DNA Methylation May be Involved in the Analgesic Effect of Hyperbaric Oxygen via Regulating FUNDC1

Abstract

Background. Neuropathic pain (NP) is a type of chronic pain which lacks predictable, effective, and safe therapeutic options. We investigated the role of hyperbaric oxygen (HBO) in expression of FUN14 domain-containing 1 (FUNDC1), which is associated with DNA methylation. Methods. We randomly divided rats into four groups: sham operation (S), S + HBO, chronic constriction injury (CCI), and CCI + HBO. Lumbar (L)4 and L5 dorsal root ganglia (DRGs) were used to assess expression of DNA methyltransferase (DNMT)1, DNMT3a, and DNMT3b by western blotting and RT-PCR. Pain-related behaviors were evaluated using mechanical withdrawal threshold and thermal withdrawal latency analysis. Western blotting was also used to assess expression of FUNDC1, BCL2, and adenovirus E1B19 kDa-interacting protein 3-like (NIX) and BCL2 and adenovirus E1B19 kDa-interacting protein3 (BNIP3). And we also examined the changes of FUNDC1 with immunofluorescence. Nonnucleoside DNA methyltransferase inhibitor RG108 was administered prior to CCI. The pain-related behavior and western blotting changes were examined in all groups. Results. DNMT3a expression was higher on day 14 after CCI. HBO downregulated DNMT3a mRNA and protein expression, but not those of DNMT1 and DNMT3b. HBO increased pain-related behavior significantly, while it was down-regulated by RG108. In HBO groups, FUNDC1, NIX, and BNIP3 expression was upregulated more significantly than in the CCI group. In addition, FUNDC1 protein colocalized with NeuN and rarely with glutamine synthetase. However, expression was reduced when RG108 was administered. Immunofluorescence showed that FUNDC1 was upregulated after HBO treatment. Conclusion. Our findings suggest that DNA methylation is involved in the analgesic effect of HBO via the regulation of FUNDC1.

Cdyl Deficiency Brakes Neuronal Excitability and Nociception through Promoting Kcnb1 Transcription in Peripheral Sensory Neurons

“…For instance, HDAC inhibitors such as SAHA and TSA counteracted the hypersensitivity in chronic pain; [ 48 , 49 ] DNMT inhibitors such as RG108 and zebularine also produced analgesia in animal models. [ 50 , 51 ] Given that CDYL is responsible for pain sensation as a transcriptional corepressor, targeting CDYL may be beneficial for the treatment of neuropathic pain. As a result, we developed a potent CDYL antagonist UNC6261, and peripheral utilization of UNC6261 in vivo exerted an inhibitory influence on DRG neuronal excitability and pain sensation.…”

The role of ectopic P granules protein 5 homolog (EPG5) in DHPG‐induced pain sensitization in mice

“…We likewise observed the similar changes of RNF11 (Fold change = 0.13). A recent study confirmed that hyperbaric oxygen therapy relieves pain in neuropathic pain rats by up‐regulating the expression of FUN14 domain‐containing protein 1 (Fundc1) through DNA methylation (Liu et al, 2020). Importantly, the expression of Fundc1 was also significantly reduced in our results (Fold change = 0.61).…”

RNA interference-mediated silencing of DNA methyltransferase 1 attenuates neuropathic pain by accelerating microglia M2 polarization

“…Transfer of microglia polarization from M1 to M2 phenotype is considered a prospective therapeutic strategy for NP [ 51 ]. Additionally, DNA methylation affects the development of NP and DNMT1 is a principle isoform of DNMTs to sustain DNA methylation in mammals [ 44 ]. The PI3K/Akt pathway is necessitated for NP progression and maintenance [ 52 ].…”

“…NP rat models were constructed through chronic constriction injury (CCI) [ 44 ]. Rats were firstly anesthetized with an intraperitoneal injection of 50 mg/kg of 2% sodium pentobarbital (Sigma-Aldrich, Merck KGaA, Darmstadt, Germany).…”

“…All rats were habituated to the environment prior to behavioral testing [ 44 ]. The mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL) of rats were measured on days 0, 3, 7, and 14 after CCI induction [ 9 ].…”