Glutamate carboxypeptidase inhibition reduces the severity of chemotherapy-induced peripheral neurotoxicity in rat.
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.
Carozzi
Valentina A
VA
Department of Neurosciences and Biomedical Technologies, University of Milano-Bicocca, U8, Via Cadore 48, 20052 Monza (MB), Italy. v.carozzi@campus.unimib.it
Chiorazzi
Alessia
A
Canta
Annalisa
A
Lapidus
Rena G
RG
Slusher
Barbara S
BS
Wozniak
Krystyna M
KM
Cavaletti
Guido
G
D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D001835:Body Weight / Q000187:drug effects; D002268:Carboxypeptidases / Q000378:metabolism*; D004151:Dipeptides / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D064420:Drug-Related Side Effects and Adverse Reactions; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics / Q000627:therapeutic use; D005260:Female; D005727:Ganglia, Spinal / Q000473:pathology; D018698:Glutamic Acid / Q000378:metabolism; D018696:Neuroprotective Agents / Q000493:pharmacokinetics / Q000627:therapeutic use; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced* / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D018709:Statistics, Nonparametric
D000970:Antineoplastic Agents; D004151:Dipeptides; D004791:Enzyme Inhibitors; D018696:Neuroprotective Agents; C027172:isospaglumic acid; D018698:Glutamic Acid; D002268:Carboxypeptidases; C026134:glutamate carboxypeptidase