Combination therapy with transductive anti-death FNK protein and FK506 ameliorates brain damage with focal transient ischemia in rat.
Combination therapy with transductive anti-death FNK protein and FK506 ameliorates brain damage with focal transient ischemia in rat.
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DOI：
10.1111/j.0022-3042.2008.05360.x
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发表时间：
2008-07
影响因子：
4.7
通讯作者：
K. Katsura;Kumiko Takahashi;S. Asoh;Megumi Watanabe;M. Sakurazawa;I. Ohsawa;Takashi Mori;H. Igarashi;Seiji Ohkubo;Y. Katayama;S. Ohta
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文献类型：
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作者：
K. Katsura;Kumiko Takahashi;S. Asoh;Megumi Watanabe;M. Sakurazawa;I. Ohsawa;Takashi Mori;H. Igarashi;Seiji Ohkubo;Y. Katayama;S. Ohta
许多实用疗法已被探索作为缺血性脑梗塞的临床应用，然而，大多数仍不足以治疗急性卒中。我们在这里展示了一种在大鼠局灶性脑缺血模型中潜在的联合治疗方法，以改善神经症状，并最大限度地减少脑梗塞体积。我们应用了具有三个氨基酸取代基(Y22F、Q26N和R165K)(FNK)的人工抗死亡Bcl-XL衍生物(FNK)与蛋白转导结构域肽(PTD-FNK)融合的蛋白质转导技术。缺血1h后给予免疫抑制剂FK506，延迟30min后给予PTD-FNK，可使全脑和皮质的脑梗塞体积分别减少到27%和14%。该手术不仅缩小了脑梗塞体积和水肿，而且明显改善了神经症状。治疗效果在缺血后至少持续1周。FK506在体外抑制PTD-FNK的转导，这解释了FK506给药时滞的要求。另一项体外实验表明，PTD-FNK在FK506前30min给药时，通过降低细胞内钙离子浓度而获得最大的保护作用。我们认为，这种联合治疗将提供两种药物的协同保护作用，减少FK506的不良影响。
Many practical therapies have been explored as clinical applications for ischemic cerebral infarction; however, most are still insufficient to treat acute stroke. We show here a potential combination therapy in a rat focal ischemic model to improve neurological symptoms as well as to reduce infarct volumes at the maximum level. We applied protein transduction technology using artificial anti-death Bcl-xl derivative with three amino acid-substitutions (Y22F, Q26N and R165K) (FNK) protein fused with a protein-transduction-domain peptide (PTD-FNK). When PTD-FNK was administrated 1 h after initiating ischemia followed by the administration of an immunosuppressant FK506 with a 30-min time lag, infarct volumes of the total brain and cortex were markedly reduced to 27% and 14%, respectively. This procedure not only reduced the infarct volume and edema, but also markedly improved neurological symptoms. The therapeutic effect continued for at least 1 week after ischemia. FK506 inhibited the transduction of PTD-FNK in vitro, which explains the requirement of a time lag for the administration of FK506. An additional in vitro experiment showed that PTD-FNK, when administered 30 min before FK506, gave the maximal protective effect by reducing the intracellular calcium concentration. We propose that this combination therapy would provide a synergistic protective effect by both drugs, reducing adverse the effects of FK506.