Activation of RAGE/STAT3 pathway by methylglyoxal contributes to spinal central sensitization and persistent pain induced by bortezomib

Wei, Jia-You; Liu, Cuicui; Ouyang, Handong; Ma, Chao; Xie, Man-Xiu; Liu, Meng; Lei, Wanlong; Ding, Huan‐Huan; Wu, Shaoling; Xin, Wenjun

doi:10.1016/j.expneurol.2017.07.010

Cited by 27 publications

(37 citation statements)

References 42 publications

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“…Consistent with our previous study [ 23 ], intraperitoneal administration of bortezomib (0.4 mg/kg for five consecutive days) markedly decreased the mechanical withdrawal threshold (Fig. 1a ).…”

Section: Resultssupporting

confidence: 92%

Reduction of SIRT1 epigenetically upregulates NALP1 expression and contributes to neuropathic pain induced by chemotherapeutic drug bortezomib

Chen

Fan

Luo

et al. 2018

J Neuroinflammation

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BackgroundBortezomib is a frequently used chemotherapeutic drug for the treatment of multiple myeloma and other nonsolid malignancies. Accumulating evidence has demonstrated that bortezomib-induced persistent pain serves as the most frequent reason for treatment discontinuation.MethodsThe von Frey test was performed to evaluate neuropathic pain behavior, and real-time quantitative reverse transcription polymerase chain reaction, chromatin immunoprecipitation, western blot, immunohistochemistry, and small interfering RNA were performed to explore the molecular mechanisms in adult male Sprague-Dawley rats.ResultsWe found that application of bortezomib significantly increased the expression of NALP1 protein and mRNA levels in spinal dorsal horn neurons, and intrathecal application of NALP1 siRNA attenuated the bortezomib-induced mechanical allodynia. In addition, bortezomib also decreased the SIRT1 expression, and treatment with SIRT1 activator resveratrol ameliorated the NALP1 upregulation and mechanical allodynia induced by bortezomib. Meanwhile, knockdown of SIRT1 using the SIRT1 siRNA induced the NALP1 upregulation in dorsal horn and mechanical allodynia in normal animal. These results suggested that reduction of SIRT1 induced the NALP1 upregulation in dorsal horn neurons, and participated in bortezomib-induced mechanical allodynia. Importantly, we found that the binding of SIRT1 and NALP1 promoter region did not change before and after bortezomib treatment, but SIRT1 downregulation increased p-STAT3 expression. Furthermore, the activation of STAT3 enhanced the recruitment of p-STAT3 to the Nalp1 gene promoter, which increased the acetylation of histone H3 and H4 in NALP1 promoter regions and epigenetically upregulated NALP1 expression in the rodents with bortezomib treatment.ConclusionThese findings suggested a new epigenetic mechanism for NALP1 upregulation involving SIRT1 reduction and subsequent STAT3-mediated histone hyperacetylation in NALP1 promoter region in dorsal horn neurons, which contributed to the bortezomib-induced mechanical allodynia.

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Section: Resultssupporting

confidence: 92%

Reduction of SIRT1 epigenetically upregulates NALP1 expression and contributes to neuropathic pain induced by chemotherapeutic drug bortezomib

Chen

Fan

Luo

et al. 2018

J Neuroinflammation

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“…Elevated MG levels in Zucker Diabetic Fatty rats (Griggs et al, 2016 ) leads us to speculate that MG may induce AC1-dependent spinal sensitization in type 2 painful diabetic neuropathy. This speculation is supported by another study showing that electrical stimulation of the sciatic nerve resulted in long-term potentiation only when exogenous MG was applied to the spinal cord dorsal horn (Wei et al, 2017 ). Furthermore, pharmacological blockade of AC1 by NB001 abolishes long-term potentiation in the spinal cord (Wang et al, 2011 ).…”

Section: Discussionmentioning

confidence: 83%

“…AGEs are sufficient to induce mechanical hypersensitivity (Liu et al, 2017 ), likely through the receptor for AGEs (RAGE). RAGE specifically recognizes MG-AGEs (Xue et al, 2014 ) and is involved in diabetic neuropathy (Toth et al, 2008 ) and MG-evoked spinal sensitization (Wei et al, 2017 ). Chronic intrathecal administration of MG produced mechanical hypersensitivity and increased AGE levels in the DRG (Liu et al, 2017 ).…”

Section: Discussionmentioning

confidence: 99%

“…Several lines of evidence suggest that pain is mediated by MG-TRPA1 activity at the presynaptic, central terminals of primary sensory neurons. (1) Application of the TRPA1 agonists AITC (Kosugi et al, 2007 ), cinnemaldehyde (Uta et al, 2010 ), or MG (Wei et al, 2017 ) to spinal cord slices increased the frequency of spontaneous miniature excitatory postsynaptic currents, suggesting a presynaptic mechanism of potentiated neurotransmitter release. (2) Spinal administration of cinnemaldehyde (Wei et al, 2011 ) or MG (Liu et al, 2017 ; Wei et al, 2017 ) produced hypersensitivity at the hindpaw.…”

Section: Discussionmentioning

confidence: 99%

“…(1) Application of the TRPA1 agonists AITC (Kosugi et al, 2007 ), cinnemaldehyde (Uta et al, 2010 ), or MG (Wei et al, 2017 ) to spinal cord slices increased the frequency of spontaneous miniature excitatory postsynaptic currents, suggesting a presynaptic mechanism of potentiated neurotransmitter release. (2) Spinal administration of cinnemaldehyde (Wei et al, 2011 ) or MG (Liu et al, 2017 ; Wei et al, 2017 ) produced hypersensitivity at the hindpaw. (3) Spinal administration of the TRPA1 antagonists Chembridge-5861528 (Wei et al, 2011 ) or HC030031 (current results) reduced hypersensitivity after activation of peripheral TRPA1 by intraplantar formalin or MG, respectively.…”

Section: Discussionmentioning

confidence: 99%

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Methylglyoxal Requires AC1 and TRPA1 to Produce Pain and Spinal Neuron Activation

et al. 2017

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Methylglyoxal (MG) is a metabolite of glucose that may contribute to peripheral neuropathy and pain in diabetic patients. MG increases intracellular calcium in sensory neurons and produces behavioral nociception via the cation channel transient receptor potential ankyrin 1 (TRPA1). However, rigorous characterization of an animal model of methylglyoxal-evoked pain is needed, including testing whether methylglyoxal promotes negative pain affect. Furthermore, it remains unknown whether methylglyoxal is sufficient to activate neurons in the spinal cord dorsal horn, whether this requires TRPA1, and if the calcium-sensitive adenylyl cyclase 1 isoform (AC1) contributes to MG-evoked pain. We administered intraplantar methylglyoxal and then evaluated immunohistochemical phosphorylation of extracellular signal-regulated kinase (p-ERK) and multiple pain-like behaviors in wild-type rats and mice and after disruption of either TRPA1 or AC1. Methylglyoxal produced conditioned place avoidance (CPA) (a measure of affective pain), dose-dependent licking and lifting nociceptive behaviors, hyperalgesia to heat and mechanical stimulation, and p-ERK in the spinal cord dorsal horn. TRPA1 knockout or intrathecal administration of a TRPA1 antagonist (HC030031) attenuated methylglyoxal-evoked p-ERK, nociception, and hyperalgesia. AC1 knockout abolished hyperalgesia but not nociceptive behaviors. These results indicate that intraplantar administration of methylglyoxal recapitulates multiple signs of painful diabetic neuropathy found in animal models of or patients with diabetes, including the activation of spinal nociresponsive neurons and the potential involvement of a TRPA1-AC1 sensitization mechanism. We conclude that administration of MG is a valuable model for investigating both peripheral and central components of a MG-TRPA1-AC1 pathway that contribute to painful diabetic neuropathy.

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Pharmacoepigenetic Processors: Epigenetic Drugs, Drug Resistance, Toxicoepigenetics, and Nutriepigenetics

Cacabelos

Carril

Sanmartín

2019

Pharmacoepigenetics

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Activation of RAGE/STAT3 pathway by methylglyoxal contributes to spinal central sensitization and persistent pain induced by bortezomib

Cited by 27 publications

References 42 publications

Reduction of SIRT1 epigenetically upregulates NALP1 expression and contributes to neuropathic pain induced by chemotherapeutic drug bortezomib

Reduction of SIRT1 epigenetically upregulates NALP1 expression and contributes to neuropathic pain induced by chemotherapeutic drug bortezomib

Methylglyoxal Requires AC1 and TRPA1 to Produce Pain and Spinal Neuron Activation

Pharmacoepigenetic Processors: Epigenetic Drugs, Drug Resistance, Toxicoepigenetics, and Nutriepigenetics

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