Evidence Details for Nr4a1
PMID Title Journal Year Abstract
32796318 Acupuncture alleviates chronic pain and comorbid conditions in a mouse model of neuropathic pain: the involvement of DNA methylation in the prefrontal cortex. Pain. 2021 Feb 1;162(2):514-530. doi: 10.1097/j.pain.0000000000002031. 2021 Feb 1 Chronic pain reduces life quality and is an important clinical problem associated with emotional and cognitive dysfunction. Epigenetic regulation of DNA methylation is involved in the induction of abnormal behaviors and pathological gene expression. We examined whether acupuncture can restore epigenetic changes caused by chronic pain, and identified the underlying mechanisms in neuropathic pain mice. Acupuncture treatment for 6 months (3 days/week) improved mechanical/cold allodynia and the emotional/cognitive dysfunction caused by left partial sciatic nerve ligation (PSNL)-induced neuropathic pain. The effects of acupuncture were associated with global DNA methylation recovery in the prefrontal cortex (PFC). Analysis of DNA methylation patterns in PFC indicated that 1364 overlapping genes among 4442 and 4416 methylated genes in the PSNL vs sham and PSNL vs acupuncture points groups, respectively, were highly associated with the DNA methylation process. Acupuncture restored the reduced expression of 5-methylcytosine, methyl-cytosine-phospho-guanine binding protein 2, and DNA methyltransferase family enzymes induced by PSNL in PFC. Methylation levels of Nr4a1 and Chkb associated with mitochondrial dysfunction were decreased in PFC of the PSNL mice, and increased by acupuncture. By contrast, high expression of Nr4a1 and Chkb mRNA in PSNL mice decreased after acupuncture. We also found that acupuncture inhibited the expression of Ras pathway-related genes such as Rasgrp1 and Rassf1. Finally, the expression of Nr4a1, Rasgrp1, Rassf1, and Chkb mRNA increased in the neuronal cells treated with Mecp2 small interfering RNA. These results suggest that acupuncture can relieve chronic pain-induced comorbid conditions by altering DNA methylation of Nr4a1, Rasgrp1, Rassf1, and Chkb in the PFC."

Evidence Sentence: Methylation levels of Nr4a1 and Chkb associated with mitochondrial dysfunction were decreased in PFC of the PSNL mice, and increased by acupuncture.
Evidence Sentence: By contrast, high expression of Nr4a1 and Chkb mRNA in PSNL mice decreased after acupuncture.
Evidence Sentence: Finally, the expression of Nr4a1, Rasgrp1, Rassf1, and Chkb mRNA increased in the neuronal cells treated with Mecp2 small interfering RNA.
Evidence Sentence: These results suggest that acupuncture can relieve chronic pain-induced comorbid conditions by altering DNA methylation of Nr4a1, Rasgrp1, Rassf1, and Chkb in the PFC.
Evidence Sentence: We identified the top 20 genes (Nr4a1, Chkb, Tekt4, Abcb6, Chchd1, Tbx1, Aifm2, Mir7069, Fxr2, Adad1, Lypo6b, Arl8a, Rtp2, Gng7, Loxl4, Gm10432, Cpne2, Npffr1, Ttll1, and Zfp787) that were shared in the PSNL vs sham (hypomethylated genes) and PSNL vs AP (hypermethylated genes) groups (Figs.
Evidence Sentence: Next, we determined the expression levels of Nr4a1, Chkb, Tekt4, Abcb6, Rasgrp1, and Rassf1 mRNA in hypo-hyper methylated and Ras pathway-related genes.
Evidence Sentence: One-way ANOVA with the Newman-Keuls post hoc test for Nr4a1 (F[2, 6] = 28.15, P = 0.0009), Rasgrp1 (F[2, 6] = 21.31, P = 0.0019), Rassf1 (F[2, 6] = 13.52, P = 0.0060), Chkb (F[2, 6] = 18.22, P = 0.0028), Tekt4 (F[2, 6] = 9.661, P = 0.0133), and Abcb6 (F[2, 6] = 3.840, P = 0.0844) in mice with PSNL-induced neuropathic pain demonstrated that AP treatment significantly decreased the mRNA expression levels in the PFC (Nr4a1, P < 0.001; Rasgrp1, P < 0.01; Rassf1, P < 0.01; Chkb, P < 0.01; Tekt4, P < 0.01; Abcb6, P < 0.01 vs PSNL; Figs.
Evidence Sentence: To determine the causal relationship between Mecp2 and Nr4a1, Rasgrp1, Rassf1, and Chkb, we observed the Mecp2 mRNA expression in neuronal cells treated with Mecp2 siRNA.
Evidence Sentence: In addition, we found that the expression of Nr4a1 (t4 = 10.06, P = 0.0006), Rasgrp1 (t4 = 4.478, P = 0.0110), Rassf1 (t4 = 6.685, P = 0.0026), and Chkb (t4 = 4.234, P = 0.0133) was significantly increased as a result of the Mecp2 siRNA treatment (Nr4a1, P < 0.001; Chkb, P < 0.05; Rasgrp1, P < 0.05; Rassf1, P < 0.01 vs Control; Figs.