Effects of natural and synthetic isothiocyanate-based H 2 S-releasers against chemotherapy-induced neuropathic pain: Role of Kv7 potassium channels

Abstract

a b s t r a c tHydrogen sulfide (H 2 S) is a crucial signaling molecule involved in several physiological and pathological processes. Nonetheless, the role of this gasotransmitter in the pathogenesis and treatment of neuropathic pain is controversial.The aim of the present study was to investigate the pain relieving profile of a series of slow releasing H 2 S donors (the natural allyl-isothiocyanate and the synthetics phenyl-and carboxyphenylisothiocyanate) in animal models of neuropathic pain induced by paclitaxel or oxaliplatin, anticancer drugs characterized by a dose-limiting neurotoxicity. The potential contribution of Kv7 potassium channels modulation was also studied.Mice were treated with paclitaxel (2.0 mg kg À1) i.p. on days 1, 3, 5 and 7; oxaliplatin (2.4 mg kg À1) was administered i.p. on days 1e2, 5e9, 12e14. Behavioral tests were performed on day 15. In both models, single subcutaneous administrations of H 2 S donors (1.33, 4.43, 13.31 mmol kg À1 ) reduced the hypersensitivity to cold non-noxious stimuli (allodynia-related measurement). The prototypical H 2 S donor NaHS was also effective. Activity was maintained after i.c.v. administrations. On the contrary, the Slacking molecule allyl-isocyanate did not increase pain threshold; the H 2 S-binding molecule hemoglobin abolished the pain-relieving effects of isothiocyanates and NaHS. The anti-neuropathic properties of H 2 S donors were reverted by the Kv7 potassium channel blocker XE991. Currents carried by Kv7.2 homomers and Kv7.2/Kv7.3 heteromers expressed in CHO cells were potentiated by H 2 S donors.Sistemically-or centrally-administered isothiocyanates reduced chemotherapy-induced neuropathic pain by releasing H 2 S. Activation of Kv7 channels largely mediate the anti-neuropathic effect.

Study of nuclear factor-2 erythroid related factor-2 activator, berberine, in paclitaxel induced peripheral neuropathy pain model in rats

“…Animals were observed for tail flick and cold allodynia latency on every 7th day (day 0, 7, 14, 21, 28). Rats developed neuropathy from day 14 and that persisted up to day 28 which was found to be at par with previous studies by Di Cesare Mannelli et al …”

“…[6,24] Animals were observed for tail flick and cold allodynia latency on every 7th day (day 0, 7,14,21,28). Rats developed neuropathy from day 14 and that persisted up to day 28 which was found to be at par with previous studies by Di Cesare Mannelli et al [29,30] In PTX group, all the animals developed neuropathy from day 14 as there was a decrease in the latency time of tail flick and cold allodynia, whereas in ATL pretreated group, there was no decrease in latency was observed in tail flick and cold allodynia. The current study showed that administration of ATL prevents the development of PTX induced peripheral neuropathy in rats.…”

“…In literature, various protocols for paclitaxel induced peripheral neuropathy in rats are available . We have also able to establish the paclitaxel induced peripheral neuropathy in rats.…”

Moringin, A Stable Isothiocyanate from Moringa oleifera, Activates the Somatosensory and Pain Receptor TRPA1 Channel In Vitro

“…Recently the role of H2S release from glucosinolates/isothiocyanates as a potent mechanism of protective action in the cardiovascular compartment and in the nervous system has been reported [22], as well as the role of H2S-mediated pain-relieving effects of natural and synthetic isothiocyanates [23]. Due to the presence of the polar O-glycosylated phenol substituent, moringin is a solid, odorless and relatively stable compound at room temperature; these are uncommon features for most isothiocyanates obtained by crucifer plants, such as benzyl-and allylisothiocyanate from mustard which are usually small and volatile compounds, with a pungent smell.…”

Chemistry, pharmacology, and cellular uptake mechanisms of thiometallate sulfide donors

“…Hydrogen sulfide (comprising H 2 S and HS − ) is the third endogenous gasotransmitter alongside NO and carbon monoxide and acts as a signalling molecule across numerous physiological systems (Kimura, 2014;Szabo et al, 2014). Given exogenously in preclinical studies, sulfide protected against diverse pathological conditions, ranging from circulatory (Wang, Wang, Guo, & Zhu, 2011), neurodegenerative (Zhang & Bian, 2014) and arthritic (Wu et al, 2016) disorders to diabetes (Wu et al, 2009), pain (Di Cesare Mannelli et al, 2017), and cancer (Lee et al, 2014). Our particular interest in sulfide relates to its ability to transiently reduce cellular respiration by inhibition of mitochondrial cytochrome C oxidase (Szabo et al, 2014).…”