Topical application of disodium isostearyl 2‐O‐L‐ascorbyl phosphate, an amphiphilic ascorbic acid derivative, reduces neuropathic hyperalgesia in rats

Abstract

BACKGROUND AND PURPOSECav3.2 T-type calcium channels, targeted by H2S, are involved in neuropathic hyperalgesia in rats and ascorbic acid inhibits Cav3.2 channels. Therefore, we evaluated the effects of intraplantar (i.pl.) administration of ascorbic acid or topical application of disodium isostearyl 2-O-L-ascorbyl phosphate (DI-VCP), a skin-permeable ascorbate derivative on hyperalgesia induced by NaHS, an H2S donor, and on neuropathic hyperalgesia. EXPERIMENTAL APPROACHIn rats mechanical hyperalgesia was evoked by i.pl. NaHS, and neuropathic hyperalgesia was induced by L5 spinal nerve cutting (L5SNC) or by repeated administration of paclitaxel, an anti-cancer drug. Dermal ascorbic acid levels were determined colorimetrically. KEY RESULTSThe NaHS-evoked Cav3.2 channel-dependent hyperalgesia was inhibited by co-administered ascorbic acid. Topical application of DI-VCP, but not ascorbic acid, prevented the NaHS-evoked hyperalgesia, and also increased dermal ascorbic acid levels. Neuropathic hyperalgesia induced by L5SNC or paclitaxel was reversed by i.pl. NNC 55-0396, a selective T-type calcium channel blocker, ascorbic acid or DI-VCP, and by topical DI-VCP, but not by topical ascorbic acid. The effects of i.pl. ascorbic acid and topical DI-VCP in the paclitaxel-treated rats were characterized by the faster onset and greater magnitude, compared with their effects in the L5SNC rats. Dermal ascorbic acid levels in the hindpaw significantly decreased after paclitaxel treatment, but not L5SNC, which was reversed by topical DI-VCP. CONCLUSIONS AND IMPLICATIONSAscorbic acid, known to inhibit Cav3.2 channels, suppressed neuropathic hyperalgesia. DI-VCP ointment for topical application may be of benefit in the treatment of neuropathic pain. Abbreviations

T-type Calcium Channels: Functional Regulation and Implication in Pain Signaling

“…Strikingly, we have detected significant decrease in levels of ascorbic acid (vitamin C), known to selectively inhibit Ca v 3.2 (see Fig. 1), in the hindpaw tissue of rats with paclitaxelinduced neuropathy (13). We have also shown that intraplantar injection of ascorbic acid or topical application of disodium isostearyl 2-O-l-ascorbyl phosphate (DI-VCP), a skin-permeable ascorbate derivative, abolishes the H 2 S-induced hyperalgesia and paclitaxel-induced neuropathy and also partially inhibits the spinal nerve injury-induced neuropathy (13).…”

“…1), in the hindpaw tissue of rats with paclitaxelinduced neuropathy (13). We have also shown that intraplantar injection of ascorbic acid or topical application of disodium isostearyl 2-O-l-ascorbyl phosphate (DI-VCP), a skin-permeable ascorbate derivative, abolishes the H 2 S-induced hyperalgesia and paclitaxel-induced neuropathy and also partially inhibits the spinal nerve injury-induced neuropathy (13). These findings are consistent with some clinical evidence for the decreased plasma vitamin C levels in post-herpetic neuralgia patients (33,34) and for the therapeutic value of ascorbic acid in patients with post-herpetic neuralgia (33,35) or with complex regional pain syndrome after wrist fractures (36).…”

Redox Regulation of Neuronal Voltage-Gated Calcium Channels

“…Thus, H191 is an important site for fine tuning of neuronal excitability in cells that express T-channels. However, because highly redox reactive metals such as copper (Cu (50), in an excellent in vivo pain study, have shown that a skin-permeable formulation of ointment containing ascorbic acid applied to peripheral receptive fields of nociceptors suppressed neuropathic hyperalgesia induced by application of NaHS (donor of H 2 S in tissues) or by mechanical injury of the spinal nerve or by systemic administration of the neurotoxic anti-cancer drug paclitaxel. In this study, the analgesic effects of ascorbate were mimicked fully by the T-type channel blocker NNC 55-0396.…”

Functional upregulation of the H2S/Cav3.2 channel pathway accelerates secretory function in neuroendocrine-differentiated human prostate cancer cells

“…H 2 S targets multiple molecules including ion channels, such as ATP-sensitive K + (K ATP ) channels [5,6], T-type Ca 2+ channels [7][8][9][10], L-type Ca 2+ channels [11,12], transient receptor potential ankyrin-1 [13] and large conductance Ca 2 + -activated K + channels [14]. Among three isoforms of T-type Ca 2+ channels, Ca v 3.2 mediates the facilitation of somatic and visceral pain signals by H 2 S [7,8,15,16], and the increased activity of the H 2 S/Ca v 3.2 pathway is involved in neuropathic pain and in pancreatic and bladder nociception accompanying pancreatitis and cystitis, respectively [17][18][19][20][21]. The enhanced activity of Ca v 3.2 by NaHS, a donor of H 2 S, also causes neuronal differentiation characterized by neurite outgrowth and functional upregulation of high voltage-activated Ca 2+ channels in NG108-15 cells (mouse neuroblastoma  rat glioma hybrid cells) [22][23][24].…”