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

Muñoz, Frances M.; Gao, Ruby; Tian, Yadong; Henstenburg, Brian A.; Barrett, James E.; Hu, Huijuan

doi:10.1038/s41598-017-03813-7

Cited by 61 publications

(37 citation statements)

References 74 publications

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“…Recent study found 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 signalling pathway of the central nervous system [29]. Another study found that Abeta-stimulated ROS generation in microglial cells is regulated by ATP released from the microglia in an autocrine manner [30].…”

Section: Discussionmentioning

confidence: 78%

H3 relaxin inhibits the collagen synthesis via ROS‐ and P2X7R‐mediated NLRP3 inflammasome activation in cardiac fibroblasts under high glucose

Zhang

et al. 2018

J Cellular Molecular Medi

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Excessive production of reactive oxygen species (ROS) and P2X7R activation induced by high glucose increases NLRP3 inflammasome activation, which contributes to the pathogenesis of diabetic cardiomyopathy. Although H3 relaxin has been shown to inhibit cardiac fibrosis induced by isoproterenol, the mechanism has not been well studied. Here, we demonstrated that high glucose (HG) induced the collagen synthesis by activation of the NLRP3 inflammasome, leading to caspase‐1 activation, interleukin‐1β (IL‐1β) and IL‐18 secretion in neonatal rat cardiac fibroblasts. Moreover, we used a high‐glucose model with neonatal rat cardiac fibroblasts and showed that the activation of ROS and P2X7R was augmented and that ROS‐ and P2X7R‐mediated NLRP3 inflammasome activation was critical for the collagen synthesis. Inhibition of ROS and P2X7R decreased NLRP3 inflammasome‐mediated collagen synthesis, similar to the effects of H3 relaxin. Furthermore, H3 relaxin reduced the collagen synthesis via ROS‐ and P2X7R‐mediated NLRP3 inflammasome activation in response to HG. These results provide a mechanism by which H3 relaxin alleviates NLRP3 inflammasome‐mediated collagen synthesis through the inhibition of ROS and P2X7R under HG conditions and suggest that H3 relaxin represents a potential drug for alleviating cardiac fibrosis in diabetic cardiomyopathy.

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Section: Discussionmentioning

confidence: 78%

H3 relaxin inhibits the collagen synthesis via ROS‐ and P2X7R‐mediated NLRP3 inflammasome activation in cardiac fibroblasts under high glucose

Zhang

et al. 2018

J Cellular Molecular Medi

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“…Finally, ATP (adenosine triphosphate) by an action on a variety of purine receptors expressed on afferent terminals and second order neurons and non neuronal cells has been broadly implicated in inflammatory, visceral and neuropathic pain states [57][58][59][60] . Thus, intrathecal delivery of a stable ATP analogue (BzATP: 2',3'-O-(4-benzoylbenzoyl)-ATP) results in a long-lasting allodynia in mice 71,72 .…”

Section: Introductionmentioning

confidence: 99%

Long-lasting Analgesia via Targetedin vivoEpigenetic Repression of Nav1.7

Moreno

Catroli

Alemán

et al. 2019

Preprint

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One sentence summary:In situ epigenome engineering approach for genomically scarless, durable, and non-addictive management of pain. ABSTRACTCurrent treatments for chronic pain rely largely on opioids despite their unwanted side effects and risk of addiction. Genetic studies have identified in humans key targets pivotal to nociceptive processing, with the voltage-gated sodium channel, Na V 1.7 (SCN9A), being perhaps the most promising candidate for analgesic drug development.Specifically, a hereditary loss-of-function mutation in Na V 1.7 leads to insensitivity to pain without other neurodevelopmental alterations. However, the high sequence similarity between Na V subtypes has frustrated efforts to develop selective inhibitors. Here, we investigated targeted epigenetic repression of Na V 1.7 via genome engineering approaches based on clustered regularly interspaced short palindromic repeats (CRISPR)-dCas9 and zinc finger proteins as a potential treatment for chronic pain.Towards this end, we first optimized the efficiency of Na V 1.7 repression in vitro in Neuro2A cells, and then by the lumbar intrathecal route delivered both genomeengineering platforms via adeno-associated viruses (AAVs) to assess their effects in three mouse models of pain: carrageenan-induced inflammatory pain, paclitaxel-induced neuropathic pain and BzATP-induced pain. Our results demonstrate: one, effective repression of Na V 1.7 in lumbar dorsal root ganglia; two, reduced thermal hyperalgesia in the inflammatory state; three, decreased tactile allodynia in the neuropathic state; and four, no changes in normal motor function. We anticipate this genomically scarless and non-addictive pain amelioration approach enabling Long-lasting Analgesia via Targeted in vivo Epigenetic Repression of Nav1.7, a methodology we dub pain LATER, will have significant therapeutic potential, such as for preemptive administration in 2 anticipation of a pain stimulus (pre-operatively), or during an established chronic pain state.

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“…However, extracellular sites of action of intracellular-produced NADH acting on extracellular redox-sensitive NMDAR sites could be considered. Indeed, it has been suggested that NADH (and NAD + ) can be transported across the plasma membrane 43 via the purinergic P2X7 receptor 44 , a receptor also expressed in neurons 45 , 46 . Thus it is conceivable that intracellularly formed NADH is released through P2X7 receptors and acts on extracellular redox-sensitive sites of the NMDAR.…”

Section: Discussionmentioning

confidence: 99%

Dual action of L-Lactate on the activity of NR2B-containing NMDA receptors: from potentiation to neuroprotection

Jourdain

Rothenfusser

Benadiba

et al. 2018

Sci Rep

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L-Lactate is a positive modulator of NMDAR-mediated signaling resulting in plasticity gene induction and memory consolidation. However, L-Lactate is also able to protect neurons against excito-toxic NMDAR activity, an indication of a mitigating action of L-Lactate on NMDA signaling. In this study, we provide experimental evidence that resolves this apparent paradox. Transient co-application of glutamate/glycine (1 μM/100 μM; 2 min) in primary cultures of mouse cortical neurons triggers a NMDA-dependent Ca2+ signal positively modulated by L-Lactate (10 mM) or DTT (1 mM) but decreased by Pyruvate (10 mM). This L-Lactate and DTT-induced potentiation is blocked by Ifenprodil (2 μM), a specific blocker of NMDARs containing NR2B sub-units. In contrast, co-application of glutamate/glycine (1 mM/100 μM; 2 min) elicits a NMDAR-dependent excitotoxic death in 49% of neurons. L-Lactate and Pyruvate significantly reduce this rate of cell death processes (respectively to 23% and 9%) while DTT has no effect (54% of neuronal death). This L-Lactate-induced neuroprotection is blocked by carbenoxolone and glibenclamide, respectively blockers of pannexins and KATP. In conclusion, our results show that L-Lactate is involved in two distinct and independent pathways defined as NMDAR-mediated potentiation pathway (or NADH pathway) and a neuroprotective pathway (or Pyruvate/ATP pathway), the prevalence of each one depending on the strength of the glutamatergic stimulus.

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

Cited by 61 publications

References 74 publications

H3 relaxin inhibits the collagen synthesis via ROS‐ and P2X7R‐mediated NLRP3 inflammasome activation in cardiac fibroblasts under high glucose

H3 relaxin inhibits the collagen synthesis via ROS‐ and P2X7R‐mediated NLRP3 inflammasome activation in cardiac fibroblasts under high glucose

Long-lasting Analgesia via Targetedin vivoEpigenetic Repression of Nav1.7

Dual action of L-Lactate on the activity of NR2B-containing NMDA receptors: from potentiation to neuroprotection

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