Hydrogen-Rich Saline Activated Autophagy via HIF-1α Pathways in Neuropathic Pain Model

Abstract

Background Neuropathic pain is a chronic and intractable pain, with very few effective analgesics. It involves an impaired cell autophagy process. Hydrogen-rich saline (HRS) reportedly reduces allodynia and hyperalgesia in a neuropathic pain model; however, it is unknown whether these effects involve autophagy induction. Methods We investigated the relationship between HRS and cell autophagy in a neuropathic pain model generated by chronic constriction injury (CCI) in Sprague–Dawley rats. Rats received an intraperitoneal injection of HRS (10 mL/kg daily, from 1 day before until 14 days after CCI), 3MA (autophagy inhibitor), 2ME2 (HIF-1α inhibitor), or EDHB (HIF-1α agonist). The mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL) were tested 1 day before and 1, 3, 7, 10, and 14 days after the operation. HIF-1α and cell autophagy markers in the spinal cord were evaluated by western blotting and real-time PCR assays at 14 days after CCI. Autophagosomes with double membranes were identified by transmission electron microscopy. Results CCI caused behavioral hypersensitivity to mechanical and thermal stimulation in the hind-paw of the injured side. HRS improved MWT and TWL, activated autophagy, and increased autophagosomes and autolysosomes in CCI rats. 3-MA aggravated hyperalgesia and allodynia and suppressed autophagy, while EDHB attenuated hyperalgesia and activated the autophagy procedure and the HIF-1α downstream target gene BNIP3. HIF-1α inhibitors reversed the regulatory effects of HRS on autophagy in CCI rats at 14 days after spinal cord injury. Conclusion HRS reduced mechanical hyperalgesia and activation of cell autophagy in neuropathic pain through a HIF1-dependent pathway.

<p>Hyperbaric oxygen relieves neuropathic pain through AKT/TSC2/mTOR pathway activity to induce autophagy</p>

“…Moreover, studies uncovered that autophagy process was disrupted in neuropathic pain, localized on neurons, GAB-Aergic interneurons, astrocytes, microglia, and Schwann cells 2,37,38. Studies also indicated that treatments increased autophagy activity, prevented the onset and delayed the chronification of neuropathic pain, and ameliorated neuropathic pain-related behaviors 3,39…”

Hypoxia inducible factor-1 (HIF-1α) reduced inflammation in spinal cord injury via miR-380-3p/ NLRP3 by Circ 0001723

“…More importantly, intermittent hypoxia can also induce the increased HIF-1α expression [9]. Therefore, HIF-1α may participate in the intermittent hypoxia-induced autophagy activation [25]. Besides, HIF-1α can induce the over-expression of transcription factor p62.…”

“…Besides, HIF-1α can induce the over-expression of transcription factor p62. Subsequently, it can release p62 from its binding with Bcl-2 protein, and the activated p62 can take part in forming autophagy [ 25 ]. In our study, we have found that HIF-1α was reduced in SCI model rats, which was contrary to the previous study [ 26 ].…”

Recent Advances in Studies of Molecular Hydrogen against Sepsis

“…Studies have demonstrated that molecular hydrogen plays a protective role by modulating autophagy in multiple diseases and conditions, including sepsis 11, 12, 20, ischemia- reperfusion injury96-98, organ transplantation 70, 99-102, and pathological neuralgia 103-105 (Table 5). However, the regulation of autophagy by molecular hydrogen remains controversial, and the regulatory mechanism is very complex (Fig.…”

“…In addition, a number of studies have shown that HRS promotes autophagy in rats with neuropathic pain and plays a protective role103-105; the underlying mechanism of which is activation of hypoxia inducing factor-1 (HIF-1α) by HRS105 (Fig. 8D).…”