title: 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.affiliation: Department of Experimental Medicine, Section of Pharmacology L. Donatelli, Faculty of Medicine and Surgery, Second University of Naples, Via Costantinopoli, 16 80138 Naples, Italy.
authors.forename: Catia
authors.initials: C
authors.lastname: Giordano
authors.forename: Dario
authors.initials: D
authors.lastname: Siniscalco
authors.forename: Daniela
authors.initials: D
authors.lastname: Melisi
authors.forename: Livio
authors.initials: L
authors.lastname: Luongo
authors.forename: Annalisa
authors.initials: A
authors.lastname: Curcio
authors.forename: Marie
authors.initials: M
authors.lastname: Soukupova
authors.forename: Enza
authors.initials: E
authors.lastname: Palazzo
authors.forename: Ida
authors.initials: I
authors.lastname: Marabese
authors.forename: Maria
authors.initials: M
authors.lastname: De Chiaro
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Rimoli
authors.forename: Francesco
authors.initials: F
authors.lastname: Rossi
authors.forename: Sabatino
authors.initials: S
authors.lastname: Maione
authors.forename: Vito
authors.initials: V
authors.lastname: de Novellis
mesh_terms: D000700:Analgesics / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000473:pathology; D001794:Blood Pressure / Q000187:drug effects; D020169:Caspases / Q000235:genetics; D005690:Galactose / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D051274:Glucose Transporter Type 3 / Q000378:metabolism; D006930:Hyperalgesia / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects / Q000473:pathology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009437:Neuralgia / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D009457:Neuroglia / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D019335:Nitroarginine / Q000378:metabolism* / Q000494:pharmacology* / Q000627:therapeutic use; D011355:Prodrugs / Q000378:metabolism*; D011597:Psychomotor Performance / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012584:Sciatic Nerve / Q000187:drug effects / Q000293:injuries / Q000378:metabolism / Q000503:physiopathology; D013997:Time Factors
chemical_list: D000700:Analgesics; D051274:Glucose Transporter Type 3; D011355:Prodrugs; D012333:RNA, Messenger; D019335:Nitroarginine; D052247:Nitric Oxide Synthase Type II; D020169:Caspases; D019331:NG-Nitroarginine Methyl Ester; D005690:Galactose