Combined medication of lovastatin with rolipram suppresses severity of experimental autoimmune encephalomyelitis.
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.
Paintlia
Ajaib S
AS
Darby Children's Research Institute, Medical University of South Carolina, USA. paintlia@musc.edu
Paintlia
Manjeet K
MK
Singh
Inderjit
I
Singh
Avtar K
AK
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
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D010726:Phosphodiesterase Inhibitors; D008148:Lovastatin; D020889:Rolipram
Xenobiotica. 1989 Jun;19(6):683-92
2669364
Glia. 2008 Jul;56(9):954-62
18383345
Eur J Neurosci. 2005 Nov;22(9):2199-206
16262658
Acta Neurol Scand. 2000 Oct;102(4):209-17
11071104
Mult Scler. 2005 Jun;11(3):296-301
15957510
J Neuroimmunol. 2005 Aug;165(1-2):83-91
15958276
J Mol Neurosci. 2001 Aug;17(1):45-58
11665862
Annu Rev Biochem. 1996;65:241-69
8811180
Acta Neurol Scand. 2007 Aug;116(2):96-9
17661794
J Immunol. 2003 Feb 1;170(3):1524-30
12538717
Neuropharmacology. 2001;40(2):262-9
11114405
Am J Pathol. 2006 Sep;169(3):1012-25
16936274
Nat Med. 1995 Mar;1(3):244-8
7585041
J Neuroimmunol. 1996 May;66(1-2):103-14
8964903
Autoimmunity. 2000 Sep;32(2):93-9
11078155
N Engl J Med. 2006 Mar 2;354(9):911-23
16510745
Proc Natl Acad Sci U S A. 1995 Apr 11;92(8):3601-5
7536938
Nat Med. 2006 May;12(5):518-25
16633347
FASEB J. 2005 May;19(7):804-6
15728660
J Exp Med. 2006 Feb 20;203(2):401-12
16476765
Nature. 2002 Nov 7;420(6911):78-84
12422218
J Virol. 1998 May;72(5):3711-9
9557653
PLoS One. 2008 Apr 09;3(4):e1928
18398457
J Immunol. 2000 Jan 15;164(2):1117-24
10623864
Mol Pharmacol. 2008 May;73(5):1381-93
18239032
J Neurol Sci. 2005 Jun 15;233(1-2):173-7
15949504
Exp Neurol. 2008 May;211(1):214-26
18346732
FASEB J. 2005 Sep;19(11):1407-21
16126908
J Neurosci Res. 2004 Jul 1;77(1):63-81
15197739
Atherosclerosis. 2008 Apr;197(2):829-39
17826781
Thorax. 1991 Jul;46(7):512-23
1877039
J Immunol. 2002 Apr 15;168(8):4087-4094
11937568
Mult Scler. 2002 Dec;8(6):485-91
12474988
J Immunol. 2008 May 15;180(10):6988-96
18453621
Mult Scler. 1999 Apr;5(2):126-33
10335522
Lancet. 2004 May 15;363(9421):1607-8
15145635
J Neuroimmunol. 2000 Jul 1;106(1-2):69-77
10814784
Springer Semin Immunopathol. 1985;8(3):197-208
3931271
J Clin Invest. 2004 Mar;113(6):788-94
15067307
FASEB J. 2006 Feb;20(2):374-6
16365386
J Exp Med. 2007 Jan 22;204(1):161-70
17200411
J Clin Invest. 1997 Dec 1;100(11):2671-9
9389730
J Neuroimmunol. 1996 Aug;68(1-2):1-11
8784254
J Neuroimmunol. 1999 Jun 1;97(1-2):119-28
10408965
Ann Neurol. 2000 Jan;47(1):127-31
10632113
J Pharmacol Exp Ther. 2005 Feb;312(2):786-93
15358814
Cell Mol Neurobiol. 2006 Jul-Aug;26(4-6):385-405
16633891
Glia. 1989;2(5):308-17
2530171
Nat Rev Immunol. 2004 Oct;4(10):762-74
15459668
J Neurosci. 2003 Dec 3;23(35):11104-11
14657168
J Neuroimmunol. 1994 Oct;54(1-2):129-44
7523443
J Clin Invest. 2006 Apr;116(4):1037-44
16543951
J Neurosci Res. 2001 Oct 15;66(2):155-62
11592110
J Immunol. 2002 Sep 1;169(5):2231-5
12193686
J Immunol. 2005 Jun 1;174(11):6772-80
15905518
FASEB J. 2005 Aug;19(10):1347-9
15939737
J Neuroimmunol. 2005 Nov;168(1-2):13-20
16182379
Swiss Med Wkly. 2001 Jan 27;131(3-4):41-6
11219190
J Cell Biochem. 2004 Nov 15;93(5):917-28
15389871
Xenobiotica. 1988 May;18(5):561-71
3400274
Nat Immunol. 2007 Feb;8(2):172-80
17206145
Curr Opin Immunol. 1997 Dec;9(6):872-83
9492992