The galactosylation of N(ω)-nitro-L-arginine enhances its anti-nocifensive or anti-allodynic effects by targeting glia in healthy and neuropathic mice.

Abstract

This study has investigated whether the galactosyl ester prodrug of N(ω)-nitro-L-arginine (NAGAL), shows enhanced analgesic efficacy in healthy mice and in models of visceral and neuropathic pain: the writhing test and the spared nerve injury (SNI), respectively. NAGAL was compared to methyl ester pro-drug of N(ω)-nitro-l-arginine (L-NAME), a widely exploited non-specific nitric oxide synthase (NOS) inhibitor, for analgesic potential. The writhing test revealed that the ED(50) value, along with the 95% confidence limit (CL) was 3.82 (1.77-6.04) mg/kg for NAGAL and, 36.75 (20.07-68.37) mg/kg for L-NAME. Notably, NAGAL elicited a greater anti-allodynic effect than L-NAME did in neuropathic mice. Biomolecular and morphological studies revealed that spared nerve injury increased the expressions of pro-inflammatory enzymes (caspase-1) and two glial cell biomarkers: integrin alpha M (ITGAM) and glial fibrillary acidic protein (GFAP) in the spinal cord. Finally, GLUT-3, an isoform of the hexose transporters capable to bind NAGAL and inducible NOS (iNOS), were found to be over-expressed in the activated astrocytes of the spinal cord of neuropathic mice. NAGAL administration normalized expression levels of these biomarkers. NAGAL showed a greater efficacy in inhibiting visceral pain and allodynia than L-NAME possibly by a greater cell permeation through the hexose transporter which is highly over-expressed by activated glia.

• Authors: Catia Giordano, Dario Siniscalco, Daniela Melisi, Livio Luongo, Annalisa Curcio, Marie Soukupova, Enza Palazzo, Ida Marabese, Maria De Chiaro, Maria Grazia Rimoli, Francesco Rossi, Sabatino Maione, Vito de Novellis
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 656 Issue 1-3 Pg. 52-62 (Apr 10 2011) ISSN: 1879-0712 [Electronic] Netherlands
• PMID: 21296071 (Publication Type: Journal Article)
• Copyright: Copyright © 2011 Elsevier B.V. All rights reserved.

Chemical References

• Analgesics
• Glucose Transporter Type 3
• Prodrugs
• RNA, Messenger
• Nitroarginine
• Nitric Oxide Synthase Type II
• Caspases
• NG-Nitroarginine Methyl Ester
• Galactose

Topics

• Analgesics (metabolism, pharmacology, therapeutic use)
• Animals
• Astrocytes (drug effects, pathology)
• Blood Pressure (drug effects)
• Caspases (genetics)
• Galactose (metabolism)
• Gene Expression Regulation, Enzymologic (drug effects)
• Glucose Transporter Type 3 (metabolism)
• Hyperalgesia (drug therapy, metabolism, pathology, physiopathology)
• Male
• Mice
• Mice, Inbred C57BL
• Microglia (drug effects, pathology)
• NG-Nitroarginine Methyl Ester (pharmacology)
• Neuralgia (metabolism, pathology, physiopathology)
• Neuroglia (cytology, drug effects, metabolism, pathology)
• Nitric Oxide Synthase Type II (metabolism)
• Nitroarginine (metabolism, pharmacology, therapeutic use)
• Prodrugs (metabolism)
• Psychomotor Performance (drug effects)
• RNA, Messenger (genetics, metabolism)
• Sciatic Nerve (drug effects, injuries, metabolism, physiopathology)
• Time Factors