Systemic administration of an antagonist of the ATP-sensitive receptor P2X7 improves recovery after spinal cord injury

Peng, Weiguo; Cotrina, Maria Luisa; Han, Xiaoning; Yu, Hongmei; Bekar, Lane K.; Blum, Livnat; Takano, Takahiro; Tian, Guo-Feng; Goldman, Steven A.; Nedergaard, Maiken

doi:10.1073/pnas.0902531106

Cited by 390 publications

(403 citation statements)

References 32 publications

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“…A feedforward, ATP-induced release of ATP from astrocytes is one possible mechanism. 74 Experimental studies have shown that P2X 7 antagonists reduce injury and postinjury inflammation when administered acutely after spinal cord injury 75 or stroke. 76 However, there is also report of stroke exacerbation by P2X 7 antagonists.…”

Section: Purinergic Receptorsmentioning

confidence: 99%

Microglial Activation in Stroke: Therapeutic Targets

2010

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Summary:Microglial activation is an early response to brain ischemia and many other stressors. Microglia continuously monitor and respond to changes in brain homeostasis and to specific signaling molecules expressed or released by neighboring cells. These signaling molecules, including ATP, glutamate, cytokines, prostaglandins, zinc, reactive oxygen species, and HSP60, may induce microglial proliferation and migration to the sites of injury. They also induce a nonspecific innate immune response that may exacerbate acute ischemic injury. This innate immune response includes release of reactive oxygen species, cytokines, and proteases. Microglial activation requires hours to days to fully develop, and thus presents a target for therapeutic intervention with a much longer window of opportunity than acute neuroprotection. Effective agents are now available for blocking both microglial receptor activation and the microglia effector responses that drive the inflammatory response after stroke. Effective agents are also available for targeting the signal transduction mechanisms linking these events. However, the innate immune response can have beneficial as well deleterious effects on outcome after stoke, and a challenge will be to find ways to selectively suppress the deleterious effects of microglial activation after stroke without compromising neurovascular repair and remodeling.

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Section: Purinergic Receptorsmentioning

confidence: 99%

Microglial Activation in Stroke: Therapeutic Targets

2010

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“…Together, these changes could increase vulnerability of neighboring neurons, even those not directly affected by the initial insult (45). Thus, inhibition of P2X 7 Rs and Px1 and Cx HCs may be therapeutic in spinal cord inflammation, and, recently, the P2X 7 R antagonist, brilliant blue G, was shown to be neuroprotective in a rodent model of traumatic spinal cord injury (46).…”

Section: Fgf-1 Treatment Reduces Intercellular Coupling With Little Ementioning

confidence: 99%

FGF-1 induces ATP release from spinal astrocytes in culture and opens pannexin and connexin hemichannels

Garré

Retamal

Cassina

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

155

162

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Spinal astrocytes are coupled by connexin (Cx) gap junctions and express pannexin 1 (Px1) and purinergic receptors. Fibroblast growth factor 1 (FGF-1), which is released in spinal cord injury, activated spinal astrocytes in culture, induced secretion of ATP, and permeabilized them to relatively large fluorescent tracers [ethidium (Etd) and lucifer yellow (LY)] through "hemichannels" (HCs). HCs can be formed by connexins or pannexins; they can open to extracellular space or can form gap junction (GJ) channels, one HC from each cell. (Pannexins may not form gap junctions in mammalian tissues, but they do in invertebrates). HC types were differentiated pharmacologically and by Px1 knockdown with siRNA and by use of astrocytes from Cx43 knockout mice. Permeabilization was reduced by apyrase (APY), an ATPase, and by P2X 7 receptor antagonists, implicating secretion of ATP and autocrine and/or paracrine action. Increased permeability of cells exposed to FGF-1 or ATP for 2 h was mediated largely by Px1 HCs activated by P2X 7 receptors. After a 7-h treatment, the permeability was mediated by both Cx43 and Px1 HCs. FGF-1 also caused reduction in gap junctional communication. Botulinum neurotoxin A, a blocker of vesicular release, reduced permeabilization when given 30 min before FGF-1 application, but not when given 1 h after FGF-1. We infer that ATP is initially released from vesicles and then it mediates continued release by action on P2X 7 receptors and opening of HCs. These changes in HCs and gap junction channels may promote inflammation and deprive neurons of astrocyte-mediated protection in spinal cord trauma and neurodegenerative disease.astroglia | growth factor | connexon | pannexon | neurodegeneration

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“…For example, ADP is delivered into the extracellular space from activated platelets by granular release or from inflammatory cells after activation. 46,47 Although extracellular nucleotides such as ATP and ADP serve as signaling molecules themselves, and have been implicated in ischemia-driven inflammation 48 or purinergic chemotaxis, 49,50 they also serve as the main biologic source for the enzymatic production of adenosine in the extracellular space.…”

Section: Extracellular Adenosine Generationmentioning

confidence: 99%