FK506 reduces infarct volume due to permanent focal cerebral ischemia by maintaining BAD turnover and inhibiting cytochrome c release.

Abstract

It has been reported that immunosuppressant FK506 inhibited ischemic neuronal injury in forebrain ischemia or transient focal cerebral ischemia, but the mechanisms of the neuroprotective effect have not been clarified. In permanent focal cerebral ischemia, we investigated whether FK506 caused remission of brain infarction, and how mechanism was concerned. Male Balb/c mice were subjected to permanent middle cerebral artery (MCA) occlusion. They were treated with 1.0 or 3.0 mg/kg FK506 or vehicle 30 min before ischemia. Infarct volume was assessed by 2,3,5-triphenyltetrazolium chloride (TTC) method after 24 h. Cytochrome c release from mitochondria was evaluated by Western blotting and immunocytochemistry after ischemia. Simultaneously, the immunoreactivity of total and phosphorylated BAD was also studied using immunocytochemistry. We demonstrated that pretreatment with 3.0 mg/kg FK506 salvaged the tissue damage in the infarct rim and significantly reduced infarct volume to 75.5% (P<0.05), and FK506 inhibited cytochrome c release on 6 h after ischemia for Western blot analysis (P<0.05). Immunocytochemical study showed that permanent MCA occlusion increased the amount of cytochrome c and total BAD in the cytosol, but not phosphorylated BAD, in the ischemic core and the infarct rim as early as 1 h after ischemia, and FK506 inhibited the increases in the infarct rim. The results suggest that FK506 may, at least in part, ameliorate tissue damage due to permanent focal cerebral ischemia in the infarct rim through maintaining BAD turnover and inhibiting cytochrome c release from mitochondria.

• Authors: Hideo Shichinohe, Satoshi Kuroda, Takeo Abumiya, Jun Ikeda, Tohru Kobayashi, Tetsuyuki Yoshimoto, Yoshinobu Iwasaki
• Journal: Brain research (Brain Res) Vol. 1001 Issue 1-2 Pg. 51-9 (Mar 19 2004) ISSN: 0006-8993 [Print] Netherlands
• PMID: 14972653 (Publication Type: Comparative Study, Journal Article)

Chemical References

• Bad protein, mouse
• Carrier Proteins
• Immunosuppressive Agents
• Tetrazolium Salts
• bcl-Associated Death Protein
• triphenyltetrazolium
• Cytochromes c
• Tacrolimus

Topics

• Analysis of Variance
• Animals
• Blotting, Western (methods)
• Brain Infarction (drug therapy, etiology, pathology)
• Carrier Proteins (metabolism)
• Cytochromes c (metabolism)
• Dose-Response Relationship, Drug
• Immunohistochemistry (methods)
• Immunosuppressive Agents (therapeutic use)
• Infarction, Middle Cerebral Artery (complications, drug therapy)
• Male
• Mice
• Mice, Inbred BALB C
• Neocortex (metabolism, pathology)
• Phosphorylation
• Tacrolimus (therapeutic use)
• Tetrazolium Salts
• Time Factors
• bcl-Associated Death Protein