ing in neuronal damage and death in a variety of brain regions (Frederickson et al., 2004; Sensi and Jeng, 2004).
Traumatic brain injury (TBI) induces a variety of damaging oxidative processes, and a number of studies show a role for zinc deficiency in the induction of reactive oxygen species (ROS). Zinc deficiency may therefore exacerbate the oxidative damage associated with TBI. This hypothesis is supported by work in cultured rat neurons (differentiated PC12 cells) showing that deficiencies in extracellular zinc resulted in an increase in neuronal oxidation via the activation of the NMDA receptor. This in turn led to calcium influx and to the calcium-mediated activation of protein kinase C/NADPH (nicotinamide adenine dinucleotide phosphate) oxidase as well as nitric oxide synthase (Aimo et al., 2010). Other work has implicated zinc deficiency in mitochondrial accumulation and release of ROS (Corniola et al., 2008). This mechanism is dependent on the tumor suppressor protein p53. Nuclear targets of p53 in zinc deficiency include genes that arrest the cell cycle and induce apoptotic mechanisms leading to cell death (Corniola et al., 2008). Finally, in response to TBI, anti-oxidant mechanisms are increased in the brain. For example, increases in several isoforms (I, II, and III) of the zinc- and copper-binding protein metallothionein have been reported after brain injury (Penkowa et al., 2001; Yeiser et al., 1999). Zinc deficiency blunts this response. Because the metal-binding metallothioneins have been shown to play an antioxidant role, these data suggest that zinc deficiency may impair antioxidant mechanisms that are needed to protect neurons and other cell types in the brain after TBI.
A relevant selection of human and animal studies (from the year 1990) examining the effectiveness of zinc supplementation on providing resilience or treating TBI in the acute and subacute phases of injury is presented in Table 16-1. This table also includes some supporting evidence from human studies on zinc supplementation for other CNS injuries, such as stroke and seizure. The occurrence or absence of adverse effects in humans is included if reported by the authors.
Dietary requirements for zinc are determined not only by the roles of zinc in the brain, but also by the necessity of adequate zinc for immune function, tissue repair and replacement, nutrient digestion, and energy metabolism in all organ systems. There is, however, no single widely accepted or routinely available biomarker for zinc status (IOM, 2006). Marginal zinc deficiency is particularly difficult to identify and is thus likely to go unrecognized. The Committee on Mineral Requirements for Cognitive and Physical Performance of Military Personnel (IOM, 2006) reported that high-intensity exercise can increase urinary zinc excretion by 20–40 percent. This, combined with severe environmental conditions that promote sweating, means that many active-duty military personnel have high zinc losses. These losses must be replaced by dietary intake.
The current Recommended Dietary Allowance (RDA) for zinc in the general population is 9 mg/day for females between the ages of 14 and 18, 8 mg/day for females 19 years and older, and 11 mg/day for males 14 years and older. In the general population, data from the National Health and Nutrition Examination Survey (2002) suggest that 11 percent of males and 17 percent of females have regular intakes below the recommended amounts. Owing to the increased requirements resulting from physical activity and potential increased excretion (via sweat and urine, as well as increased muscle turnover), the Military Daily Recommended Intake (MDRI) for zinc is 12 mg/day for females and 15 mg/day for males (IOM, 2006). Revisions to the MDRIs, based on current DRIs, are imminent.
Because of zinc’s important role in the modulation of immunity, zinc supplements have