The importance of Zn in brain function and neurobiology is widely acknowledged, and many human neurological diseases have been linked to Zn deficiency. However, the mechanism by which dietary Zn deficiency may lead to pathology in the brain, an organ highly susceptible to oxidative damage, is not yet clear. Investigations into the effect of oxidative stress on brain function are often complicated by the high propensity of brain tissue to develop artifactual indices of oxidative stress in vivo. We will pioneer the application of non-invasive in vivo MRI and 31P-NMR techniques to study the role of Zn nutrition in maintaining the integrity of the blood brain barrier(BBB) and brain energy metabolism under oxidative stress. Further, we will identify possible cellular and molecular mechanisms for Zn deficiency pathology under oxidative stress. Hence the focus of this proposal is to examine the role of Zn nutrition in coping with oxidative stress to prevent brain disorders. The long term goal of this research is to understand the basic mechanism underlying the relationship between dietary Zn and optimal central nervous system(CNS) function. We speculate that sub-optimal Zn nutrition weakens BBB integrity and that oxidative stress superimposed upon Zn deficiency disrupts the protective function of the BBB, an event that may be pivotal in the pathogenesis of many brain disorders. Consequently, perturbations of cerebral homeostasis following loss of BBB integrity may lead to impaired energy metabolism and increased oxidative stress within the brain, a sequence of metabolic and biochemical changes by which Zn deficiency may contribute to the development of brain disorders. Thus, the hypothesis of this project is that Zn protects the BBB against oxidative stress through its antioxidant and membrane stabilization properties and therefore helps to maintain the homeostasis of brain metabolism and prevent brain disorders. To test this hypothesis, we will quantify changes in BBB permeability and brain energy metabolism, assess the balance between free radical defense and free radical generation, and measure the extent of oxidative damage in the brain of Zn deficient rats during exposure to hyperoxia. In addition, the possible underlying mechanisms will be explored. This research will contribute significantly to our understanding of the mechanistic roles of Zn in the etiology of brain disorders and lead to the development of better strategies for disease prevention.
