Glutamate Carboxypeptidase Inhibition Reduces the

Authors: Valentina A Carozzi Alessia Chiorazzi Annalisa Canta Rena G Lapidus Barbara S Slusher Krystyna M Wozniak Guido Cavaletti

Publish Date: 2009/09/15

Volume: 17, Issue: 4, Pages: 380-391

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Abstract

Chemotherapy is the most common method to treat cancer The use of certain antineoplastic drugs however is associated with the development of peripheral neuropathy that can be doselimiting Excitotoxic glutamate release leading to excessive glutamatergic neurotransmission and activation of Nmethyldaspartate NMDA receptors is associated with neuronal damage and death in several nervous system disorders NAcetylaspartylglutamate NAAG is an abundant neuropeptide widely distributed in the central and peripheral nervous system which is physiologically hydrolyzed by the enzyme glutamate carboxypeptidase into NAcetylaspartyl NAA and glutamate Pharmacological inhibition of glutamate carboxypeptidase results in decreased glutamate and increased endogenous NAAG and has been shown to provide neuroprotection in several preclinical models Here we report the neuroprotective effect of an orally available glutamate carboxypeptidase inhibitor on three wellestablished animal models of chemotherapy cisplatin paclitaxel bortezomibinduced peripheral neuropathy In all cases glutamate carboxypeptidase inhibition significantly improved the chemotherapyinduced nerve conduction velocity deficits In addition morphological and morphometrical alterations induced by cisplatin and bortezomib in dorsal root ganglia DRG were improved by glutamate carboxypeptidase inhibition Our data support a novel approach for the treatment of chemotherapyinduced peripheral neuropathy

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