Mycophenolate mofetil inhibits the development of Coxsackie B3-virus-induced myocarditis in mice.
BACKGROUND
Viral replication as well as an immunopathological component are assumed to be involved in the development of coxsackie B virus (CBV)-induced myocarditis. We observed that mycophenolic acid (MPA), the active metabolite of the immunosuppressive agent mycophenolate mofetil (MMF), inhibits coxsackie B3 virus (CBV3) replication in primary Human myocardial fibroblasts. We therefore studied whether MMF, which is thus endowed with a direct antiviral as well as immunosuppressive effect, may prevent CBV-induced myocarditis in a murine model.


RESULTS
Four week old C3H-mice were infected with CBV3 and received twice daily, for 7 consecutive days (from one day before to 5 days post-virus inoculation) treatment with MMF via oral gavage. Treatment with MMF resulted in a significant reduction in the development of CBV-induced myocarditis as assessed by morphometric analysis, i.e. 78% reduction when MMF was administered at 300 mg/kg/day (p < 0.001), 65% reduction at 200 mg/kg/day (p < 0.001), and 52% reduction at 100 mg/kg/day (p = 0.001). The beneficial effect could not be ascribed to inhibition of viral replication since titers of infectious virus and viral RNA in heart tissue were increased in MMF-treated animals as compared to untreated animals.


CONCLUSIONS
The immunosuppressive agent MMF results in an important reduction of CBV3-induced myocarditis in a murine model.
Padalko
Elizaveta
E
Laboratory of Chemotherapy, Rega Institute, Katholieke Universiteit Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium. epadalk1@jhmi.edu
Verbeken
Erik
E
Matthys
Patrick
P
Aerts
Joeri L
JL
De Clercq
Erik
E
Neyts
Johan
J
D000818:Animals; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D004305:Dose-Response Relationship, Drug; D029822:Enterovirus B, Human / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development; D004769:Enterovirus Infections / Q000517:prevention & control* / Q000821:virology; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008815:Mice, Inbred Strains; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D009205:Myocarditis / Q000473:pathology / Q000517:prevention & control* / Q000821:virology; D012367:RNA, Viral / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014709:Vero Cells; D014779:Virus Replication / Q000187:drug effects
D007166:Immunosuppressive Agents; D012367:RNA, Viral; D009173:Mycophenolic Acid