title: Combined medication of lovastatin with rolipram suppresses severity of experimental autoimmune encephalomyelitis.
abstract: Combinations of new medications or existing therapies are gaining momentum over monotherapy to treat central nervous system (CNS) demyelinating diseases including multiple sclerosis (MS). Recent studies established that statins (HMG-CoA reductase inhibitors) are effective in experimental autoimmune encephalomyelitis (EAE), an MS model and are promising candidates for future MS medication. Another drug, rolipram (phosphodiesterase-4 inhibitor) ameliorates the clinical severity of EAE via induction of various anti-inflammatory and neuroprotective activities. In this study, we tested whether combining the suboptimal doses of these drugs can suppress the severity of EAE. Prophylactic studies revealed that combined treatment with suboptimal doses of statins perform better than their individually administered optimal doses in EAE as evidenced by delayed clinical scores, reduced disease severity, and rapid recovery. Importantly, combination therapy suppressed the progression of disease in an established EAE case via attenuation of inflammation, axonal loss and demyelination. Combination treatment attenuated inflammatory T(H)1 and T(H)17 immune responses and induced T(H)2-biased immunity in the peripheral and CNS as revealed by serological, quantitative, and immunosorbant assay-based analyses. Moreover, the expansion of T regulatory (CD25(+)/Foxp3(+)) cells and self-immune tolerance was apparent in the CNS. These effects of combined drugs were reduced or minimal with either drug alone in this setting. In conclusion, our findings demonstrate that the combination of these drugs suppresses EAE severity and provides neuroprotection thereby suggesting that this pharmacological approach could be a better future therapeutic strategy to treat MS patients.
authors.affiliation: Darby Children's Research Institute, Medical University of South Carolina, USA. paintlia@musc.edu
authors.forename: Ajaib S
authors.initials: AS
authors.lastname: Paintlia
authors.forename: Manjeet K
authors.initials: MK
authors.lastname: Paintlia
authors.forename: Inderjit
authors.initials: I
authors.lastname: Singh
authors.forename: Avtar K
authors.initials: AK
authors.lastname: Singh
mesh_terms: D000818:Animals; D003711:Demyelinating Diseases / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D005260:Female; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007108:Immune Tolerance / Q000187:drug effects / Q000276:immunology; D008148:Lovastatin / Q000494:pharmacology*; D009410:Nerve Degeneration / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D051381:Rats; D011917:Rats, Inbred Lew; D020889:Rolipram / Q000494:pharmacology*; D012720:Severity of Illness Index; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000473:pathology; D018417:Th1 Cells / Q000276:immunology / Q000473:pathology; D018418:Th2 Cells / Q000276:immunology / Q000473:pathology
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D010726:Phosphodiesterase Inhibitors; D008148:Lovastatin; D020889:Rolipram
references.citation: Xenobiotica. 1989 Jun;19(6):683-92
references.pmid: 2669364
references.citation: Glia. 2008 Jul;56(9):954-62
references.pmid: 18383345
references.citation: Eur J Neurosci. 2005 Nov;22(9):2199-206
references.pmid: 16262658
references.citation: Acta Neurol Scand. 2000 Oct;102(4):209-17
references.pmid: 11071104
references.citation: Mult Scler. 2005 Jun;11(3):296-301
references.pmid: 15957510
references.citation: J Neuroimmunol. 2005 Aug;165(1-2):83-91
references.pmid: 15958276
references.citation: J Mol Neurosci. 2001 Aug;17(1):45-58
references.pmid: 11665862
references.citation: Annu Rev Biochem. 1996;65:241-69
references.pmid: 8811180
references.citation: Acta Neurol Scand. 2007 Aug;116(2):96-9
references.pmid: 17661794
references.citation: J Immunol. 2003 Feb 1;170(3):1524-30
references.pmid: 12538717
references.citation: Neuropharmacology. 2001;40(2):262-9
references.pmid: 11114405
references.citation: Am J Pathol. 2006 Sep;169(3):1012-25
references.pmid: 16936274
references.citation: Nat Med. 1995 Mar;1(3):244-8
references.pmid: 7585041
references.citation: J Neuroimmunol. 1996 May;66(1-2):103-14
references.pmid: 8964903
references.citation: Autoimmunity. 2000 Sep;32(2):93-9
references.pmid: 11078155
references.citation: N Engl J Med. 2006 Mar 2;354(9):911-23
references.pmid: 16510745
references.citation: Proc Natl Acad Sci U S A. 1995 Apr 11;92(8):3601-5
references.pmid: 7536938
references.citation: Nat Med. 2006 May;12(5):518-25
references.pmid: 16633347
references.citation: FASEB J. 2005 May;19(7):804-6
references.pmid: 15728660
references.citation: J Exp Med. 2006 Feb 20;203(2):401-12
references.pmid: 16476765
references.citation: Nature. 2002 Nov 7;420(6911):78-84
references.pmid: 12422218
references.citation: J Virol. 1998 May;72(5):3711-9
references.pmid: 9557653
references.citation: PLoS One. 2008 Apr 09;3(4):e1928
references.pmid: 18398457
references.citation: J Immunol. 2000 Jan 15;164(2):1117-24
references.pmid: 10623864
references.citation: Mol Pharmacol. 2008 May;73(5):1381-93
references.pmid: 18239032
references.citation: J Neurol Sci. 2005 Jun 15;233(1-2):173-7
references.pmid: 15949504
references.citation: Exp Neurol. 2008 May;211(1):214-26
references.pmid: 18346732
references.citation: FASEB J. 2005 Sep;19(11):1407-21
references.pmid: 16126908
references.citation: J Neurosci Res. 2004 Jul 1;77(1):63-81
references.pmid: 15197739
references.citation: Atherosclerosis. 2008 Apr;197(2):829-39
references.pmid: 17826781
references.citation: Thorax. 1991 Jul;46(7):512-23
references.pmid: 1877039
references.citation: J Immunol. 2002 Apr 15;168(8):4087-4094
references.pmid: 11937568
references.citation: Mult Scler. 2002 Dec;8(6):485-91
references.pmid: 12474988
references.citation: J Immunol. 2008 May 15;180(10):6988-96
references.pmid: 18453621
references.citation: Mult Scler. 1999 Apr;5(2):126-33
references.pmid: 10335522
references.citation: Lancet. 2004 May 15;363(9421):1607-8
references.pmid: 15145635
references.citation: J Neuroimmunol. 2000 Jul 1;106(1-2):69-77
references.pmid: 10814784
references.citation: Springer Semin Immunopathol. 1985;8(3):197-208
references.pmid: 3931271
references.citation: J Clin Invest. 2004 Mar;113(6):788-94
references.pmid: 15067307
references.citation: FASEB J. 2006 Feb;20(2):374-6
references.pmid: 16365386
references.citation: J Exp Med. 2007 Jan 22;204(1):161-70
references.pmid: 17200411
references.citation: J Clin Invest. 1997 Dec 1;100(11):2671-9
references.pmid: 9389730
references.citation: J Neuroimmunol. 1996 Aug;68(1-2):1-11
references.pmid: 8784254
references.citation: J Neuroimmunol. 1999 Jun 1;97(1-2):119-28
references.pmid: 10408965
references.citation: Ann Neurol. 2000 Jan;47(1):127-31
references.pmid: 10632113
references.citation: J Pharmacol Exp Ther. 2005 Feb;312(2):786-93
references.pmid: 15358814
references.citation: Cell Mol Neurobiol. 2006 Jul-Aug;26(4-6):385-405
references.pmid: 16633891
references.citation: Glia. 1989;2(5):308-17
references.pmid: 2530171
references.citation: Nat Rev Immunol. 2004 Oct;4(10):762-74
references.pmid: 15459668
references.citation: J Neurosci. 2003 Dec 3;23(35):11104-11
references.pmid: 14657168
references.citation: J Neuroimmunol. 1994 Oct;54(1-2):129-44
references.pmid: 7523443
references.citation: J Clin Invest. 2006 Apr;116(4):1037-44
references.pmid: 16543951
references.citation: J Neurosci Res. 2001 Oct 15;66(2):155-62
references.pmid: 11592110
references.citation: J Immunol. 2002 Sep 1;169(5):2231-5
references.pmid: 12193686
references.citation: J Immunol. 2005 Jun 1;174(11):6772-80
references.pmid: 15905518
references.citation: FASEB J. 2005 Aug;19(10):1347-9
references.pmid: 15939737
references.citation: J Neuroimmunol. 2005 Nov;168(1-2):13-20
references.pmid: 16182379
references.citation: Swiss Med Wkly. 2001 Jan 27;131(3-4):41-6
references.pmid: 11219190
references.citation: J Cell Biochem. 2004 Nov 15;93(5):917-28
references.pmid: 15389871
references.citation: Xenobiotica. 1988 May;18(5):561-71
references.pmid: 3400274
references.citation: Nat Immunol. 2007 Feb;8(2):172-80
references.pmid: 17206145
references.citation: Curr Opin Immunol. 1997 Dec;9(6):872-83
references.pmid: 9492992