Effects of hyperbaric oxygen therapy on neuropathic pain via mitophagy in microglia

Abstract

PurposeHyperbaric oxygen (HBO) therapy has been suggested to palliate neuropathic pain, but the mechanisms involved are not well understood. This study explored the involvement of microglial mitophagy via HBO relative to neuropathic pain therapy.Materials and methodsA total of 80 male Sprague Dawley rats were randomly divided into two groups: a normal group (n = 40) and a mitophagy inhibitor group (n = 40) in which the mitophagy inhibitor cyclosporin A (CsA) was administrated prior to chronic constriction injury (CCI). Groups (n = 10 rats per group) consisted of the following: control (C), sham operation (S), sciatic nerve with chronic constriction injury (CCI), and a CCI plus HBO treatment (CCI + HBO). Pain-related behaviors were evaluated using mechanical withdraw tendency and thermal withdraw latency analysis. Mitochondrial membrane potential was measured, and Western blot was employed to assess expression of NIX and BNIP3. Immunofluorescence changes in neuron protein (NESTIN) and mitochondria inner or outer layer proteins (TIM23, TOM20) were examined.ResultsHBO significantly ameliorated pain-related behaviors, which were downregulated by mitophagy inhibitors (P < 0.05). Mitochondrial membrane potential indexes were decreased after HBO therapy, but were reversed in the mitophagy inhibitor group (P < 0.05). HBO upregulated NIX and BNIP3 expression, which did not occur in the CCI group (P < 0.05). However, expression was reduced when mitophagy inhibitors were administered. Immunofluorescence examination showed that mitophagy in microglia was induced by CCI, which was upregulated after HBO treatment. This phenomenon was not observed in the mitophagy inhibitor group.ConclusionsHBO therapy palliated CCI-induced neuropathic pain in rats by upregulating microglial mitophagy. These results could serve as guidelines to improve neuropathic pain therapy using HBO to maximize therapeutic efficiency.

Repeated Exposure to Hyperbaric Hyperoxia Affects Mitochondrial Functions of the Lung Fibroblasts

“…At the cellular and subcellular levels, HBO therapy is known to increase production of reactive oxygen and nitrogen species (RONS), which may account for both beneficial and potentially toxic effects of HBO (Poff et al 2016). Increased production of RONS stimulates expression of genes related to defense against oxidative stress (Matsunami et al 2009), might be involved in induction of mitophagy (Han et al 2017), suppresses MAPK signaling and mitochondrial apoptotic pathway (Niu et al 2013), and could be implicated in stimulation of angiogenesis, proliferation and differentiation of mesenchymal stem cells (Lin et al 2014).…”

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

“…Moreover, HBO promotes capillary regeneration and improves microcirculation. Our previous study tested HBO in rats with induced mitophagy in NP [3]. As expected, HBO reduced the pain behavior test and maintained nerve function because HBO increased mitophagy, which was significantly related to the dephosphorylated LC3-interacting region (LIR) motif of FUNDC1.…”

“…Our previous study showed that the analgesic effect of HBO on NP is associated with mitophagy in rats [3]. In the present study, we investigated the molecular mechanism of the mitophagic effect of HBO.…”

“…In our previous study, we verified that HBO can upregulate mitophagy. However, we do not know whether the mechanisms are associated with DNMTs [3]. We evaluated expression of DNMTs by western blotting and RT-PCR in rats.…”

“…Hyperbaric oxygen (HBO) is a noninvasive treatment that has been widely investigated and can relieve NP [2]. Our previous research discovered that the alleviating effect of HBO on NP is associated with mitophagy [3]; however, the detailed mechanisms of how mitophagy alleviates pain are not fully understood.…”