Abstract
Metallothionein-II (MT-II) is an ubiquitously expressed small-molecular-weight protein and highly induced in various species and tissues upon stress, inflammation, and ischemia. MT-deficiency exacerbates ischemic injury in rodent stroke models in vitro and in vivo. However, there is conflicting data on the potential neuroprotective effect of exogenously applied metallothionein. Thus, we applied MT-II in an in vitro stroke model and intraperitoneally (i.p.) in two in vivo standard models of transient middle cerebral artery occlusion (MCAO) (a ‘stringent’ one [60min MCAO/48h reperfusion] and a ‘mild’ one [30min MCAO/72h reperfusion]), as well as i.v. together with recombinant tissue plasminogen activator (rtPA) to evaluate if exogenous MT-II-application protects against ischemic stroke. Whereas MT-II did not protect against 60min MCAO, there was a significant reduction of direct and indirect infarct volumes and neurological deficit in the MT-II (i.p.) treated animals in the ‘mild’ model at 3d after MCAO. Furthermore, MT-II also improved survival of the mice after MCAO, suppressed TNF-α mRNA induction in ischemic brain tissue, and protected primary neuronal cells against oxygen-glucose-deprivation in vitro. Thus, exogenous application of MT-II protects against ischemic injury in vitro and in vivo. However, long-term studies with different species and larger sampling sizes are required before a clinical use can be envisaged.
Highlights
Ischemic stroke is the second leading cause of death worldwide and the absolute number of stroke patients is still increasing despite a decrease in age-standardized rates of stroke mortality in the last two decades [1]
We tested if exogenous metallothionein-II is able to protect primary neuronal cells against ischemic injury in vitro
Rat primary neuronal cells incubated with various concentrations of exogenous metallothionein-II were exposed to oxygen- glucose deprivation (OGD) for 3.5h
Summary
Ischemic stroke is the second leading cause of death worldwide and the absolute number of stroke patients is still increasing despite a decrease in age-standardized rates of stroke mortality in the last two decades [1]. Ischemic brain injury is caused by a complex cascade of pathophysiological events including exitotoxicity, peri-infarct depolarizations, apoptosis, and inflammation [2,3]. Manifold interventions have been proven successful in experimental stroke studies. Most of them failed in the clinical studies with human stroke patients [4].
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