星形胶质细胞和神经损伤

星形胶质细胞的选择性调控

NIH Public AccessAuthor ManuscriptStroke. Author manuscript; available in PMC 2009 September 1.Published in final edited form as: Stroke. 2009 March; 40(3 Suppl): S8–12. doi:10.1161/STROKEAHA.108.533166.

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Astrocytes and ischemic injuryTakahiro Takano, NancyAnn Oberheim, Maria Luisa Cotrina, and Maiken Nedergaard Division of Glial Disease and Therapeutics. Center for Translational Neuromedicine. Department of Neurosurgery. University of Rochester Medical School. 601 Elmwood Avenue, Rochester, NY 14642

AbstractIschemic injury is traditionally viewed from an axiomatic perspective of neuronal loss. Yet the ischemic infarct encompasses all cell types, including astrocytes. This review will discuss the idea that astrocytes play a fundamental role in the pathogenesis of ischemic neuronal death. It is proposed that stroke injury is primarily a consequence of the failure of astrocytes to support the essential metabolic needs of neurons. This‘gliocentric view’ of stroke injury predicts that pharmacological interventions specifically targeting neurons are unlikely to succeed, because it is not feasible to preserve neuronal viability in an environment that fails to meet essential metabolic requirements. Neuroprotective efforts targeting the functional integrity of astrocytes may constitute a superior strategy for future neuroprotection.

IntroductionOver the past decade, a virtual revolution has occurred in our understanding of the physiology of astrocytes, and of their interactions with neurons in the normal brain 1, 2. For example, astrocytes actively propagate Ca2+ signals to neighboring neurons, whose level of synaptic activity they can actively modulate 3, 4. Key mediators of astrocyte-neuron signaling are glutamate 5 and ATP/adenosine 6. While much current work is focused on the role of gliotransmitters in synaptic transmission, the potential harmful effects of glutamate/ATP release from astrocytes in the ischemic penumbra has not been defined. Also, astrocytes have recently been implicated in the local control of blood flow 7-9, but it is not established how ischemia affects the ability of astrocytes to modulate vascular tone. We will here critically evaluate astrocytes as a potential new therapeutic target in stroke. Although the contribution of astrocytes to the process of ischemic infarction has not been clearly defined, an abundance of data already suggests the importance of astrocytes in both the initiation and propagation of secondary ischemic injury. Pathology of focal stroke Focal ischemia, or prolonged occlusion of a cerebral vessel, initiates the process of ischemic infarction, in which all tissue elements are affected. Ischemic infarcts are sharply demarcated and the transition between the infarct and the surrounding tissue is frequently less than 100μm. All cell types, including neurons, astrocytes, and the vasculature are dead in a chronic infarct

, whereas cells in the per-infarct areas are preserved. No evidence for neuronal loss outside chronic infarcts has been identified in either human or rodent brain 10, 11. In contrast, transient artery occlusion is frequently associated with selective neuronal injury with little, if any loss of astrocytes 12. Functional recovery after prolonged or permanent artery occlusion

Correspondence should be addressed to: Maiken Nedergaard, Divison of Glial Disease and Therapeutics, Center for Translational Neuromedicine, Department of Neurosurgery, University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, NY 14642, E-mail: nedergaard@urmc.rochester.edu..

星形胶质细胞的选择性调控

is often poor, indicating that ischemic infarcts have a much worse prognosis than transient

ischemic attacks (TIA) associated with selective neuronal injury.

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NIH-PA Author ManuscriptSupportive functions of astrocytesAstrocytes are the principal housekeeping cells of the nervous system. Their main supportivetasks are to scavenge transmitters released during synaptic activity, control ion and waterhomeostasis, release neurotrophic factors, shuttle metabolite and waste products, and toparticipate in the formation of the blood-brain-barrier 13. Failure of any of these supportivefunctions of astrocytes will, either alone or in combination, constitute a threat for neuronalsurvival. In fact, the all-and-none pattern of ischemic infarction indicates that neurons are notcapable of surviving in the absence of astrocytes. Unfortunately, our current understanding ofhow ischemia affects basic astrocytic functions is incomplete 14. It has not been establishedto which degree astrocytic glutamate uptake is impaired in the ischemic penumbra. It istherefore not possible to predict whether impairment of astrocytic glutamate uptake contributesmore significantly to neuronal death, than for example a decrease in astrocytic K+ bufferingcapacity.Astrocytes Ca2+ oscillations and Ca2+ wavesA growing body of evidence has in the last decade documented that astrocytes are more thanthe supportive cells of CNS. Astrocytes express neurotransmitter receptors and respond toneuronal activity by increases in cytosolic Ca2+ 15. Astrocytes display two distinct types ofCa2+ signaling modalities: Ca2+ oscillations and propagating Ca2+ waves 16. Ca2+ oscillationsare repetitive monophasic increases in cytosolic Ca2+ limited to a single cell. Ca2+ oscillationscan be evoked by exposure to several different transmitters, including glutamate, GABA, andATP 17. They can also be triggered by removal of extracellular Ca2+, or by exposure of culturedastrocytes to hypoosmotic solutions 18. An extensive literature has documented that astrocyticCa2+ oscillations involves activation of PLA, IP3 production, and release of Ca2+ from

intracellular stores, rather than Ca2+ influx through membrane channels 17.

The second modality of astrocytic Ca2+ signaling, propagating Ca2+ waves, can be stimulated

by focal electrical stimulation, mechanical stimulation, lowering extracellular Ca2+ levels, or

by local application of transmitters (glutamate or ATP). High frequency neuronal spiking has

been shown to induce astrocytic Ca2+ waves in organotypic slices and in anesthetized mice

following sensory stimulation 19, 20. In general, Ca2+ waves propagate with a velocity of

around 8 20 μm/s and expand over a maximum radius of 100 to 300 μM, including 10 to 50

astrocytes per wave. Initially, it was proposed that propagation of Ca2+ waves was conducted

through the diffusion of IP3 and/or calcium through intercellular gap junctions 21. Using

pharmacologic approaches, it was demonstrated that an extracellular agent, ATP, was the actual

diffusible messenger 22. Similar studies have in parallel shown that ATP mediates Ca2+ waves

in several non-excitable cells, including epithelium, liver, heart, and osteoblasts (see Berridge

2000 48). Wave propagation is mediated by P2Y receptors, likely including multiple purinergic

receptor subtypes in astrocytes, including P2Y1, P2Y2, and P2Y4 23. Ca2+ waves can be

viewed as a pathway for amplification of astrocytic activation. When an astrocyte reaches a

certain level of activation, it will release ATP that in turn increases Ca2+ in its neighbors

resulting in a spatial expansion of astrocytic activation 49. Purinergic signaling plays important

roles in coordination and synchronization of astrocytic responses to synaptic transmission.

Accordingly, inhibition of astrocytic P2Y receptors reduced and delayed Ca2+ increases in

cortical astrocytes following whisker stimulation 20. Little is known with regard to the effect

of ischemia on purinergic signaling. However, traumatic spinal cord injury is associated with

prolonged increases in astrocytic ATP release. Motor neurons express multiple purinergic

receptors, including P2×7 receptors. Administration of P2×7 receptor antagonists reduces