Intrathecal 5-azacytidine inhibits global DNA methylation and methyl- CpG-binding protein 2 expression and alleviates neuropathic pain in rats following chronic constriction injury

Wang, Ying; Liu, Chang; Guo, Qulian; Yan, Jianqin; Zhu, Xiaoyan; Huang, Changsheng; Zou, Wangyuan

doi:10.1016/j.brainres.2011.08.040

Cited by 102 publications

(98 citation statements)

References 35 publications

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“…DNMT1 is the key maintenance methyltransferase (Howell et al, 2001), whereas DNMT3a and DNMT3b are responsible for de novo methylation (Okano et al, 1999). The expression patterns of these DMNTs in the spinal cord after peripheral nerve injury, inflammation, or paw incision (Tochiki et al, 2012;Sun et al, 2015;Wang et al, 2016) are quite inconsistent, which may be due to different animal models, different species, or different time points. In the present study, neither Dnmt1 nor Dnmt3a was changed, but both mRNA and protein level of DNMT3b were decreased 10 d after SNL in mice.…”

Section: Discussionmentioning

confidence: 99%

Promoted Interaction of C/EBPα with Demethylated Cxcr3 Gene Promoter Contributes to Neuropathic Pain in Mice

Jiang¹,

Wu²,

Shi³

et al. 2017

J. Neurosci.

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DNA methylation has been implicated in the pathogenesis of chronic pain. However, the specific genes regulated by DNA methylation under neuropathic pain condition remain largely unknown. Here we investigated how chemokine receptor CXCR3 is regulated by DNA methylation and how it contributes to neuropathic pain induced by spinal nerve ligation (SNL) in mice. SNL increased Cxcr3 mRNA and protein expression in the neurons of the spinal cord. Meanwhile, the CpG (5Ј-cytosine-phosphate-guanine-3Ј) island in the Cxcr3 gene promoter region was demethylated, and the expression of DNA methyltransferase 3b (DNMT3b)

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Section: Discussionmentioning

confidence: 99%

Promoted Interaction of C/EBPα with Demethylated Cxcr3 Gene Promoter Contributes to Neuropathic Pain in Mice

Jiang¹,

Wu²,

Shi³

et al. 2017

J. Neurosci.

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“…Gene promoter DNA methylation suppresses gene expression, whereas gene promoter DNA demethylation facilitates gene upregulation (38,39). Wang et al (40) reported a role of DNA methylation in nerve injury-induced pain. We have previously reported that DNA demethylation of the cbs gene promoter is involved in inflammatory hyperalgesia (27) and gastric hypersensitivity (9), which is consistent with the upregulation of cystathionine b-synthetase (an endogenous synthetase of hydrogen sulfide) and mRNA.…”

Section: Discussionmentioning

confidence: 99%

Promoted Interaction of Nuclear Factor-κB With Demethylated Purinergic P2X3 Receptor Gene Contributes to Neuropathic Pain in Rats With Diabetes

Zhang

Zhou

et al. 2015

Diabetes

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Painful diabetic neuropathy is a common complication of diabetes produced by mechanisms that as yet are incompletely defined. The aim of this study was to investigate the roles of nuclear factor-kB (NF-kB) in the regulation of purinergic receptor P2X ligand-gated ion channel 3 (P2X3R) plasticity in dorsal root ganglion (DRG) neurons of rats with painful diabetes. Here, we showed that hindpaw pain hypersensitivity in streptozocininduced diabetic rats was attenuated by treatment with purinergic receptor antagonist suramin or A-317491. The expression and function of P2X3Rs was markedly enhanced in hindpaw-innervated DRG neurons in diabetic rats. The CpG (cytosine guanine dinucleotide) island in the p2x3r gene promoter region was significantly demethylated, and the expression of DNA methyltransferase 3b was remarkably downregulated in DRGs in diabetic rats. The binding ability of p65 (an active form of NF-kB) with the p2x3r gene promoter region and p65 expression were enhanced significantly in diabetes. The inhibition of p65 signaling using the NF-kB inhibitor pyrrolidine dithiocarbamate or recombinant lentiviral vectors designated as lentiviral vector-p65 small interfering RNA remarkably suppressed P2X3R activities and attenuated diabetic pain hypersensitivity. Insulin treatment significantly attenuated pain hypersensitivity and suppressed the expression of p65 and P2X3Rs. Our findings suggest that the p2x3r gene promoter DNA demethylation and enhanced interaction with p65 contributes to P2X3R sensitization and diabetic pain hypersensitivity.

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“…MMPs have been reported to cause inflammation and NP after peripheral nerve injury [1] . Several studies have shown a relationship between DNA methylation and MMP expression and NP after CNS injury [6,29,30] . Here, in this paper, we show the effect of FA, a dietary supplement and key methylator of the CNS, on the expression of MMP2.…”

Section: Discussionmentioning

confidence: 99%

“…Studies have shown that promoter methylation suppresses the transcription of MMPs and that intrathecal administration of DNA methyl transferase inhibitor following chronic constriction injury (CCI) results in the suppression of global DNA methylation and the methyl-CpGbinding protein 2 (MeCP2) expression, both of which are correlated to a decrease in NP in injured rats [6] . In contrast, SCI results in an increase in global DNA methylation [6] . It is known that hyper methylation of the promotor can silence gene expression [7][8][9][10] .…”

Section: Introductionmentioning

confidence: 99%

Folic Acid Modulates Matrix Metalloproteinase-2 Expression, Alleviates Neuropathic Pain, and Improves Functional Recovery in Spinal Cord-Injured Rats

Miranpuri¹,

Meethal²,

Sampene³

et al. 2017

Ann Neurosci

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Background: The molecular underpinnings of spinal cord injury (SCI) associated with neuropathic pain (NP) are unknown. Recent studies have demonstrated that matrix metalloproteinases (MMPs) such as MMP2 play a critical role in inducing NP following SCI. Promoter methylation of MMPs is known to suppress their transcription and reduce NP. In this context, it has been shown in rodents that folic acid (FA), an FDA approved dietary supplement and key methyl donor in the central nervous system (CNS), increases axonal regeneration and repair of injured CNS in part via methylation. Purpose: Based on above observations, in this study, we test whether FA could decrease MMP2 expression and thereby decrease SCI-induced NP. Methods: Sprague-Dawley male rats weighing 250-270 g received contusion spinal cord injuries (cSCIs) with a custom spinal cord impactor device that drops a 10 g weight from a height of 12.5 mm. The injured rats received either i.p. injections of FA (80 µg/kg) or water (control) 3 days prior and 17 days post-cSCI (mid phase) or for 3 days pre-cSCI and 14 days post-cSCI ending on the 42nd day of cSCI (late phase). The functional neurological deficits due to cSCI were then assessed by Basso, Beattie, and Bresnahan (BBB) scores either on post-impaction days 0 through 18 post-cSCI (mid phase) or on days 0, 2, 7, 14, 21, 28, 35, and 42 (late phase). Baseline measurements were taken the day before starting treatments. Thermal hyperalgesia (TH) testing for pain was performed on 4 days pre-cSCI (baseline data) and on days 18, 21, 28, 35, and 42 post-cSCI. Following TH testing, animals were euthanized and spinal cords harvested for MMP-2 expression analysis. Result: The FA-treated groups showed higher BBB scores during mid phase (day 18) and in late phase (day 42) of injury compared to controls, suggesting enhanced functional recovery. There is a transient decline in TH in animals from the FA-treated group compared to controls when tested on days 18, 21, 28, and 35, indicative of a decrease in NP. However, when tested 25 days after stopping FA administration on day 42 of cSCI, no significant difference in TH was observed between FA-treated and control animals. Western blot analysis of the injured spinal cord from FA-treated animals showed significant decline in MMP2 expression compared to spinal cord samples from water-treated controls. Conclusion: Together, these data suggest that FA could alleviate NP and improve functional recovery post-SCI, possibly by reducing the expression of MMP2. Further studies will open up a novel and easy natural therapy, ideal for clinical translation with minimal side effects, for managing SCI-induced NP. Such studies might also throw light on a possible epigenetic mechanism in FA-induced recovery after SCI.

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Intrathecal 5-azacytidine inhibits global DNA methylation and methyl- CpG-binding protein 2 expression and alleviates neuropathic pain in rats following chronic constriction injury

Cited by 102 publications

References 35 publications

Promoted Interaction of C/EBPα with Demethylated Cxcr3 Gene Promoter Contributes to Neuropathic Pain in Mice

Promoted Interaction of C/EBPα with Demethylated Cxcr3 Gene Promoter Contributes to Neuropathic Pain in Mice

Promoted Interaction of Nuclear Factor-κB With Demethylated Purinergic P2X3 Receptor Gene Contributes to Neuropathic Pain in Rats With Diabetes

Folic Acid Modulates Matrix Metalloproteinase-2 Expression, Alleviates Neuropathic Pain, and Improves Functional Recovery in Spinal Cord-Injured Rats

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