Cilostazol reduces ischemic brain damage partly by inducing metallothionein-1 and -2.
The neuroprotective effect of cilostazol, an antiplatelet drug, was examined after 24 h permanent middle cerebral artery (MCA) occlusion in mice, and explored the possible underlying mechanism by examining metallothionein (MT)-1 and -2 induction in vivo. Cilostazol (30 mg/kg) was intraperitoneally administered at 12 h before, 1 h before, and just after MCA occlusion. Mice were euthanized at 24 h after the occlusion, and the neuronal damage was evaluated using 2,3,5-triphenyltetrazolium chloride (TTC) staining. Cilostazol significantly reduced the infarct area and volume, especially in the cortex. Real-time RT-PCR revealed increased mRNA expressions for MT-1 and -2 in the cortex of normal brains at 6 h after cilostazol treatment without MCA occlusion. MT-1 and -2 immunoreactivity was also increased in the cortex of such mice, and this immunoreactivity was observed in the ischemic hemisphere at 24 h after MCA occlusion (without cilostazol treatment). The strongest MT-1 and -2 immunoreactivity was detected in MCA-occlused mice treated with cilostazol [in the peri-infarct zone of the cortex (penumbral zone)]. These findings indicate that cilostazol has neuroprotective effects in vivo against permanent focal cerebral ischemia, especially in the penumbral zone in the cortex, and that MT-1 and -2 may be partly responsible for these neuroprotective effects.
Wakida
K
K
Department of Biofunctional Molecules, Gifu Pharmaceutical University, 5-6-1 Mitahora-higashi, Gifu 502-8585, Japan.
Morimoto
N
N
Shimazawa
M
M
Hozumi
I
I
Nagase
H
H
Inuzuka
T
T
Hara
H
H
D000818:Animals; D002545:Brain Ischemia / Q000473:pathology* / Q000517:prevention & control*; D002540:Cerebral Cortex / Q000473:pathology; D000077407:Cilostazol; D004790:Enzyme Induction / Q000187:drug effects; D007150:Immunohistochemistry; D020243:Infarction, Anterior Cerebral Artery / Q000473:pathology; D008297:Male; D008668:Metallothionein / Q000096:biosynthesis*; D051379:Mice; D008810:Mice, Inbred C57BL; D020768:Middle Cerebral Artery / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013777:Tetrazoles / Q000494:pharmacology*
C491054:Mt2 protein, mouse; D018696:Neuroprotective Agents; D013777:Tetrazoles; D008668:Metallothionein; D000077407:Cilostazol