RgIA4 Accelerates Recovery from Paclitaxel-Induced Neuropathic Pain in Rats

Abstract

Chemotherapeutic drugs are widely utilized in the treatment of human cancers. Painful chemotherapy-induced neuropathy is a common, debilitating, and dose-limiting side effect for which there is currently no effective treatment. Previous studies have demonstrated the potential utility of peptides from the marine snail from the genus Conus for the treatment of neuropathic pain. α-Conotoxin RgIA and a potent analog, RgIA4, have previously been shown to prevent the development of neuropathy resulting from the administration of oxaliplatin, a platinum-based antineoplastic drug. Here, we have examined its efficacy against paclitaxel, a chemotherapeutic drug that works by a mechanism of action distinct from that of oxaliplatin. Paclitaxel was administered at 2 mg/kg (intraperitoneally (IP)) every other day for a total of 8 mg/kg. Sprague Dawley rats that were co-administered RgIA4 at 80 µg/kg (subcutaneously (SC)) once daily, five times per week, for three weeks showed significant recovery from mechanical allodynia by day 31. Notably, the therapeutic effects reached significance 12 days after the last administration of RgIA4, which is suggestive of a rescue mechanism. These findings support the effects of RgIA4 in multiple chemotherapeutic models and the investigation of α9α10 nicotinic acetylcholine receptors (nAChRs) as a non-opioid target in the treatment of chronic pain.Patients have exhibited several types of neuropathies, including numbness, chronic pain, and allodynia (painful hypersensitivity) to mechanical or thermal stimuli [5]. Amongst patients, however, the type, duration, and severity of neuropathy can vary [6]. While the prevalence and manifestations of paclitaxel-induced neuropathy have been well documented, the underlying mechanisms are still being characterized. Several adjuvant treatments have been used in an attempt to combat the effects of chemotherapy-induced peripheral neuropathy (CIPN). However, there are currently no FDA-approved medications for the prevention or treatment of CIPN.Cone snails have historically displayed a repertoire of therapeutic molecules. The venomous marine gastropods of the genus Conus are a diverse collection of snails that have developed complex hunting and envenomation strategies. The venoms of these snails contain hundreds of unique peptides, and the contents of these venoms can also change in response to defensive or predatory stimuli [7]. Cone snails have refined a suite of bioactive peptides that can exquisitely and potently discriminate among receptors involved in neurotransmission. These targets include G-protein-coupled receptors and voltage-and ligand-gated ion channels [8]. The chemical arsenal of each snail also contains bioactive compounds that have been characterized as prey-endogenous mimetics, such as the insulin-like peptide used by Conus geographus, which more closely resembles fish insulin than its own [9]. The discovery of this molecular mimicry strategy spurred the characterization of several other hormone/neuropeptide-like peptides in the venom reperto...

The New Application of Real-time Cell-monitoring Analysis System to Detect Cellular Responses in Human Umbilical Vein Endothelial to Paclitaxel

“…A large number of studies using rodent dorsal root ganglion neurons or in vivo rodent models have been performed to elucidate the mechanisms of angialgia, such as those underlying paclitaxel-induced neuropathic pain. (17,18) However, these mechanisms are likely complex, and a quantitative evaluation of angialgia that represents the degree of pain caused by chemotherapy is difficult using conventional methods. Human evaluation of pain is confounded by the fact that it is a subjective phenomenon.…”

Nicotinic Acetylcholine Receptor Involvement in Inflammatory Bowel Disease and Interactions with Gut Microbiota

“…It has been shown that inhibiting the α9α10 receptor with the selective antagonist α-conotoxin RgIA reduced the severity of inflammation in the DSS model of colitis in mice [118]. RgIA and its analogs have been shown to have disease-modifying effects in a number of neuropathic and inflammatory disease models including sciatic nerve injury, diabetic neuropathy, and neuropathies associated with the use of the anti-cancer drugs paclitaxel and oxaliplatin [119][120][121][122]. An important mechanism through which RgIA exerts the observed therapeutic effects is by inhibiting the recruitment of lymphocytes and macrophages to damaged nerve tissues, although the exact mechanisms by which this occurs are currently unknown.…”

Preclinical and Clinical Evidence of Therapeutic Agents for Paclitaxel-Induced Peripheral Neuropathy

“…In addition to the aforementioned, many other drugs have been identified to reduce PIPN via several therapeutic targets, such as glutamate nerve systems [65,66], phosphodiesterase (PDE) [67,68], opioid receptors [72], acetylcholine receptor [77][78][79][80], cAMP/protein kinase A (PKA) signal [40], protein kinase C (PKC) [62,81], mitogen-activated protein kinase (MAPK) [28,39,49,53,56,[81][82][83], organic anion-transporting polypeptide 1b2 (OATP1B2) [84], mammalian target of rapamycin (mTOR) [51], and others [85][86][87][88][89][90][91][92][93][94][95][96][97][98][99][100][101][102][103], at the pre-clinical research level.…”