Mechanical allodynia and spinal up-regulation of P2X4 receptor in experimental autoimmune neuritis rats

Zhang, Z.; Fauser, U.; Schluesener, Hermann J.

doi:10.1016/j.neuroscience.2007.12.042

Cited by 63 publications

(49 citation statements)

References 24 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.

422

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.

422

378

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“…In spinal cord, microglia and astrocytes are activated in response to peripheral nerve injury to secrete proinflammatory cytokines, like IL-6, TNF-␣, and IL-1␤, which contribute to central sensitization of neuropathic pain (39,40). In EAN, the major pathological changes are seen in PNS but spinal glia activation and expression of inflammatory molecules have been described and are due to peripheral nerve injury and nonspecific infiltration of reactive T cells and macrophages (5,41). In spinal cords, both microglia and astrocytes contribute to the development of neuropathic pain in a variety of models, however their roles are different (42).…”

Section: Discussionmentioning

confidence: 99%

“…Pathologically, EAN is characterized by breakdown of the blood-nerve barrier, robust accumulation of reactive T cells and macrophages in the PNS and demyelination of peripheral nerves (3). Glia activation in spinal cords of EAN rats was observed as well and is considered to relate to pain hypersensitivity in EAN (5). Reactive lymphocytes and macrophages orchestrate a robust local inflammation that causes demyelination and axon degeneration and are essential for the development of EAN.…”

Section: E Xperimental Autoimmune Neuritis (Ean)mentioning

confidence: 99%

Compound A, a Plant Origin Ligand of Glucocorticoid Receptors, Increases Regulatory T Cells and M2 Macrophages to Attenuate Experimental Autoimmune Neuritis with Reduced Side Effects

Zhang¹,

Zhang²,

Schluesener³

2009

The Journal of Immunology

118

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Experimental autoimmune neuritis (EAN) is a helper T cell-mediated autoimmune demyelinating inflammatory disease of the peripheral nervous system and serves as the animal model for human inflammatory demyelinating polyneuropathies. Compound A, a plant-derived phenyl aziridine precursor, was reported to activate glucocorticoid receptors to exert transrepression but not transactivation properties. In this study, we investigated the effects of Compound A in EAN rats. Compound A greatly suppressed paraparesis in EAN, even when administrated after the appearance of the first neurological signs. Accumulation of macrophages and lymphocytes, demyelination, and mRNA levels of inflammatory molecules in sciatic nerves of EAN were greatly attenuated by Compound A. In addition, Compound A inhibited progression of neuropathic pain and repressed microglia but not astrocyte activation and IL-1β and TNF-α up-regulation in EAN spinal cords. In EAN sciatic nerves, Compound A treatment increased numbers of anti-inflammatory M2 macrophages. Furthermore, Compound A induced the switch of macrophages from inflammatory M1 type to anti-inflammatory M2 type in vitro. In lymph nodes of EAN rats, Compound A depressed Th1 and Th17 cytokines, but increased Th2 cytokine and Foxp3 expression. An increase of Foxp3+/CD4+ regulatory T cells was seen in peripheral blood of EAN rats following Compound A treatment. In addition, Compound A did not cause a hyperglycemia effect in EAN rats as compared with the immunosuppressive steroid prednisolone. Therefore, our data demonstrated that Compound A could effectively suppress EAN with reduced side effects by attenuating inflammation, suggesting that Compound A could be a potent candidate for treatment of autoimmune neuropathies.

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“…Similarly, a single intraperitoneal injection of LPS triggered hyperalgesia associated with the activation of microglia and the upregulation of P2X 4 receptor expression in the spinal cord (338). A considerable increase in P2X 4 receptor expression, which paralleled the development of mechanical allodynia, was also identified in rats with experimental autoimmune neuritis (44), a commonly used model of acute inflammatory demyelinating polyradiculoneuropathy, the latter being the most common subtype of GuillainBarre syndrome (1035). Similarly a significant increase in microglial expression of P2X 4 receptors was observed following 4/5 overhemisection of the dorsal spinal cord of rats (815).…”

Section: P2x 4 Receptors and Neuropathic Painmentioning

confidence: 95%

Physiology of Microglia

Kettenmann

Hanisch

Нода

et al. 2011

Physiological Reviews

3,134

2,981

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Microglial cells are the resident macrophages in the central nervous system. These cells of mesodermal/mesenchymal origin migrate into all regions of the central nervous system, disseminate through the brain parenchyma, and acquire a specific ramified morphological phenotype termed “resting microglia.” Recent studies indicate that even in the normal brain, microglia have highly motile processes by which they scan their territorial domains. By a large number of signaling pathways they can communicate with macroglial cells and neurons and with cells of the immune system. Likewise, microglial cells express receptors classically described for brain-specific communication such as neurotransmitter receptors and those first discovered as immune cell-specific such as for cytokines. Microglial cells are considered the most susceptible sensors of brain pathology. Upon any detection of signs for brain lesions or nervous system dysfunction, microglial cells undergo a complex, multistage activation process that converts them into the “activated microglial cell.” This cell form has the capacity to release a large number of substances that can act detrimental or beneficial for the surrounding cells. Activated microglial cells can migrate to the site of injury, proliferate, and phagocytose cells and cellular compartments.

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Mechanical allodynia and spinal up-regulation of P2X4 receptor in experimental autoimmune neuritis rats

Cited by 63 publications

References 24 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

Compound A, a Plant Origin Ligand of Glucocorticoid Receptors, Increases Regulatory T Cells and M2 Macrophages to Attenuate Experimental Autoimmune Neuritis with Reduced Side Effects

Physiology of Microglia

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