Spinal cord injury induces early and persistent lesional P2X4 receptor expression

Schwab, Jan M.; Guo, Liang-Hao; Schluesener, Hermann J.

doi:10.1016/j.jneuroim.2005.02.016

Cited by 81 publications

(60 citation statements)

References 9 publications

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“…Thus, targeting the P2X4R-p38 -MAPKsignaling pathway in spinal microglia could prove useful in the development of novel therapeutic approaches for treating pain hypersensitivity caused by nerve injury. In addition, involvement of microglial P2X4Rs reported after injury to a peripheral nerve is increasingly being found in other models of CNS pathology such as inflammation Zhang et al, 2008), CNS injury (Schwab et al, 2005;Zhang et al, 2006), and in glioblastoma brain tumors (Guo et al, 2004). Therefore, the implications of our findings may extend not only to pathological pain states but also to a diversity of CNS disorders.…”

Section: Discussionmentioning

confidence: 55%

P2X4-Receptor-Mediated Synthesis and Release of Brain-Derived Neurotrophic Factor in Microglia Is Dependent on Calcium and p38-Mitogen-Activated Protein Kinase Activation

Trang¹,

Beggs²,

Wan³

et al. 2009

J. Neurosci.

420

378

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Microglia in the dorsal horn of the spinal cord are increasingly recognized as being crucial in the pathogenesis of pain hypersensitivity after injury to a peripheral nerve. It is known that P2X4 purinoceptors (P2X4Rs) cause the release of brain-derived neurotrophic factor (BDNF) from microglia, which is necessary for maintaining pain hypersensitivity after nerve injury. However, there is a critical gap in understanding how activation of microglial P2X4Rs leads to the release of BDNF. Here, we show that stimulating P2X4Rs with ATP evokes a biphasic release of BDNF from microglia: an early phase occurs within 5 min, whereas a late phase peaks 60 min after ATP stimulation. Concomitant with the late phase of release is an increased level of BDNF within the microglia. Both phases of BDNF release and the accumulation within the microglia are dependent on extracellular Ca 2ϩ . The late phase of BDNF release and accumulation, but not the early phase of release, are suppressed by inhibiting transcription and translation, indicating that activation of P2X4R causes an initial release of a pre-existing pool of BDNF followed by an increase in de novo synthesis of BDNF. The release of BDNF is abolished by inhibiting SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor)-mediated exocytosis. Furthermore, we find that the P2X4R-evoked release and synthesis of BDNF are dependent on activation of p38-mitogen-activated protein kinase (MAPK). Together, our findings provide a unifying mechanism for pain hypersensitivity after peripheral nerve injury through P2X4R-evoked increase in Ca 2ϩ and activation of p38-MAPK leading to the synthesis and exocytotic release of BDNF from microglia.

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Section: Discussionmentioning

confidence: 55%

P2X4-Receptor-Mediated Synthesis and Release of Brain-Derived Neurotrophic Factor in Microglia Is Dependent on Calcium and p38-Mitogen-Activated Protein Kinase Activation

Trang¹,

Beggs²,

Wan³

et al. 2009

J. Neurosci.

420

378

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“…Interestingly, only neurons were found to express P2X 4 in the spinal cord during the acute phase after SCI. However, other groups have reported that activated microglia in the spinal cord upregulate P2X 4 expression after peripheral (sciatic) nerve injury, although the increased expression peaked during the second week after lesion in this particular model (Cavaliere et al, 2003;Tsuda et al, 2003;Schwab et al, 2005;Ulmann et al, 2008). In the chronic phase after SCI, P2X 4 does not seem to play a significant role, yet the improved functional recovery observed in P2X 4 -KO compared with WT mice was maintained up to at least day 35.…”

Section: Discussionmentioning

confidence: 60%

“…Increased expression of P2X 4 is observed in injured tissue after SCI (Schwab et al, 2005), traumatic brain injury (Zhang et al, 2006), and cerebral ischemia (Cavaliere et al, 2003). Moreover, P2X 4 receptors are elevated in spinal cord microglia after peripheral nerve injury (Tsuda et al, 2003;Ulmann et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

P2X₄Receptors Influence Inflammasome Activation after Spinal Cord Injury

Vaccari¹,

Bastien²,

Yurcisin³

et al. 2012

J. Neurosci.

162

141

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P2X 4 and P2X 7 are the predominant purinergic P2X receptor subtypes expressed on immune and neural cells. These receptor subtypes traffic between intracellular compartments and the plasma membrane and form protein interactions with each other to regulate ATPdependent signaling. Our recent studies have shown that P2X 7 receptors in neurons and astrocytes activate NLRP1 inflammasomes, but whether P2X 4 receptors regulate inflammasome signaling is essentially unknown. Here, we demonstrate that P2X 4 receptors are expressed in neurons of the spinal cord. We provide direct evidence that spinal cord injury (SCI) induces an innate inflammatory response that leads to increased caspase-l cleavage and

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“…Another study revealed an upregulation of P2X1 and P2X2 at the site of neurodegeneration following axotomy (Viscomi et al, 2004). P2X4 is expressed at increased concentrations in response to tissue injury following spinal cord injury (Schwab et al, 2005), traumatic brain injury (Zhang et al, 2006) and in spinal cord microglia following peripheral nerve injury (Tsuda et al, 2003;Ulmann et al, 2008). After stab wound injury, P2X1 and P2X7 receptor immunoreactivity was observed on astrocytes that were previously absent (Franke et al, 2004).…”

Section: The Role Of P2x Receptors In Neuroinflammationmentioning

confidence: 99%

Purinergic mechanisms in neuroinflammation: An update from molecules to behavior

et al. 2016

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a b s t r a c tThe principle functions of neuroinflammation are to limit tissue damage and promote tissue repair in response to pathogens or injury. While neuroinflammation has utility, pathophysiological inflammatory responses, to some extent, underlie almost all neuropathology. Understanding the mechanisms that control the three stages of inflammation (initiation, propagation and resolution) is therefore of critical importance for developing treatments for diseases of the central nervous system. The purinergic signaling system, involving adenosine, ATP and other purines, plus a host of P1 and P2 receptor subtypes, controls inflammatory responses in complex ways. Activation of the inflammasome, leading to release of pro-inflammatory cytokines, activation and migration of microglia and altered astroglial function are key regulators of the neuroinflammatory response. Here, we review the role of P1 and P2 receptors in mediating these processes and examine their contribution to disorders of the nervous system. Firstly, we give an overview of the concept of neuroinflammation. We then discuss the contribution of P2X, P2Y and P1 receptors to the underlying processes, including a discussion of cross-talk between these different pathways. Finally, we give an overview of the current understanding of purinergic contributions to neuroinflammation in the context of specific disorders of the central nervous system, with special emphasis on neuropsychiatric disorders, characterized by chronic low grade inflammation or maternal inflammation. An understanding of the important purinergic contribution to neuroinflammation underlying neuropathology is likely to be a necessary step towards the development of effective interventions.

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Spinal cord injury induces early and persistent lesional P2X4 receptor expression

Cited by 81 publications

References 9 publications

P2X4-Receptor-Mediated Synthesis and Release of Brain-Derived Neurotrophic Factor in Microglia Is Dependent on Calcium and p38-Mitogen-Activated Protein Kinase Activation

P2X4-Receptor-Mediated Synthesis and Release of Brain-Derived Neurotrophic Factor in Microglia Is Dependent on Calcium and p38-Mitogen-Activated Protein Kinase Activation

P2X₄Receptors Influence Inflammasome Activation after Spinal Cord Injury

Purinergic mechanisms in neuroinflammation: An update from molecules to behavior

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Spinal cord injury induces early and persistent lesional P2X4 receptor expression

Cited by 81 publications

References 9 publications

P2X4-Receptor-Mediated Synthesis and Release of Brain-Derived Neurotrophic Factor in Microglia Is Dependent on Calcium and p38-Mitogen-Activated Protein Kinase Activation

P2X4-Receptor-Mediated Synthesis and Release of Brain-Derived Neurotrophic Factor in Microglia Is Dependent on Calcium and p38-Mitogen-Activated Protein Kinase Activation

P2X4Receptors Influence Inflammasome Activation after Spinal Cord Injury

Purinergic mechanisms in neuroinflammation: An update from molecules to behavior

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P2X₄Receptors Influence Inflammasome Activation after Spinal Cord Injury