Targeting P2X7 receptor for the treatment of central post-stroke pain in a rodent model

Kuan, Yung-Hui; Shih, Hsi-Chien; Tang, Sung‐Chun; Jeng, Jiann‐Shing; Shyu, Bai-Chuang

doi:10.1016/j.nbd.2015.02.028

Cited by 46 publications

(58 citation statements)

References 41 publications

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“…Taken all the existing data into account, we conclude that SDF1-CXCR4 signaling-mediated glial-glial/glial-neuronal communications are required for the development and maintenance of CPSP. Since it has been demonstrated that treatment with P2X7 receptor antagonist and IL-1β antibody could also reduce thalamic hemorrhage-induced microglia aggregation, neuronal excitability and allodynia phenomena in CPSP rats (Kuan et al, 2015), a common upstream regulation by HIF-1α-SDF1-CXCR4 signaling might be shared.…”

Section: Discussionmentioning

confidence: 99%

“…So far, the underlying mechanisms of CPSP remain largely unknown due to lack of valid animal studies (De Vloo et al, 2017). In a critical review on the animal models for CPSP, the experimental thalamic hemorrhage model induced by intra-thalamic collagenase (ITC) injection (Wasserman and Koeberle, 2009; Yang et al, 2014; Kuan et al, 2015; Yang Y. et al, 2016) was believed to be the only one with relatively high reproducibility (De Vloo et al, 2017). …”

Section: Introductionmentioning

confidence: 99%

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SDF1-CXCR4 Signaling Maintains Central Post-Stroke Pain through Mediation of Glial-Neuronal Interactions

Yang

Luo

Sun

et al. 2017

Front. Mol. Neurosci.

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Central post-stroke pain (CPSP) is an intractable central neuropathic pain that has been poorly studied mechanistically. Here we showed that stromal cell-derived factor 1 (SDF1 or CXCL12), a member of the CXC chemokine family, and its receptor CXCR4 played a key role in the development and maintenance of thalamic hemorrhagic CPSP through hypoxia inducible factor 1α (HIF-1α) mediated microglial-astrocytic-neuronal interactions. First, both intra-thalamic collagenase (ITC) and SDF1 injections could induce CPSP that was blockable and reversible by intra-thalamic administration of both AMD3100 (a selective CXCR4 antagonist) and inhibitors of microglial or astrocytic activation. Second, long-term increased-expression of SDF1 and CXCR4 that was accompanied by activations of both microglia and astrocytes following ITC could be blocked by both AMD-3100 and YC-1, a selective inhibitor of HIF-1α. AMD-3100 could also inhibit release of proinflammatory mediators (TNFα, IL1β and IL-6). Increased-expression of HIF-1α, SDF1, CXCR4, Iba1 and GFAP proteins could be induced by both ITC and intra-thalamic CoCl2, an inducer of HIF-1α that was blockable by both HIF-1α inhibition and CXCR4 antagonism. Finally, inhibition of HIF-1α was only effective in prevention, but not in treatment of ITC-induced CPSP. Taken together, the present study demonstrated that in the initial process of thalamic hemorrhagic state HIF-1α up-regulated SDF1-CXCR4 signaling, while in the late process SDF1-CXCR4 signaling-mediated positive feedback plays more important role in glial-glial and glial-neuronal interactions and might be a novel promising molecular target for treatment of CPSP in clinic.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

SDF1-CXCR4 Signaling Maintains Central Post-Stroke Pain through Mediation of Glial-Neuronal Interactions

Yang

Luo

Sun

et al. 2017

Front. Mol. Neurosci.

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“…Gene-linking and epidemiological studies have implicated P2X7 in a host of CNS diseases (Hansen et al, 2008;Ursu et al, 2014). In vivo studies, meanwhile, have been used to demonstrate the involvement of the P2X7 receptor in activating the inflammasome in a broad variety of rodent disease models, including cerebral ischemia (Kuan et al, 2015), epilepsy (Engel et al, 2012), Parkinson's disease (Marcellino et al, 2010), Alzheimer's disease , depression and anxiety (Basso et al, 2009) and multiple sclerosis (Sharp et al, 2008). Systemic administration of bacterial lipopolysaccharide (LPS) markedly increases the expression of P2X7 receptors in the CNS (Choi et al, 2007), offering a mechanism for changes in CNS function in response to systemic infection.…”

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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“…The characteristics of the EEG oscillation pattern and coherence coefficient in the CPSP group were highly similar to human patients (Llinás et al, 1999(Llinás et al, , 2005Sarnthein et al, 2006). TrkB-Fc treatment confirmed that changes in the GABAergic system are a causal factor for thalamocortical dysrhythmia (Kuan et al, 2015;Shih et al, 2017). The role of the glutamatergic system in the "edge effect" has not been previously investigated.…”

Section: Discussionmentioning

confidence: 52%

“…Preparation of animal model of central poststroke pain (CPSP). CPSP was induced by a thalamic hemorrhagic lesion as described in our recent studies (Kuan et al, 2015;Shih et al, 2017). The rats were prepared under the same anesthesia procedures as in the electrophysiological experiment.…”

Section: Methodsmentioning

confidence: 99%

Spontaneous Cingulate High-Current Spikes Signal Normal and Pathological Pain States

et al. 2019

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Prominent 7-12 Hz oscillations in frontal cortical networks in rats have been reported. However, the mechanism of generation and the physiological function of this brain rhythm have not yet been clarified. Multichannel extracellular field potentials of the ACC were recorded and analyzed using the current source density method in halothane-anesthetized rats. Spontaneous high-current spikes (HCSs) were localized in the deep part of layer II/III and upper part of layer V of the ACC. The frequency of HCSs in the ACC was 7-12 Hz, with an amplitude of 6.5 Ϯ 0.76 mV/mm 2 and duration of 55.24 Ϯ 2.43 ms. The power density significantly decreased (84.56 Ϯ 6.93%, p Ͻ 0.05, t test) after pinching the hindpaw and significantly increased (149.28 Ϯ 15.96%) after treatment with morphine. The suppressive effect of pinching was reversed by naloxone (0.7 mg/kg, i.p.). HCSs coincided with initiation of the depolarization of cingulate neurons and remained in a depolarized upstate. The occurrence of cingulate HCSs was persistently preceded by a hyperpolarization phase and a burst of multiunit spike activity in the medial dorsal thalamic nucleus. Spontaneous field-potential oscillations changed from 10 Hz to a lower band (i.e., ϳ7.5 Hz) when a central poststroke pain condition was induced. The central poststroke pain group had a higher average coherence coefficient compared with the control group. Our results indicate that spontaneous cingulate cortical HCSs could be initiated by thalamocortical synaptic inputs from the medial dorsal thalamic nucleus and maintained by intracortical neuronal upstate mechanisms in physiological and pathological pain states. This study elucidated the mechanism of generation and physiological function of prominent 7-12 Hz frequency oscillations in frontal cortical networks in rats. Spontaneous cingulate cortical high-current spikes in anesthetized rats could be initiated by thalamocortical synaptic inputs from the medial dorsal thalamic nucleus and maintained by intracortical neuronal upstate mechanisms. Suppression of the anterior cingulate cortex-filtered EEG during noxious stimulation may have resulted from the desynchronization of high-current spikes in the ACC. The enhancement of fast Fourier transform power after a systemic morphine injection suggested that the opioid system may play an important role in synchronizing cingulate cortical neuronal networks. Spontaneous cingulate high-current spikes may also play an important role in thalamocortical dysrhythmia in central poststroke pain.

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Targeting P2X7 receptor for the treatment of central post-stroke pain in a rodent model

Cited by 46 publications

References 41 publications

SDF1-CXCR4 Signaling Maintains Central Post-Stroke Pain through Mediation of Glial-Neuronal Interactions

SDF1-CXCR4 Signaling Maintains Central Post-Stroke Pain through Mediation of Glial-Neuronal Interactions

Purinergic mechanisms in neuroinflammation: An update from molecules to behavior

Spontaneous Cingulate High-Current Spikes Signal Normal and Pathological Pain States

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