Zinc or copper deficiency-induced impaired inflammatory response to brain trauma may be caused by the concomitant metallothionein changes

The role of zinc- and copper-deficient diets on the inflammatory response t o traumatic brain injury (TBI) has been evaluated in adult rats. As expecte d, zinc deficiency decreased food intake and body weight gain, and the latt er effect was higher than that observed in pair-fed rats. In noninjured bra ins, zinc deficiency only affected significantly lectin (increasing) and gl ial fibrillary acidic protein (GFAP) and Cu,Zn-superoxide dismutase (Cu,Zn- SOD) (decreasing) immunoreactivities (irs). In injured brains, a profound g liosis was observed in the area surrounding the lesion, along with severe d amage to neurons as indicated by neuron specific enolase (NSE) ir, and the number of cells undergoing apoptosis (measured by TUNEL) was dramatically i ncreased. Zinc deficiency significantly altered brain response to TBI, pote ntiating the microgliosis and reducing the astrogliosis, while increasing t he number of apoptotic cells. Metallothioneins (MTs) are important zinc- an d copper-binding proteins in the CNS, which could influence significantly t he brain response to TBI because of their putative roles in metal homeostas is and antioxidant defenses. MT-I+II expression was dramatically increased by TBI, and this response was significantly blunted by zinc deficiency. The MT-III isoform was moderately increased by both TBI and zinc deficiency. T BI strongly increased oxidative stress levels, as demonstrated by malondial dehyde (MDA), protein tyrosine nitration (NITT), and nuclear factor kappaB (NF-kappaB) levels irs, all of which were potentiated by zinc deficiency. F urther analysis revealed unbalanced expression of prooxidant and antioxidan t proteins besides MT, since the levels of inducible nitric oxide synthase (iNOS) and Cu,Zn-SOD were increased and decreased, respectively, by zinc de ficiency. All these effects were attributable to zinc deficiency, since pai r-fed rats did not differ from normally fed rats. In general, copper defici ency caused a similar pattern of responses, albeit more moderate. Results o btained in mice with a null mutation for the MT-I+II isoforms strongly sugg est that most of the effects observed in the rat brain after zinc and coppe r deficiencies are attributable to the concomitant changes in the MT expres sion.