Evidence for a protective role of metallothionein-1 in focal cerebral ischemia

Metallothioneins (MTs) are a family of metal binding proteins that have bee n proposed to participate in a cellular defense against zinc toxicity and f ree radicals. In the present study, we investigated whether increased expre ssion of MT in MT-I isoform-overexpressing transgenic mice (MT-TG) affords protection against mild focal cerebral ischemia and reperfusion. Transient focal ischemia was induced in control (wild type) and MT-TC mice by occludi ng the right middle cerebral artery far 45 min. Upon reperfusion, cerebral edema slowly developed and peaked at 24 hr as shown by R-weighted MRI. The volume of affected tissue was on the average 42% smaller in MT-TG mice comp ared with control mice at 6, 9, 24, and 72 hr and 14 days postreperfusion ( P < 0.01). In addition, functional studies showed that 3 weeks after reperf usion MT-TG mice showed a significantly better motor performance compared w ith control mice (P = 0.011). Although cortical baseline levels of MT-1 mRN A were similar in control and MT-TG mice, there was an increase in MT-1 mRN A levels in the ischemic cortex of MT-TG mice to 7.5 times baseline levels compared with an increase to 2.3 times baseline levels in control mice 24 h r after reperfusion, In addition, MT-TG mice showed an increased MT immunor eactivity in astrocytes, vascular endothelial cells, and neurons 24 hr afte r reperfusion whereas in control mice MT immunoreactivity was restricted ma inly to astrocytes and decreased in the infarcted tissue. These results pro vide evidence that increased expression of MT-1 protects against focal cere bral ischemia and reperfusion.