PMID- 10190690 OWN - NLM STAT- MEDLINE DCOM- 19990520 LR - 20191103 IS - 1355-0284 (Print) IS - 1355-0284 (Linking) VI - 5 IP - 1 DP - 1999 Feb TI - Inhibition of nitric oxide synthase-2 reduces the severity of mouse hepatitis virus-induced demyelination: implications for NOS2/NO regulation of chemokine expression and inflammation. PG - 48-54 AB - Infection of C57BL/6 mice with mouse hepatitis virus strain V5A13.1 (MHV-V5A13.1) results in an acute encephalitis followed by a chronic, progressive demyelinating disease with clinical and histological similarities to the human demyelinating disease Multiple Sclerosis (MS). Studies were undertaken to evaluate the contribution of NOS2 generated NO in demyelination in MHV-infected mice. MHV-infected animals were treated daily with either 8 mg of aminoguanidine (AG), a selective inhibitor of NOS2 activity, or PBS by intraperitoneal (i.p.) injection. MHV-infection of mice resulted in 20% mortality in both groups with surviving mice clearing virus below levels of detection, as measured by plaque assay, by day 12 postinfection (p.i.). A significant decrease in the severity of clinical disease was observed in AG-treated animals as compared to mice receiving PBS at days 7 and 12 p.i. (P< or =0.001 and 0.003, respectively) however, by day 21 p.i. AG-treated mice exhibited the same severity of clinical disease as control animals. Examination of brain and spinal cords from infected mice revealed a pronounced reduction in the severity of inflammation at day 7 p.i. in mice treated with AG as compared to control mice. By day 12 p.i. there was a significant decrease (P< or =0.02) in the severity of demyelination in AG-treated mice as compared to control animals yet both PBS and AG treated mice had a similar degree of demyelination by day 21 p.i. Analysis of chemokine mRNA transcripts by RNase protection assay revealed that AG-treated mice had significantly lower levels (P < or = 0.007) of transcripts for the C-C chemokine monocyte chemoattractant protein-1 (MCP-1) at day 7 p.i. as compared to control animals. By day 12 p.i., AG-treated mice and control mice had similar levels of chemokine transcripts. Together, these data suggest that inhibition of NOS2/NO slows the progression of MHV-induced demyelination. One potential mechanism by which this may occur is through controlling inflammation through modulation of chemokine expression in the CNS. FAU - Lane, T E AU - Lane TE AD - Department of Neuropharmacology, The Scripps Research Institute, La Jolla, California, USA. tlane@uci.edu FAU - Fox, H S AU - Fox HS FAU - Buchmeier, M J AU - Buchmeier MJ LA - eng GR - AI43103/AI/NIAID NIH HHS/United States GR - MH47680/MH/NIMH NIH HHS/United States GR - NS37336-01/NS/NINDS NIH HHS/United States PT - Comparative Study PT - Journal Article PT - Research Support, Non-U.S. Gov't PT - Research Support, U.S. Gov't, P.H.S. PL - United States TA - J Neurovirol JT - Journal of neurovirology JID - 9508123 RN - 0 (Chemokine CCL2) RN - 0 (Chemokines) RN - 0 (Enzyme Inhibitors) RN - 0 (Guanidines) RN - 0 (RNA, Messenger) RN - 31C4KY9ESH (Nitric Oxide) RN - EC 1.14.13.39 (Nitric Oxide Synthase) RN - SCQ4EZQ113 (pimagedine) SB - IM MH - Animals MH - Brain/metabolism MH - Chemokine CCL2/genetics/metabolism MH - Chemokines/genetics/*metabolism MH - Coronavirus Infections/complications/*metabolism MH - Demyelinating Diseases/etiology/*metabolism MH - Enzyme Inhibitors/pharmacology MH - Guanidines/pharmacology MH - Male MH - Mice MH - Mice, Inbred C57BL MH - *Murine hepatitis virus MH - Nitric Oxide/*metabolism MH - Nitric Oxide Synthase/*antagonists & inhibitors/metabolism MH - RNA, Messenger/analysis MH - Time Factors EDAT- 1999/04/06 00:00 MHDA- 1999/04/06 00:01 CRDT- 1999/04/06 00:00 PHST- 1999/04/06 00:00 [pubmed] PHST- 1999/04/06 00:01 [medline] PHST- 1999/04/06 00:00 [entrez] AID - 10.3109/13550289909029745 [doi] PST - ppublish SO - J Neurovirol. 1999 Feb;5(1):48-54. doi: 10.3109/13550289909029745.