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Combination therapy with transductive anti‐death FNK protein and FK506 ameliorates brain damage with focal transient ischemia in rat
Author(s) -
Katsura Kenichiro,
Takahashi Kumiko,
Asoh Sadamitsu,
Watanabe Megumi,
Sakurazawa Makoto,
Ohsawa Ikuroh,
Mori Takashi,
Igarashi Hironaka,
Ohkubo Seiji,
Katayama Yasuo,
Ohta Shigeo
Publication year - 2008
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2008.05360.x
Subject(s) - medicine , ischemia , pharmacology , apoptosis , adverse effect , chemistry , biochemistry
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‐ x l derivative with three amino acid‐substitutions (Y22 F , Q26 N and R165 K ) (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.