P2X7 receptor is critical in α-synuclein–mediated microglial NADPH oxidase activation

Jiang, Tianfang; Hoekstra, Jake G.; Heng, Xin; Kang, Wenyan; Ding, Jingzhong; Li, Jun; Chen, Shengdi; Zhang, Jing

doi:10.1016/j.neurobiolaging.2015.03.015

Cited by 107 publications

(107 citation statements)

References 53 publications

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“…This is in line with results obtained from models of the disease where it is reported that P2X7 is involved in the neuroinflammatory process observed in PD [105,106]. Furthermore, is reported that extracellular ␣-synuclein (␣-syn) co-precipitates with P2X7 in microglia and this interaction is related to the activation of NADPH oxidase via PI3K/AKT that increases the production of ROS, oxidative stress and could lead to increased cell death [107]. Other receptor that appears involved in the pathogenesis of PD is P2X1, the activation of which induces lysosomal dysfunction and accumulation of intracellular ␣-syn and impairment of autophagy [108].…”

Section: Purinergic Receptors and Neurodegenerative Disorderssupporting

confidence: 90%

Modulation of the neuronal network activity by P2X receptors and their involvement in neurological disorders

Sáez-Orellana

Godoy

Silva-Grecchi

et al. 2015

Pharmacological Research

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Section: Purinergic Receptors and Neurodegenerative Disorderssupporting

confidence: 90%

Modulation of the neuronal network activity by P2X receptors and their involvement in neurological disorders

Sáez-Orellana

Godoy

Silva-Grecchi

et al. 2015

Pharmacological Research

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“…Previous studies have demonstrated P2X7R activation promotes NOX-mediated ROS production in microglia 29, 36 . Therefore, we sought to determine whether NADPH oxidase (NOX) contributed to P2X7R-mediated ROS increases in SCDH neurons.…”

Section: Resultsmentioning

confidence: 88%

“…Other studies have also shown inhibition with apocynin, which prevents the assembly of NOX 50 , attenuates P2X7R-mediated ROS increases, suggesting ROS production may indeed require NOX 36, 51 . Similarly, we found apocynin abolished BzATP-induced ROS production in SCDH neurons.…”

Section: Discussionmentioning

confidence: 92%

Neuronal P2X7 receptor-induced reactive oxygen species production contributes to nociceptive behavior in mice

Muñoz

Gao

Tian

et al. 2017

Sci Rep

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ATP can activate a variety of pathways through P2 purinoreceptors, leading to neuroprotection and pathology in the CNS. Among all P2X receptors, the P2X7 receptor (P2X7R) is a well-defined therapeutic target for inflammatory and neuropathic pain. Activation of P2X7R can generate reactive oxygen species (ROS) in macrophages and microglia. However, the role of ROS in P2X7R–induced pain remains unexplored. Here, we investigated the downstream effects of neuronal P2X7R activation in the spinal cord. We found that ATP induces ROS production in spinal cord dorsal horn neurons, an effect eliminated by ROS scavenger N-tert-butyl-α-phenylnitrone (PBN) and P2X7R antagonist A438079. A similar effect was observed with a P2X7R agonist, BzATP, and was attenuated by a NADPH oxidase inhibitor apocynin. Intrathecal administration of BzATP resulted in ROS production in the spinal cord and oxidative DNA damage in dorsal horn neurons. BzATP also induced robust biphasic spontaneous nociceptive behavior. Pre-treatment with A438079 abolished all BzATP-induced nociceptive behaviors, while ROS scavengers dose-dependently attenuated the secondary response. Here, we provide evidence that neuronal P2X7R activation leads to ROS production and subsequent nociceptive pain in mice. Together, the data indicate that P2X7R-induced ROS play a critical role in the P2X7R signaling pathway of the CNS.

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“…Similarly, chronic administration of rotenone in a rodent model of PD activated the NLRP3 inflammasome pathway through microglial mitochondrial dysfunction and induced dopaminergic neuronal cell death . The P2X7 receptor, a known mediator of NLRP3 inflammasome activation and release of cytokines, is ubiquitously expressed in microglia . Activation of the P2X7 receptor by its agonist, BzATP, led to ROS‐ and CaMKK‐dependent AMPK activation, disruption of mitochondrial dynamics, autophagy, and lysosomal biogenesis followed by partial cell death.…”

Section: Nlrp3 Inflammasome‐mediated Inflammatory Pathways In Pdmentioning

confidence: 99%

Targeting the Microglial NLRP3 Inflammasome and Its Role in Parkinson's Disease

et al. 2019

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Excessive activation of microglia and subsequent release of proinflammatory cytokines play a crucial role in neuroinflammation and neurodegeneration in Parkinson's disease (PD). Components of the nucleotide‐binding oligomerization domain and leucine‐rich‐repeat‐ and pyrin‐domain‐containing 3 inflammasome complex, leucine‐rich‐repeat‐ and pyrin‐domain‐containing 3, caspase‐1, and apoptosis‐associated speck‐like protein containing a CARD, are highly expressed in activated microglia in PD patient brains. Findings suggest that neurotoxins, aggregation of α‐synuclein, mitochondrial reactive oxygen species, and disrupted mitophagy are the key regulators of microglial leucine‐rich‐repeat‐ and pyrin‐domain‐containing 3 inflammasome activation and release of interleukin‐1β and interleukin‐18 caspase‐1‐mediated pyroptotic cell death in the substantia nigra of the brain. Although this evidence suggests the leucine‐rich‐repeat‐ and pyrin‐domain‐containing 3 inflammasome may be a potential drug target for treatment of PD, the exact mechanism of how the microglia sense these stimuli and initiate leucine‐rich‐repeat‐ and pyrin‐domain‐containing 3 inflammasome signaling is unknown. Here, the molecular mechanism and regulation of microglial leucine‐rich‐repeat‐ and pyrin‐domain‐containing 3 inflammasome activation and its role in the pathogenesis of PD are discussed. Moreover, the potential of both endogenous and synthetic leucine‐rich‐repeat‐ and pyrin‐domain‐containing 3 inflammasome modulators, long noncoding RNA, microRNA to develop novel therapeutics to treat PD is presented. Overall, we recommend that the microglial leucine‐rich‐repeat‐ and pyrin‐domain‐containing 3 inflammasome can be a potential target for PD treatment. © 2019 International Parkinson and Movement Disorder Society

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P2X7 receptor is critical in α-synuclein–mediated microglial NADPH oxidase activation

Cited by 107 publications

References 53 publications

Modulation of the neuronal network activity by P2X receptors and their involvement in neurological disorders

Modulation of the neuronal network activity by P2X receptors and their involvement in neurological disorders

Neuronal P2X7 receptor-induced reactive oxygen species production contributes to nociceptive behavior in mice

Targeting the Microglial NLRP3 Inflammasome and Its Role in Parkinson's Disease

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