Glutamate carboxypeptidase inhibition reduces the severity of chemotherapy-induced peripheral neurotoxicity in rat.

Valentina A. Carozzi, Alessia Chiorazzi, Annalisa Canta, Rena G. Lapidus, Barbara Slusher, Krystyna M. Wozniak, Guido Cavaletti

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)380-391
Number of pages12
JournalNeurotoxicity Research
Volume17
Issue number4
DOIs
StatePublished - May 2010
Externally publishedYes

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Chemotherapy
Rats
Drug Therapy
Peripheral Nervous System Diseases
Neurology
Cisplatin
Glutamic Acid
Lysine Carboxypeptidase
Neural Conduction
Peripheral Nervous System
Spinal Ganglia
Neuroprotective Agents
Paclitaxel
Nervous System Diseases
N-Methyl-D-Aspartate Receptors
Neuropeptides
Synaptic Transmission
Antineoplastic Agents
Animals
Central Nervous System

ASJC Scopus subject areas

  • Neuroscience(all)
  • Toxicology

Cite this

Glutamate carboxypeptidase inhibition reduces the severity of chemotherapy-induced peripheral neurotoxicity in rat. / Carozzi, Valentina A.; Chiorazzi, Alessia; Canta, Annalisa; Lapidus, Rena G.; Slusher, Barbara; Wozniak, Krystyna M.; Cavaletti, Guido.

In: Neurotoxicity Research, Vol. 17, No. 4, 05.2010, p. 380-391.

Research output: Contribution to journalArticle

Carozzi, Valentina A. ; Chiorazzi, Alessia ; Canta, Annalisa ; Lapidus, Rena G. ; Slusher, Barbara ; Wozniak, Krystyna M. ; Cavaletti, Guido. / Glutamate carboxypeptidase inhibition reduces the severity of chemotherapy-induced peripheral neurotoxicity in rat. In: Neurotoxicity Research. 2010 ; Vol. 17, No. 4. pp. 380-391.
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