Downregulation of glucose-6-phosphate dehydrogenase contributes to diabetic neuropathic pain through upregulation of toll-like receptor 4 in rats

Sun, Qian; Zhang, Bingyu; Zhang, Pingan; Hu, Ji; Zhang, Honghong; Xu, Guang–Yin

doi:10.1177/1744806919838659

Cited by 26 publications

(21 citation statements)

References 46 publications

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“…This could be due to a contribution of a MORindependent action of fentanyl on nociceptors in their acute sensitization, in vitro. One such target might be TLR4 (Watkins et al, 2009;Stevens et al, 2013;Okudaira et al, 2016;Sun et al, 2019), activation of which produces OIH (unpublished observation). Redistribution and enhanced expression of MOR as part of neuroplasticity, is another possibility, as it has been shown to occur after inflammation and nerve injury (Ji et al, 1995;Kolesnikov et al, 2007;Schmidt et al, 2013).…”

Section: Discussionmentioning

confidence: 97%

In Vitro Nociceptor Neuroplasticity Associated with In Vivo Opioid-Induced Hyperalgesia

2019

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Opioid-induced hyperalgesia (OIH) is a serious adverse event produced by opioid analgesics. Lack of an in vitro model has hindered study of its underlying mechanisms. Recent evidence has implicated a role of nociceptors in OIH. To investigate the cellular and molecular mechanisms of OIH in nociceptors, in vitro, subcutaneous administration of an analgesic dose of fentanyl (30 g/kg, s.c.) was performed in vivo in male rats. Two days later, when fentanyl was administered intradermally (1 g, i.d.), in the vicinity of peripheral nociceptor terminals, it produced mechanical hyperalgesia (OIH). Additionally, 2 d after systemic fentanyl, rats had also developed hyperalgesic priming (opioid-primed rats), long-lasting nociceptor neuroplasticity manifested as prolongation of prostaglandin E 2 (PGE 2) hyperalgesia. OIH was reversed, in vivo, by intrathecal administration of cordycepin, a protein translation inhibitor that reverses priming. When fentanyl (0.5 nM) was applied to dorsal root ganglion (DRG) neurons, cultured from opioid-primed rats, it induced a-opioid receptor (MOR)-dependent increase in [Ca 2ϩ ] i in 26% of small-diameter neurons and significantly sensitized (decreased action potential rheobase) weakly IB4 ϩ and IB4 Ϫ neurons. This sensitizing effect of fentanyl was reversed in weakly IB4 ϩ DRG neurons cultured from opioid-primed rats after in vivo treatment with cordycepin, to reverse of OIH. Thus, in vivo administration of fentanyl induces nociceptor neuroplasticity, which persists in culture, providing evidence for the role of nociceptor MOR-mediated calcium signaling and peripheral protein translation, in the weakly IB4-binding population of nociceptors, in OIH.

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Section: Discussionmentioning

confidence: 97%

In Vitro Nociceptor Neuroplasticity Associated with In Vivo Opioid-Induced Hyperalgesia

2019

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“…Studies have proved mitochondrial oxidative stress as one of the main causes leading to neuronal damage (Leinninger et al, 2006; Vincent et al, 2011; Yerra and Kumar, 2017). Conversely, the expression and enzymatic activity of G6PD are decreased in the dorsal root ganglions of STZ-induced diabetic mice and high glucose-treated PC-12 cells (Okouchi et al, 2005; Sun et al, 2019). In the present study, both TIGAR and G6PD were decreased in the hippocampus of STZ-treated mice and high glucose-stimulated neurons.…”

Section: Discussionmentioning

confidence: 99%

“…Overload of the electron transport chain and oxidative phosphorylation also lead to mitochondrial dysfunction and oxidative stress (Edwards et al, 2008; Yan, 2014). In contrast, the activity of glucose 6-phosphate dehydrogenase (G6PD), a rate-limiting enzyme in the pentose phosphate pathway (PPP), is decreased after stimulation with high glucose (Okouchi et al, 2005; Sun et al, 2019). PPP has been regarded as a main metabolic pathway to regenerate glutathione at the expense of NADPH and protect neurons from oxidative stress (Herrero-Mendez et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

TIGAR Attenuates High Glucose-Induced Neuronal Apoptosis via an Autophagy Pathway

Zhou

Yao

et al. 2019

Front. Mol. Neurosci.

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Hyperglycemia-induced neuronal apoptosis is one of the important reasons for diabetic neuropathy. Long-time exposure to high glucose accelerates many aberrant glucose metabolic pathways and eventually leads to neuronal injury. However, the underlying mechanisms of metabolic alterations remain unknown. TP53-inducible glycolysis and apoptosis regulator (TIGAR) is an endogenous inhibitor of glycolysis and increases the flux of pentose phosphate pathway (PPP) by regulating glucose 6-phosphate dehydrogenase (G6PD). TIGAR is highly expressed in neurons, but its role in hyperglycemia-induced neuronal injury is still unclear. In this study, we observed that TIGAR and G6PD are decreased in the hippocampus of streptozotocin (STZ)-induced diabetic mice. Correspondingly, in cultured primary neurons and Neuro-2a cell line, stimulation with high glucose induced significant neuronal apoptosis and down-regulation of TIGAR expression. Overexpression of TIGAR reduced the number of TUNEL-positive neurons and prevented the activation of Caspase-3 in cultured neurons. Furthermore, enhancing the expression of TIGAR rescued high glucose-induced autophagy impairment and the decrease of G6PD. Nitric oxide synthase 1 (NOS1), a negative regulator of autophagy, is also inhibited by overexpression of TIGAR. Inhibition of autophagy abolished the protective effect of TIGAR in neuronal apoptosis in Neuro-2a. Importantly, overexpression of TIGAR in the hippocampus ameliorated STZ-induced cognitive impairment in mice. Therefore, our data demonstrated that TIGAR may have an anti-apoptosis effect via up-regulation of autophagy in diabetic neuropathy.

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“…While congenital G6PDd is well known, its acquired deficiency is less appreciated. It accompanies insulin resistance (52) and hypertension (53,54), grouped together as the metabolic syndrome. In addition, advancing age also lowers it (55).…”

Section: Acquired G6pddmentioning

confidence: 99%

Centrality of G6PD in COVID-19: The Biochemical Rationale and Clinical Implications

Buinitskaya¹,

Gurinovich²,

Wlodaver

et al. 2020

Front. Med.

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Introduction: COVID-19 is a novel and devastating disease. Its manifestations vary from asymptomatic to lethal. Moreover, mortality rates differ based on underlying health conditions and ethnicity. We investigated the biochemical rationale behind these observations using machine reasoning by the sci.AI system (https://sci.ai/). Facts were extracted and linked from publications available in nlm.nih.gov and Europe PMC to form the dataset which was validated by medical experts. Results: Based on the analysis of experimental and clinical data, we synthesized detailed biochemical pathways of COVID-19 pathogenesis which were used to explain epidemiological and clinical observations. Clinical manifestations and biomarkers are highlighted to monitor the course of COVID-19 and navigate treatment. As depicted in the Graphical Abstract, SARS-CoV-2 triggers a pro-oxidant (PO) response leading to the production of reactive oxygen species (ROS) as a normal innate defense. However, SARS-CoV-2's unique interference with the antioxidant (AO) system, through suppression of nitric oxide (NO) production in the renin-angiotensin-aldosterone system (RAAS), leads to an excessive inflammatory PO response. The excessive PO response becomes critical in cohorts with a compromised AO system such as patients with glucose-6-phosphate dehydrogenase deficiency (G6PDd) where NO and glutathione (GSH) mechanisms are impaired. G6PDd develops in patients with metabolic syndrome. It is mediated by aldosterone (Ald) which also increases specifically in COVID-19. Conclusion: G6PD is essential for an adequate immune response. Both G6PDd and SARS-CoV-2 compromise the AO system through the same pathways rendering G6PDd the Achilles' heel for COVID-19. Thus, the evolutionary antimalarial advantage of the G6PDd cohort can be a disadvantage against SARS-CoV-2.

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Downregulation of glucose-6-phosphate dehydrogenase contributes to diabetic neuropathic pain through upregulation of toll-like receptor 4 in rats

Cited by 26 publications

References 46 publications

In Vitro Nociceptor Neuroplasticity Associated with In Vivo Opioid-Induced Hyperalgesia

In Vitro Nociceptor Neuroplasticity Associated with In Vivo Opioid-Induced Hyperalgesia

TIGAR Attenuates High Glucose-Induced Neuronal Apoptosis via an Autophagy Pathway

Centrality of G6PD in COVID-19: The Biochemical Rationale and Clinical Implications

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