Role of iNOS-NO-cGMP signaling in modulation of inflammatory and myelination processes

Author(s)

Raposo, Catarina ^[1] ; de Almeida Luna, Rayana Leal ^[2] ; Santana Nunes, Ana Karolina ^[2] ; Thome, Rodolfo ^[3] ; Peixoto, Christina Alves ^[2]

Affiliation

^[1] Univ Estadual Campinas UNICAMP, Inst Biol, Dept Histol & Embriol, BR-13083862 Campinas, SP - Brazil

^[2] Fundacao Oswaldo Cruz, Ctr Pesquisas Aggeu Magalhaes, Lab Ultraestrutura, BR-50670420 Recife, PE - Brazil

^[3] Univ Estadual Campinas UNICAMP, Inst Biol, Dept Biol Estrutural & Func, BR-13083862 Campinas, SP - Brazil

• Document type: Journal article
• Source: Brain Research Bulletin; v. 104, p. 60-73, MAY 2014.
• Web of Science Citations: 19

Abstract

Nitric oxide (NO) is the main activator of the soluble guanylate cyclase (sGC)-guanosine 3'5' cyclic monophosphate (cGMP) pathway. The level of cGMP is regulated by phosphodiesterases (PDEs), which break down cGMP. It has been reported that levels of NO in the central nervous system (CNS) can greatly increase during demyelination and/or neuroinflammation. Controversially, in demyelination models, mice without iNOS may develop more severe cases of disease. Furthermore, cGMP accumulation caused by PDE inhibitors has an anti-inflammatory/neuroprotective effect in MS-models. The role of the NO-cGMP pathway in the nervous tissue is, therefore, complex and not fully understood. The aim of the present study was to contribute to existing knowledge of the role of this pathway in the CNS. Wild type (WT - C57BL/6) and iNOS(-/-) animals were treated with sildenafil (25 mg/kg) for 8 weeks. Control animals were not treated. VCAM and ICAM (adhesion proteins), GFAP and Iba-1 (astrocyte and microglia markers, respectively), PKG (cGMP-dependent protein kinase), sGC, eNOS (constitutive endothelial NO sinthase) and GSTpi (a marker of mature oligodendrocytes) were evaluated in the cerebellum using immunohistochemistry or western blotting. Myelin was assessed by luxol fast blue staining and election transmission microscopy. Treatment with sildenafil reduced ICAM and VCAM levels (anti-inflammatory effect) and increased GFAP and Iba-1 expression (clearance phenotype) in WT animals. The expression of VCAM, ICAM, GFAP, PKG and sGC was lower in iNOS(-/-) mice than in WT control animals. The treatment of iNOS(-/-) animals with sildenafil resulted in an increase of all proteins (pro-inflammatory effect). There was overexpression of eNOS in untreated iNOS-/- mice. The myelin structure of iNOS-/- animals was damaged in comparison with WT control. Sildenafil increased GSTpi and resulted in an improved myelin structure in iNOS(-/-) mice. In conclusion, NO-cGMP signaling plays a role in the regulation of inflammation and myelination processes. The accumulation of cGMP produced opposite effects in WT and iNOS(-/-) mice. This can be explained by the overexpression of eNOS in iNOS(-/-) mice, unbalancing cGMP signaling, or cGMP has a dual role in inflammation. Drugs that modulate the NO-sGC-cGMP pathway may be clinically beneficial in the treatment of neuroinflammatory/demyelinating disorders, but further studies of the regulation of this pathway are required. (C) 2014 Elsevier Inc. All rights reserved. (AU)

• FAPESP's process: 11/08005-6 - Study of Phoneutria nigriventer spider venom mechanism in the blood brain barrier and in the neural tissue and analysis of two purified toxins action as vehicle in the Glioma treatment
• Grantee: Catarina Raposo Dias Carneiro
• Support Opportunities: Scholarships in Brazil - Post-Doctoral