Glutamate Carboxypeptidase Inhibition Reduces the Severity of Chemotherapy-Induced Peripheral Neurotoxicity in Rat

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 dose-limiting. Excitotoxic glutamate release, leading to excessive glutamatergic neurotransmission and activation of N-methyl-D-aspartate (NMDA) receptors, is associated with neuronal damage and death in several nervous system disorders. N-Acetyl-aspartyl-glutamate (NAAG) is an abundant neuropeptide widely distributed in the central and peripheral nervous system which is physiologically hydrolyzed by the enzyme glutamate carboxypeptidase into N-Acetyl-aspartyl (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 well-established animal models of chemotherapy (cisplatin, paclitaxel, bortezomib)-induced peripheral neuropathy. In all cases, glutamate carboxypeptidase inhibition significantly improved the chemotherapy-induced 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 chemotherapy-induced peripheral neuropathy.

The Orally Active Glutamate Carboxypeptidase II Inhibitor E2072 Exhibits Sustained Nerve Exposure and Attenuates Peripheral Neuropathy

“…4). These data add support to previously reported effects of GCPII inhibition in cisplatin-, paclitaxel-, and bortezomib-induced models of peripheral neuropathy (Carozzi et al, 2010). In this context, it is especially important to note that E2072 did not interfere with chemotherapy antineoplastic efficacy at up to 3000 times its minimally effective neuroprotective dose.…”

Chemotherapy-Induced Neuropathy

“…& Venlafaxine reduction of acute and chronic oxaliplatin-induced hyperexcitability has been suggested [46]. & Inhibition of glutamate carboxypeptidase II, a central and peripheral nervous system metallopeptidase responsible for cleaving the abundant dipeptide N-acetyl-aspartyl glutamate and liberating glutamate, can treat peripheral nerve changes in experimental models of neuropathy involving cisplatin, paclitaxel, and bortezomib [47]. & Calpain inhibition using AK295 reduced the severity of paclitaxelinduced CIPN [48].…”

The Glutamatergic Neurotransmission in the Central Nervous System

“…the CNS damage induced by excessive glutamatergic signaling, has been linked to chronic neurodegenerative disorders including *Address correspondence to this author at the Department of Neuroscience and Biomedical Technologies, University of Milano-Bicocca, Via Cadore 48, 20900 Monza (MB), Italy; Tel: +39 02 6448 8116; Fax: +39 02 6448 8250; E-mail: paola.marmiroli@unimib.it amyotrophic lateral sclerosis (ALS), multiple sclerosis, Parkinson's disease as well as in ischemia and traumatic brain injury. Moreover, indirect evidence of a possible role of glutamate in peripheral neuropathies of different origin has been recently provided [4][5][6]. Since glutamate is unable to cross the blood-brain barrier [7], it is established that in order to exert its effects it must be directly produced in the CNS.…”