J Immunol 2003 Apr 1;170(7):3874-82
Dasgupta S, Zhou Y, Jana M, Banik NL, Pahan K.
Department of Oral Biology, University of Nebraska Medical Center, Lincoln, NE 68583. Center for Biotechnology, University of Nebraska, Lincoln, NE 68588. Department of Neurology, Medical University of South Carolina, Charleston, SC 29425.
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.