Hydrogen-Rich Water as a Novel Therapeutic Strategy for the Affective Disorders Linked with Chronic Neuropathic Pain in Mice

Abstract

Neuropathic pain manifested with allodynia and hyperalgesia usually becomes a chronic condition accompanied with mood disorders. Clinical therapies for neuropathic pain are still unsatisfactory with notable side effects. Recent studies have reported the protective role of molecular hydrogen (H2) in different diseases including neurological disorders, such as Alzheimer’s as well as its antidepressant activities in animals with chronic stress. This study explored the effects of treatment with hydrogen-rich water (HRW) in male mice with neuropathic pain induced by the chronic constriction of the sciatic nerve (CCI) and the accompanying affective deficits. The likely pathways implied in the HRW analgesic activity, as well as the interaction between heme oxygenase 1 (HO-1) enzyme and H2 during neuropathic pain were also studied. The results showed: (i) the inhibitory effects of the repetitive treatment with HRW on the allodynia and hyperalgesia provoked by CCI; (ii) the anxiolytic and antidepressant actions of HRW in animals with neuropathic pain; (iii) the contribution of the antioxidant enzymes (HO-1 and NAD(P)H: quinone oxidoreductase 1) and the ATP sensitive potassium channels in the painkiller activities of HRW during neuropathic pain; (iv) a positive interaction between the HO-1 and H2 systems in inhibiting the CCI-induced neuropathy; and (v) the antioxidant, antinociceptive, anti-inflammatory and/or antiapoptotic features of HRW treatment in the dorsal root ganglia and/or amygdala of sciatic nerve-injured mice. This study demonstrates new protective actions of H2 and suggests that treatment with HRW might be an interesting therapeutic strategy for chronic neuropathic pain and its associated mood disorders.

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“…The reversal of the analgesic effects of HRW with the co-administration with ML-385, SnPP, or dicoumarol revealed the involvement of the antioxidant system in the inhibition of the mechanical and thermal allodynia produced by HRW in animals with PIPN. These data supported other studies made with H 2 [27] or H 2 S donors, which also activated the Nrf2/HO-1 and/or NQO1 path for inhibiting nerve injury-induced neuropathic pain in rodents [33].…”

“…Indeed, the PTX-induced allodynia was completely inhibited after three and seven days of treatment with HRW administered at 2T or 1T per day. These findings agree with the inhibitory actions produced by HRW or hydrogen-rich saline in mice with nerve injury-induced neuropathic pain [24][25][26][27], with the prevention of remifentanil-provoked post-surgical hyperalgesia [50] and with the improved hyperalgesia induced by oxaliplatin [51]. Our results also supported the major effectiveness produced by the double daily administration of HRW versus the simple as recently demonstrated in animals with neuropathic pain provoked by nerve injury [27].…”

“…Several works indicated the contribution of the plasticity changes in memory impairments and that several drugs can improve these deficits by restoring the altered expression of MAPK activated by chemotherapy in the CNS [14]. The reversion of the increased expression of p-ERK 1 /2 caused by PTX with the HRW treatment agreed with the effects produced by this treatment in the PFC of sciatic nerve-injured mice [27] and further suggested that the normalization of the plasticity changes produced by HRW might be involved in the recovery of memory deficits produced by this treatment in PTX-injected mice.…”

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“…To examine the probable involvement of the Nrf2/HO-1 and NQO1 pathway in the analgesic actions of HRW, the effects of the intraperitoneal and subplantar administration of HRW or VEH, injected at 2T or 1T per day, in animals intraperitoneally or subplantarly co-treated with 25 mg/kg or 625 μg of ML385, a Nrf2 inhibitor [ 42 ], 10 mg/kg or 250 μg of tin protoporphyrin IX (SnPP), an HO-1 inhibitor [ 43 ], 10 mg/kg or 250 µg of dicoumarol, a NQO1 inhibitor [ 44 ], or VEH (DMSO 1% in SS) were assessed ( n = 6 animals for group). The HRW concentration and doses of ML-385, SnPP and dicoumarol were chosen in line with earlier studies [ 41 , 45 ].…”

“…All drugs were intraperitoneally and subplantarly injected in a volume of 10 mL/kg and 30 μL, respectively. HRW was administered 1 h before testing, while ML-385, SnPP, and dicoumarol were administered at 30 min before the tests, in accordance with earlier studies [ 41 , 45 ]. All drugs were newly prepared prior to their administration.…”