Tacrolimus (FK506) causes disease aggravation in models for inherited peripheral myelinopathies.
Mice hetero- or homozygously deficient for myelin protein zero (P0+/-, P0-/- mice) are models for distinct forms of inherited de- or dysmyelinating neuropathies, respectively. P0+/- mice show a demyelinating neuropathy with a pathogenetic implication of CD8+ T-lymphocytes and macrophages, while P0-/- mice show dysmyelination with axonal loss. It was, therefore, of interest to treat both mutants with FK506 (Tacrolimus), an agent with immunosuppressive and neuroprotective properties. Treatment of P0+/- mice led to an aggravation of demyelination, without affecting nervous CD8+ T-lymphocytes, but reducing splenic CD4+ cells. Treatment of P0-/- mice resulted in a substantial increase of the dysmyelination-related axon loss. Treatment of wildtype mice did not cause pathological changes in peripheral nerves. Our study shows that FK506 may not be suitable for the treatment of the human nerve disorders. Furthermore, when used as an immunosuppressant, the drug may generate detrimental neurological side effects in patients with an additional hereditary neuropathy.
Ip
Chi Wang
CW
Department of Neurology, Developmental Neurobiology, University of Wuerzburg, Josef-Schneider-Str. 11, D-97080 Wuerzburg, Germany.
Kroner
Antje
A
Kohl
Bianca
B
Wessig
Carsten
C
Martini
Rudolf
R
D000818:Animals; D001369:Axons / Q000187:drug effects / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D002607:Charcot-Marie-Tooth Disease / Q000188:drug therapy / Q000503:physiopathology; D003711:Demyelinating Diseases / Q000188:drug therapy / Q000276:immunology / Q000503:physiopathology*; D004195:Disease Models, Animal; D005434:Flow Cytometry; D007150:Immunohistochemistry; D007166:Immunosuppressive Agents / Q000633:toxicity*; D008264:Macrophages / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008854:Microscopy, Electron; D018993:Myelin P0 Protein / Q000235:genetics; D009186:Myelin Sheath / Q000187:drug effects* / Q000473:pathology; D009431:Neural Conduction; D010525:Peripheral Nerves / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D013154:Spleen / Q000378:metabolism; D016559:Tacrolimus / Q000633:toxicity*
D007166:Immunosuppressive Agents; D018993:Myelin P0 Protein; D016559:Tacrolimus