Sodium phenylacetate inhibits adoptive transfer of experimental allergic encephalomyelitis in SJL/J mice at multiple steps.
Experimental allergic encephalomyelitis (EAE) is the animal model for multiple sclerosis. The present study underlines the importance of sodium phenylacetate (NaPA), a drug approved for urea cycle disorders, in inhibiting the disease process of adoptively transferred EAE in female SJL/J mice at multiple steps. Myelin basic protein (MBP)-primed T cells alone induced the expression of NO synthase (iNOS) and the activation of NF-kappaB in mouse microglial cells through cell-cell contact. However, pretreatment of MBP-primed T cells with NaPA markedly inhibited its ability to induce microglial expression of iNOS and activation of NF-kappaB. Consistently, adoptive transfer of MBP-primed T cells, but not that of NaPA-pretreated MBP-primed T cells, induced the clinical symptoms of EAE in female SJL/J mice. Furthermore, MBP-primed T cells isolated from NaPA-treated donor mice were also less efficient than MBP-primed T cells isolated from normal donor mice in inducing iNOS in microglial cells and transferring EAE to recipient mice. Interestingly, clinical symptoms of EAE were much less in mice receiving NaPA through drinking water than those without NaPA. Similar to NaPA, sodium phenylbutyrate, a chemically synthesized precursor of NaPA, also inhibited the disease process of EAE. Histological and immunocytochemical analysis showed that NaPA inhibited EAE-induced spinal cord mononuclear cell invasion and normalized iNOS, nitrotyrosine, and p65 (the RelA subunit of NF-kappaB) expression within the spinal cord. Taken together, our results raise the possibility that NaPA or sodium phenylbutyrate taken through drinking water or milk may reduce the observed neuroinflammation and disease process in multiple sclerosis patients.
Dasgupta
Subhajit
S
Department of Oral Biology, University of Nebraska Medical Center, Lincoln, NE 68583-0740, USA.
Zhou
You
Y
Jana
Malabendu
M
Banik
Naren L
NL
Pahan
Kalipada
K
D000208:Acute Disease; D000284:Administration, Oral; D019264:Adoptive Transfer / Q000379:methods; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects / Q000276:immunology; D002908:Chronic Disease; D018450:Disease Progression; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000201:enzymology / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D005260:Female; D006131:Growth Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000494:pharmacology*; D007274:Injections, Intraperitoneal; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D008815:Mice, Inbred Strains; D017628:Microglia / Q000187:drug effects / Q000201:enzymology / Q000276:immunology; D004676:Myelin Basic Protein / Q000037:antagonists & inhibitors / Q000276:immunology; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II; D010648:Phenylacetates / Q000008:administration & dosage / Q000494:pharmacology*; D010654:Phenylbutyrates / Q000008:administration & dosage / Q000494:pharmacology; D012720:Severity of Illness Index; D013116:Spinal Cord / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology / Q000637:transplantation; D051996:Transcription Factor RelA; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000096:biosynthesis
D000894:Anti-Inflammatory Agents, Non-Steroidal; D004791:Enzyme Inhibitors; D006131:Growth Inhibitors; D007166:Immunosuppressive Agents; D004676:Myelin Basic Protein; D016328:NF-kappa B; D010648:Phenylacetates; D010654:Phenylbutyrates; D051996:Transcription Factor RelA; C002744:3-nitrotyrosine; D014443:Tyrosine; C075773:4-phenylbutyric acid; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C025136:phenylacetic acid