Regulation of metallothionein concentrations in rat brain: effect of glucocorticoids, zinc, copper, and endotoxin

Abstract

The effects of known inducers of liver metallothionein (MT) synthesis on MT concentrations in the rat brain have been determined using antibodies that are specific for MT I and II and do not cross-react with MT III. There were substantial differences in the MT concentrations in different areas of the brain. Dexamethasone increased MT levels after 24 h in the frontal cortex, cortex, medulla oblongata plus pons, midbrain, striatum, hippocampus, and cerebellum but not in the hypothalamus. Corticosterone produced similar results except in the hippocampus. Long-lasting adrenocorticotropic hormone increased MT concentrations after 12 h in midbrain and striatum but not in the liver. Adrenalectomy decreased MT concentrations after 6 days in the medulla oblongata plus pons, striatum, hippocampus, and hypothalamus but increased concentrations in the liver and kidneys; these effects were reversed by corticosterone. The role of glucocorticoids in the regulation of MT levels therefore differs between tissues and within specific areas of the brain. Injection of zinc or copper intracerebroventricularly and the use of a zinc-deficient diet increased and decreased MT levels, respectively, in some but not all brain areas. Endotoxin increased liver MT but not brain MT I levels after 8 h.

Induction of metallothionein in astrocytes and microglia in the spinal cord from the myelin-deficient jimpy mouse

“…In the spinal cord, the mean microglial densities in the mutant white matter Ž . Ž are about threefold 10-12 days and fivefold [20][21][22] . days higher than in normal animals.…”

The Stoichiometric Transition from Zn6Cu1-Metallothionein to Zn7-Metallothionein Underlies the Up-regulation of Metallothionein (MT) Expression

“…The reason for this high diversity of MT isoforms is currently unknown. MT1 and MT2 can be induced in vivo by factors including zinc (5), glucocorticoids (6), cytokines such as IL-6 and TNF␣ (7)(8)(9), and regulatory response elements in their genes (10).…”

Brain Metallothionein in Stress

“…Since stress caused by surgery associated with intracerebroventricular (i.c.v.) administration of saline or ether anesthesia was not able to induce MT levels in any of the eight brain areas studied [66], it may be concluded that brain MT is also sensitive to the intensity/length of exposure to the stressor.…”

“…These results were confirmed and extended in a study from our laboratory, which indicated MT induc tion by zinc (0.44 pmol i.e.v. in the third ven tricle) in some but not all rat brain areas, a process apparently driven by increased zinc uptake [66]. Thus, zinc can induce brain MT levels and, as stated above, restraint stress increases extracellular zinc levels in some brain areas [47], After measuring cytosolic zinc levels in the same brain areas where MT levels have been measured, however, it ap pears that no clear parallelism can be drawn between zinc and MT levels in basal situa tions ( fig.…”

“…5). Furthermore, adrenalectomy de creases brain MT levels in some brain areas, an effect reversed by corticosterone therapy [66]. Thus, glucocorticoids appear to be in volved in brain MT regulation in basal condi tions, and are logical candidates for mediat ing the putative effect of stress on brain MT levels.…”