The galactosylation of N()-nitro-L-arginine enhances its anti-nocifensive or anti-allodynic effects by targeting glia in healthy and neuropathic mice
| Autor: | Vito de Novellis, Dario Siniscalco, Daniela Melisi, Maria Grazia Rimoli, Livio Luongo, Enza Palazzo, Sabatino Maione, Francesco Rossi, Ida Marabese, Annalisa Curcio, Catia Giordano, Maria De Chiaro, Marie Soukupova |
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| Přispěvatelé: | Giordano, C, Siniscalco, D, Melisi, D, Luongo, Livio, Curcio, A, Soukupova, M, Palazzo, E, Marabese, Ida, DE CHIARO, M, Rimoli, Mg, Rossi, Francesco, Maione, Sabatino, DE NOVELLIS, Vito, Melisi, Daniela, Luongo, L, Marabese, I, Rimoli, MARIA GRAZIA, Rossi, F, Maione, S, DE NOVELLIS, V. |
| Jazyk: | angličtina |
| Rok vydání: | 2011 |
| Předmět: |
Male
Time Factors Arginine Socio-culturale Nitric Oxide Synthase Type II Blood Pressure Pharmacology Nitroarginine Gene Expression Regulation Enzymologic Mice Economica medicine Animals Prodrugs RNA Messenger Analgesics biology Glial fibrillary acidic protein Glucose Transporter Type 3 Chemistry Galactose Visceral pain Nerve injury Sciatic Nerve Nitric oxide synthase Mice Inbred C57BL Allodynia NG-Nitroarginine Methyl Ester Integrin alpha M Biochemistry Hyperalgesia Astrocytes Caspases Neuropathic pain biology.protein Neuralgia Microglia medicine.symptom Neuroglia Psychomotor Performance |
| Popis: | 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 Nω-nitro-l-arginine (L-NAME), a widely exploited non-specific nitric oxide synthase (NOS) inhibitor, for analgesic potential. The writhing test revealed that the ED50 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. © 2011 Elsevier B.V. |
| Databáze: | OpenAIRE |
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