Metallothioneins are multipurpose neuroprotectants during brain pathology

Metallothioneins (MTs) constitute a family of cysteine‐rich metalloproteins involved in cytoprotection during pathology. In mammals there are four isoforms (MT‐I − IV), of which MT‐I and ‐II (MT‐I + II) are the best characterized MT proteins in the brain. Accumulating studies have demonstrated MT‐I + II as multipurpose factors important for host defense responses, immunoregulation, cell survival and brain repair. This review will focus on expression and roles of MT‐I + II in the disordered brain. Initially, studies of genetically modified mice with MT‐I + II deficiency or endogenous MT‐I overexpression demonstrated the importance of MT‐I + II for coping with brain pathology. In addition, exogenous MT‐I or MT‐II injected intraperitoneally is able to promote similar effects as those of endogenous MT‐I + II, which indicates that MT‐I + II have both extra‐ and intracellular actions. In injured brain, MT‐I + II inhibit macrophages, T lymphocytes and their formation of interleukins, tumor necrosis factor‐α, matrix metalloproteinases, and reactive oxygen species. In addition, MT‐I + II enhance cell cycle progression, mitosis and cell survival, while neuronal apoptosis is inhibited. The precise mechanisms downstream of MT‐I + II have not been fully established, but convincing data show that MT‐I + II are essential for coping with neuropathology and for brain recovery. As MT‐I and/or MT‐II compounds are well tolerated, they may provide a potential therapy for a range of brain disorders.