Title : Role of Dietary Zinc in the Development, Prevention, & Treatment of Depression
Abstract:
It has been known for a number of years that patients diagnosed with depression have low serum zinc levels. Use of pre-clinical models have enabled us to establish a causative role for zinc deficiency in the development in depression-like behaviours including anorexia, anxiety, and anhedonia. Clinical and pre-clinical work have shown that dietary zinc deficiency may impair the efficacy of anti-depressant drugs and that zinc supplementation may benefit some patients who are on anti-depressant medications, including the commonly prescribed serotonin reuptake inhibitors (SSRIs). Pre-clinical models have the advantage of permitting the identification of cellular and molecular mechanisms of zinc action in the brain that provide new therapeutic targets for treating mood disorders. One particularly strong pre-clinical model is depression induced by traumatic brain injury (TBI). While patients with all forms of TBI report depression, severe cases have significant zinc loss and are particularly vulnerable to depression. The controlled cortical impact model of TBI results in depression-like behaviors as well as impairments in learning and memory. The two-bottle saccharin preference test for anhedonia revealed that dietary zinc supplementation, combined with an early i.p. zinc injection significantly reduced anhedonia (p<0.001). Our data also suggest a role for chronic supplemental zinc in preventing cognitive and behavioral deficits in vulnerable populations in the event of a TBI. Zinc supplementation four-weeks prior to injury prevented the development of depression-like behaviors as well as prevented loss of spatial learning and memory seen in injured animals that were fed a zinc adequate diet without supplementation (p<0.01). Examination of brain gene expression in the hippocampus, a region of the brain that plays a role in depression, showed that TBI altered the expression of over 170 mRNAs, approximately 70 of which were normalized in rats supplemented with zinc. We identified genes involved in cell proliferation, apoptosis, survival, repair, and differentiation, suggesting that zinc supplementation may be playing a role in adult stem cell proliferation and the growth of new neurons. This is an important finding because it is well known that anti-depressant drugs also increase proliferation of neuronal precursor cells in the hippocampus. When we measured this directly using a thymidine analog, we found that TBI doubled the number of proliferating cells in the hippocampus 24 hours post-injury (p<0.05) and, more importantly, supplemental zinc increased this number by an additional 2-fold. Furthermore, four weeks of zinc supplementation significantly increased the density of new doublecortin-positive neurons one-week post-TBI that were maintained for 4 weeks after injury (p<0.01). Together these data suggest that zinc interacts with a variety of cellular and molecular targets that could be used to develop new therapeutic targets to treat and prevent depression and depression-related orders.
