Role of Glucocorticoids on Rat Brain Metallothionein-I and -III Response to Stress

The metallothionein (MT) gene family consists of four members (MT-I through -IV) that are tightly regulated during development. Whereas MT-I and MT-II are widely expressed isoforms, MT-III has been found to be mainly expressed in the central nervous system in adult animals, and is the only isoform that inhibits survival and neurite formation of cortical neurons in vitro. A number of models of brain injury have been shown to affect MT-III mRNA levels, which has been suggested to be related to the putative neurotrophic role of this protein. However, a stress response will presumably be associated to the brain injury which could, in turn, drive MT-III regulation. In the present report the effect of a classical stress model, immobilization stress, on brain MT regulation has been studied in rats. MT-I+II protein levels were measured by radioimmunoassay in up to eight brain areas and, as expected, it was found that stress increased selectively MT-I+II levels. Adrenalectomy (ADX) had a general decreasing effect on basal MT-I+II levels; however, ADX blunted the MT-I+II response to stress in cerebellum and presumably in frontal cortex and medulla plus pons but not in the hypothalamus. MT-I mRNA measurements were in accordance with the MT-I+II protein levels in the brain areas studied. In contrast to MT-I mRNA, MT-III mRNA levels of brain cortex tended to decrease during stress, although this effect was not statistically significant. ADX also tended to decrease basal MT-III mRNA levels. Northern blot assays of pooled mRNAs suggested similar differential regulation of these two brain MT isoforms in the cerebellum. These results indicate that glucocorticoids mediate brain MT-I+II response to stress in some but not all brain areas, that a role of these hormones is likely also for MT-III, and that the regulation of MT isoforms differs substantially in the brain.