Ip Chi Wang, Kroner Antje, Kohl Bianca, Wessig Carsten, Martini Rudolf
Department of Neurology, Developmental Neurobiology, University of Wuerzburg, Josef-Schneider-Str. 11, D-97080 Wuerzburg, Germany.
Neurobiol Dis. 2009 Feb;33(2):207-12. doi: 10.1016/j.nbd.2008.10.008. Epub 2008 Nov 5.
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.
髓鞘蛋白零基因杂合或纯合缺陷的小鼠（P0+/-、P0-/-小鼠）分别是遗传性脱髓鞘或髓鞘形成异常性神经病不同形式的模型。P0+/-小鼠表现为脱髓鞘性神经病，CD8+T淋巴细胞和巨噬细胞具有致病作用，而P0-/-小鼠表现为髓鞘形成异常并伴有轴突丧失。因此，用具有免疫抑制和神经保护特性的药物FK506（他克莫司）治疗这两种突变体很有意义。用FK506治疗P0+/-小鼠导致脱髓鞘加重，对神经CD8+T淋巴细胞无影响，但减少了脾脏CD4+细胞。用FK506治疗P0-/-小鼠导致与髓鞘形成异常相关的轴突丧失大幅增加。用FK506治疗野生型小鼠未引起周围神经的病理变化。我们的研究表明，FK506可能不适用于治疗人类神经疾病。此外，当用作免疫抑制剂时，该药物可能会给患有其他遗传性神经病的患者带来有害的神经副作用。
