Immunomodulatory effect of combination therapy with lovastatin and 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside alleviates neurodegeneration in experimental autoimmune encephalomyelitis.
Combination therapy with multiple sclerosis (MS) therapeutics is gaining momentum over monotherapy for improving MS. Lovastatin, an HMG-CoA reductase inhibitor (statin), was immunomodulatory in an experimental autoimmune encephalomyelitis (EAE) model of MS. Lovastatin biases the immune response from Th1 to a protective Th2 response in EAE by a different mechanism than 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside, an immunomodulating agent that activates AMP-activated protein kinase. Here we tested these agents in combination in an EAE model of MS. Suboptimal doses of these drugs in combination were additive in efficacy against the induction of EAE; clinical symptoms were delayed and severity and duration of disease was reduced. In the central nervous system, the cellular infiltration and proinflammatory immune response was decreased while the anti-inflammatory immune response was increased. Combination treatment biased the class of elicited myelin basic protein antibodies from IgG2a to IgG1 and IgG2b, suggesting a shift from Th1 to Th2 response. In addition, combination therapy lessened inflammation-associated neurodegeneration in the central nervous system of EAE animals. These effects were absent in EAE animals treated with either drug alone at the same dose. Thus, our data suggest that agents with different mechanisms of action such as lovastatin and 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside, when used in combination, could improve therapy for central nervous system demyelinating diseases and provide a rationale for testing them in MS patients.
Paintlia
Ajaib S
AS
Medical University of South Carolina, Department of Pediatrics, 173 Ashley Ave., Charleston, SC 29425, USA.
Paintlia
Manjeet K
MK
Singh
Inderjit
I
Singh
Avtar K
AK
D055372:AMP-Activated Protein Kinases; D000620:Aminoimidazole Carboxamide / Q000008:administration & dosage / Q000031:analogs & derivatives*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004359:Drug Therapy, Combination; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D004789:Enzyme Activation / Q000187:drug effects / Q000276:immunology; D005260:Female; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage*; D007004:Hypoglycemic Agents / Q000008:administration & dosage*; D007074:Immunoglobulin G / Q000276:immunology; D007155:Immunologic Factors / Q000008:administration & dosage*; D008148:Lovastatin / Q000008:administration & dosage*; D009097:Multienzyme Complexes / Q000276:immunology; D009103:Multiple Sclerosis / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D004676:Myelin Basic Protein / Q000276:immunology; D017346:Protein Serine-Threonine Kinases / Q000276:immunology; D051381:Rats; D011917:Rats, Inbred Lew; D012265:Ribonucleotides / Q000008:administration & dosage*; D018417:Th1 Cells / Q000276:immunology / Q000473:pathology; D018418:Th2 Cells / Q000276:immunology / Q000473:pathology
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007004:Hypoglycemic Agents; D007074:Immunoglobulin G; D007155:Immunologic Factors; D009097:Multienzyme Complexes; D004676:Myelin Basic Protein; D012265:Ribonucleotides; D000620:Aminoimidazole Carboxamide; D008148:Lovastatin; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; C031143:AICA ribonucleotide