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Abstract
Experiments with transgenic over-expressing, and null mutant mice have determined that metallothionein-I and -II (MT-I/II) are protective after brain injury. MT-I/II is primarily a zinc-binding protein and it is not known how it provides neuroprotection to the injured brain or where MT-I/II acts to have its effects. MT-I/II is often expressed in the liver under stressful conditions but to date, measurement of MT-I/II expression after brain injury has focused primarily on the injured brain itself. In the present study we measured MT-I/II expression in the liver of mice after cryolesion brain injury by quantitative reverse-transcriptase PCR (RT-PCR) and enzyme-linked immunosorbent assay (ELISA) with the UC1MT antibody. Displacement curves constructed using MT-I/II knockout (MT-I/II−/−) mouse tissues were used to validate the ELISA. Hepatic MT-I and MT-II mRNA levels were significantly increased within 24 hours of brain injury but hepatic MT-I/II protein levels were not significantly increased until 3 days post injury (DPI) and were maximal at the end of the experimental period, 7 DPI. Hepatic zinc content was measured by atomic absorption spectroscopy and was found to decrease at 1 and 3 DPI but returned to normal by 7DPI. Zinc in the livers of MT-I/II−/− mice did not show a return to normal at 7 DPI which suggests that after brain injury, MT-I/II is responsible for sequestering elevated levels of zinc to the liver. Conclusion: MT-I/II is up-regulated in the liver after brain injury and modulates the amount of zinc that is sequestered to the liver.
Highlights
Metallothionein (MT) is a 6–7 kDa, cysteine rich, metal binding protein that has been shown to be neuroprotective during central nervous system (CNS) insults in studies utilising transgenic MT-I over-expressing animals [1,2,3] and MT-I/II2/2 mice [4,5,6,7,8,9,10,11]
MT-I/II expression is induced by increased intracellular zinc concentration, glucocorticoids and IL-6 [29] which indicates that MT-I/II expression may occur in conjunction with the acute phase response
The observations presented are consistent with a model whereby zinc is released from cellular stores in the liver following brain injury, and that increased MT-I/II expression functions to return zinc to the liver
Summary
Metallothionein (MT) is a 6–7 kDa, cysteine rich, metal binding protein that has been shown to be neuroprotective during central nervous system (CNS) insults in studies utilising transgenic MT-I over-expressing animals [1,2,3] and MT-I/II2/2 mice [4,5,6,7,8,9,10,11] It is not MT-III, the brain-specific isoform of MT, that provides neuroprotection [12] but the MT-I and MT-II isoforms that provide the most neuroprotection after brain injury. MT-I/II expression is induced by increased intracellular zinc concentration, glucocorticoids and IL-6 [29] which indicates that MT-I/II expression may occur in conjunction with the acute phase response
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