Metallothionein-III knockout mice aggravates the neuronal damage after transient focal cerebral ischemia.
Metallothioneins (MTs) are metal-binding proteins and have four isoforms. MT-III was, at first, found in the brains of patients with Alzheimer's disease. MT-III exists mainly in the central nervous system, and the main effects are thought to be anti-oxidative and regulate zinc levels. In some previous reports, MT-III exhibited neuroprotective effects in various pathological situations, but its detailed effects are still unclear. In the present study, we examined neuronal damage after a middle cerebral artery occlusion (MCAO) in MT-III knockout (KO) mice to elucidate the relationship between MT-III and cerebral infarction. There was no significant difference in cerebral infarction after 24-h permanent MCAO between the wild-type and MT-III KO mice. On the other hand, after 2-h MCAO and 22-h reperfusion, cerebral infarction in the MT-III KO mice was aggravated compared with the wild-type mice. Furthermore, fatal rate of MT-III KO mice increased from 3 days after MCAO, and neurological deficits at 5 and 7 days after MCAO of MT-III KO mice were worse than those of wild-type. We examined terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) staining and the immunostaining of an oxidative stress marker, 8-hydroxy-2'-deoxyguanosine (8-OHdG), at 24 h after transient MCAO. In the penumbra lesion, the positive cell numbers in both staining assays were higher in the MT-III KO mice than those of the wild-type mice. These findings indicate that neuronal damage was aggravated by reperfusion injury in the MT-III KO mice compared with the wild-type mice, suggesting that MT-III plays anti-oxidative and neuroprotective roles in transient cerebral ischemia.
Koumura
Akihiro
A
Department of Biofunctional Evaluation, Molecular Pharmacology, Gifu Pharmaceutical University, Japan.
Hamanaka
Junya
J
Shimazawa
Masamitsu
M
Honda
Akiko
A
Tsuruma
Kazuhiro
K
Uchida
Yoko
Y
Hozumi
Isao
I
Satoh
Masahiko
M
Inuzuka
Takashi
T
Hara
Hideaki
H
D000080242:8-Hydroxy-2'-Deoxyguanosine; D000818:Animals; D001921:Brain / Q000473:pathology / Q000503:physiopathology*; D002452:Cell Count; D003849:Deoxyguanosine / Q000031:analogs & derivatives; D005260:Female; D020287:In Situ Nick-End Labeling; D020244:Infarction, Middle Cerebral Artery / Q000401:mortality / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D000090023:Metallothionein 3; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000473:pathology / Q000502:physiology*; D011897:Random Allocation; D015427:Reperfusion Injury / Q000401:mortality / Q000473:pathology / Q000503:physiopathology; D013997:Time Factors
D000090023:Metallothionein 3; D009419:Nerve Tissue Proteins; D000080242:8-Hydroxy-2'-Deoxyguanosine; D003849:Deoxyguanosine