X7R KO mice whereas wild-type mice have significantly smaller lesions in transient MCAo model after ischemic preconditioning (Hirayama et al, 2015). As TLRs, P2X7R is capable of activating NF-κB through the auto-regulated MyD88 pathway (Liu et al, 2011) which may explain the effects of P2X7R in ischemic preconditioning.…”

Section: Other Pharmacological Modulations Of Inflammatory Signalimentioning

confidence: 99%

Role of microglia in ischemic focal stroke and recovery: focus on Toll-like receptors

Anttila

Whitaker

Wires

et al. 2017

Progress in Neuro-Psychopharmacology and Biological Psychiatry

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Stroke is the leading cause of disability in adults. Drug treatments that target stroke-induced pathological mechanisms and promote recovery are desperately needed. In the brain, an ischemic event triggers major inflammatory responses that are mediated by the resident microglial cells. In this review, we focus on the microglia activation after ischemic brain injury as a target of immunomodulatory therapeutics. We divide the microglia-mediated events following ischemic stroke into three categories: acute, subacute, and long-term events. This division encompasses the spatial and temporal dynamics of microglia as they participate in the pathophysiological changes that contribute to the symptoms and sequela of a stroke. The importance of Toll-like receptor (TLR) signaling in the outcomes of these pathophysiological changes is highlighted. Increasing evidence shows that microglia have a complex role in stroke pathophysiology and they mediate both detrimental and beneficial effects on stroke outcome. So far, most of the pharmacological studies in experimental models of stroke have focused on neuroprotective strategies which are impractical for clinical applications. Post-ischemic inflammation is long lasting and thus, could provide a therapeutic target for novel delayed drug treatment. However, more studies are needed to elucidate the role of microglia in the recovery process from an ischemic stroke and to evaluate the therapeutic potential of modulating post-ischemic inflammation to promote functional recovery.

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Astrocyte-Mediated Ischemic Tolerance

Cited by 102 publications

References 50 publications

Lack of functional P2X7 receptor aggravates brain edema development after middle cerebral artery occlusion

Lack of functional P2X7 receptor aggravates brain edema development after middle cerebral artery occlusion

Reactive astrocytes function as phagocytes after brain ischemia via ABCA1-mediated pathway

Role of microglia in ischemic focal stroke and recovery: focus on Toll-like receptors

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