A newly designed GABA-AT inactivator, (S)-MeCPP-115, suppresses paclitaxel-induced neuropathic pain in mice

Abstract

BackgroundChemotherapy-induced peripheral neuropathy (CIPN) is a common and debilitating side effect of paclitaxel treatment. Pharmacological strategies that enhance inhibitory tone, via inhibition of {gamma}-aminobutyric acid aminotransferase (GABA-AT), the enzyme which degrades endogenous GABA, provides analgesic benefit in preclinical studies. (S)-MeCPP-115 is a novel selective GABA-AT inactivator designed from CPP-115 to minimize off-target activity. Whether (S)-MeCPP-115 shows efficacy in preclinical pain models is unknown. MethodsIn vitro assays of cell viability were conducted to ascertain whether (S)-MeCPP-115 interfered with antitumor activity of paclitaxel or produced cytotoxicity in normal cells. Male mice received paclitaxel to induce chemotherapy-induced peripheral neuropathy in vivo. In mice with established paclitaxel-induced mechanical hypersensitivity, (S)-MeCPP-115 was administered via acute and chronic administration using intraperitoneal (i.p.) or intrathecal (i.t.) dosing strategies. Mechanical sensitivity was assessed in all mice with an electronic von Frey analgesiometer before and after paclitaxel and pharmacological treatments. Locomotor activity was also measured in the same subjects to assess possible motor impairment. ResultsIn MTT assays, (S)-MeCPP-115 did not alter the cytotoxic activity of paclitaxel in 4T1 breast cancer cells and did not produce cytotoxicity in non-tumor HEK293 cells. (S)-MeCPP-115 reduced paclitaxel-induced mechanical hypersensitivity after i.p. and i.t. administration. Therapeutic efficacy was maintained with repeated dosing without development of tolerance. (S)-MeCPP-115 did not alter paw withdrawal thresholds in mice that received the Cremophor-based vehicle in lieu of paclitaxel following acute or chronic dosing. Systemic treatment with (S)-MeCPP-115 was well tolerated, whereas i.t. administration produced only minimal locomotor effects. Conclusion(S)-MeCPP-115 did not interfere with the ability of paclitaxel to produce tumor cell cytotoxicity in vitro and did not produce cytotoxicity in non-tumor cells. Systemic and intrathecal administration of (S)-MeCPP-115 produced robust suppression of mechanical hypersensitivity in a mouse model of paclitaxel-induced CIPN without major adverse effects. Selective GABA-AT inhibition represents a promising therapeutic approach for suppressing paclitaxel-induced mechanical hypersensitivity. Further preclinical characterization of the therapeutic profile of (S)-MeCPP-115 is warranted.