Circadian Role of Vitamin A in Regulation of Redox State

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DESCRIPTION (provided by applicant): Vitamin A deficiency persists as a problem of significant public health concern in many developing countries. In Argentina 10-20 % of school-aged children are documented to be clinically vitamin A deficient. Recently, a role for vitamin A has been established in phenomena related to higher cognitive function in the adult mouse and rat brain. On the other hand, it has been shown that vitamin A deficiency results in an enhanced production of free radicals and lipid peroxidation. It is also known that lipoperoxidation and antioxidant defense system activities follow a daily variation and therefore, are under the control of cellular rhythm regulatory mechanisms. There is evidence that vitamin A and its derivatives, the retinoids, may contribute to the regulation of cell clock gene activation through retinoid nuclear receptors. Since vitamin A deficiency is known to lead to oxidative stress and lipoperoxidation and that increased levels of reactive oxygen species in the brain might contribute to reduced daily cognitive capacity, it would be important to define the role of vitamin A in the circadian expression of oxidative parameters and antioxidant enzymes, particularly in hippocampus, as it is the brain area related to learning and memory. The long-term goal is to understand how environmental and nutritional factors regulate the expression of clock and clock-controlled genes and thus the circadian metabolic, physiological and behavioral activities of a healthy individual. The objective of this application is to determine the impact of vitamin A deficiency on the circadian expression of lipid peroxidation and antioxidant genes in liver and hippocampus. The central hypothesis is that vitamin A deficiency modifies the circadian pattern of lipoperoxidation and affects the clock-controlled gene expression of antioxidant enzymes by modifying the daily availability of retinoid nuclear receptors and/or the cellular redox state. Understanding how vitamin A deficiency affects circadian patterns of lipoperoxidation and antioxidant defenses may contribute to establish a role for vitamin A in the circadian regulation of redox environment in the hippocampus, in order to get an improved cognitive daily performance.