Metallothionein-III knockout mice aggravates the neuronal damage after transient focal cerebral ischemia

• Published in: Brain research Vol. 1292; pp. 148 - 154
• Main Authors: Koumura, Akihiro, Hamanaka, Junya, Shimazawa, Masamitsu, Honda, Akiko, Tsuruma, Kazuhiro, Uchida, Yoko, Hozumi, Isao, Satoh, Masahiko, Inuzuka, Takashi, Hara, Hideaki
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier B.V 25.09.2009; Elsevier
• Subjects: Animals; Biological and medical sciences; Brain - pathology; Brain - physiopathology; Cell Count; Deoxyguanosine - analogs & derivatives; Female; In Situ Nick-End Labeling; Infarction, Middle Cerebral Artery - mortality; Infarction, Middle Cerebral Artery - pathology; Infarction, Middle Cerebral Artery - physiopathology; Male; Medical sciences; Metallothionein-III; Mice; Mice, Inbred Strains; Mice, Knockout; Middle cerebral artery occlusion; Nerve Tissue Proteins - deficiency; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Neurology; Neurons - pathology; Neurons - physiology; Oxidative stress; Random Allocation; Reperfusion; Reperfusion Injury - mortality; Reperfusion Injury - pathology; Reperfusion Injury - physiopathology; Time Factors; Vascular diseases and vascular malformations of the nervous system; MCAO; Oxidative stress; TTC; GIF; CBF; MT; CNS; 8-hydroxy-2′-deoxyguanosine; metallothionein; Metallothionein-III; growth inhibitory factor; central nervous system; TUNEL; Reperfusion; terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling; cerebral blood flow; 2,3,5-triphenyltetrazolium chloride; middle cerebral artery occlusion; 8-OHdG; Middle cerebral artery occlusion; Nervous system diseases; Rodentia; Central nervous system; Cardiovascular disease; Cerebral disorder; Encephalon; Vascular disease; Vertebrata; Mammalia; Mouse; Animal; Central nervous system disease; Knockout mouse; Brain ischemia; Mutation; Cerebrovascular disease; Metallothionein
• ISSN: 0006-8993; 1872-6240
• DOI: 10.1016/j.brainres.2009.07.050

Abstract 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.