Article

ORALLY ACTIVE GCPII INHIBITOR, E2072, EXHIBITS SUSTAINED NERVE EXPOSURE AND ATTENUATES PERIPHERAL NEUROPATHY.

1 JohnsHopkins Brain Science Institute;
Journal of Pharmacology and Experimental Therapeutics (Impact Factor: 3.89). 09/2012; DOI: 10.1124/jpet.112.197665
Source: PubMed

ABSTRACT Peripheral neuropathy from nerve trauma is a significant problem in the human population and often constitutes a dose limiting toxicity in patients receiving chemotherapy. E2072 is a potent (Ki=10 nM), selective and orally available inhibitor of glutamate carboxypeptidase II (GCPII). Here, we report that E2072 attenuates hyperalgesia and nerve conduction velocity (NCV) deficits in preclinical rodent models of neuropathic pain and oxaliplatin-induced neuropathy. In the chronic constrictive injury (CCI) model, orally administered E2072 reversed pre-existing thermal hyperalgesia in rats in a dose-dependent fashion, with a minimally effective dose of 0.1 mg/kg/day. Interestingly, multiple days of dosing of E2072 were required before analgesia was realized even though GCPII inhibitory exposures were achieved on the first day of dosing. In addition, analgesia was found to persist for up to 7 days after cessation of dosing, consistent with E2072's pharmacokinetic profile and sustained exposure. Furthermore, in a chronic oxaliplatin-induced neuropathy model, (6 mg/kg oxaliplatin ip twice weekly for 4 weeks), female BALB/C mice receiving daily oral E2072 at 1.0 and 0.1 mg/kg displayed no deficits in either caudal or digital velocity compared to significant deficits observed in oxaliplatin alone-treated mice (12±3% and 9±2% respectively). Similar findings were seen with oxaliplatin-induced digital and caudal amplitude deficits. Importantly, E2072 showed no interference with the antineoplastic efficacy of oxaliplatin in mice bearing leukemia (L1210), even at doses 100 times its neuroprotective/analgesic dose, indicating a selective effect on neuropathy. These data support the therapeutic utility of GCPII inhibitors in neuropathy and neuropathic pain.

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