Stem cell proliferation, neuronal differentiation, cell survival, and migration in the central nervous system are all important steps in the normal process of neurogenesis. These mechanisms are highly active during gestational and early neonatal brain development. Additionally, in select regions of the brain, stem cells give rise to new neurons throughout the human lifespan. Recent work has revealed key roles for the essential trace element zinc in the control of both developmental and adult neurogenesis. Given the prevalence of zinc deficiency, these findings have implications for brain development, cognition, and the regulation of mood.
In addition to being a covalent linker in molecular conjugation chemistry, the function of a 1,2,3-triazolyl moiety resulting from the copper(I)-catalyzed azide-alkyne cycloaddition reaction as a ligand for metal ions is receiving considerable attention. In this work, we characterize the thermodynamic and kinetic effects of incorporating a 1,2,3-triazolyl group in a multidentate ligand scaffold on metal coordination in the context of fluorescent zinc(II) indicator development. Ligands L14, BrL14, and FL14 (1,4-isomers) contain the 1,4- disubstituted-1,2,3-triazolyl group that is capable of binding with zinc(II) in conjunction with a di(2-picolylamino) (DPA) moiety within a multidentate ligand scaffold. The 1,2,3-triazolyl in the 1,4-isomers is therefore “integrated” in chelation. The 1,5-isomers L15, BrL15, and FL15 contain 1,2,3-triazolyls that are excluded from participating in zinc(II) coordination. These 1,2,3- triazolyls are “passive linkers”. Zinc(II) complexes of 2:1 (ligand/metal) stoichiometry are identified in solution using 1H NMR spectroscopy and isothermal titration calorimetry (ITC), and in one case, characterized in the solid state. The 1:1 ligand/zinc(II) affinity ratio of L14 over L15, which is attributed to the affinity enhancement of a 1,2,3-triazolyl group to zinc(II) over that of the solvent acetonitrile, is quantified at 18 (−1.7 kcal/mol at 298 K) using an ITC experiment. Fluorescent ligands FL14 and FL15 are evaluated for their potential in zinc(II) sensing applications under pH neutral aqueous conditions. The 1,4-isomer FL14 binds zinc(II) both stronger and faster than the 1,5-isomer FL15. Visualization of free zinc(II) ion distribution in live HeLa cells is achieved using both FL14 and FL15. The superiority of FL14 in staining endogenous zinc(II) ions in live rat hippocampal slices is evident. In summation, this work is a fundamental study of 1,2,3-triazole coordination chemistry, with a demonstration of its utility in developing fluorescent indicators.
Depression, anxiety, and impairments in learning and memory are all associated with traumatic brain injury (TBI). Because of the strong link between zinc deficiency, depression, and anxiety, in both humans and rodent models, we hypothesized that dietary zinc supplementation prior to injury could provide behavioral resiliency to lessen the severity of these outcomes after TBI. Rats were fed a marginal zinc deficient (5 ppm), zinc adequate (30 ppm), or zinc supplemented (180 ppm) diet for 4 weeks followed by a moderately-severe TBI using the well-established model of controlled cortical impact (CCI). Following CCI, rats displayed depression-like behaviors as measured by the 2-bottle saccharin preference test for anhedonia. Injury also resulted in evidence of stress and impairments in Morris water maze (MWM) performance compared to sham-injured controls. While moderate zinc deficiency did not worsen outcomes following TBI, rats that were fed the zinc supplemented diet for 4 weeks showed significantly attenuated increases in adrenal weight (p<0.05) as well as reduced depression-like behaviors (p<0.001). Supplementation prior to injury improved resilience such that there was not only significant improvements in cognitive behavior compared to injured rats fed an adequate diet (p<0.01), there were no significant differences between supplemented and sham-operated rats in MWM performance at any point in the 10-day trial. These data suggest a role for supplemental zinc in preventing cognitive and behavioral deficits associated with TBI.
Background While treatments for the behavioral deficits associated with traumatic brain injury (TBI) are currently limited, animal models suggest that zinc supplementation may increase resilience to TBI. Objective This work tests the hypothesis that zinc supplementation after TBI can be used as treatment to improve behavioral outcomes such as anxiety, depression, and learning and memory. Methods TBI was induced by controlled cortical impact to the medial frontal cortex. After TBI, rats were fed either a zinc adequate (ZA, 30 ppm) or zinc supplemented (ZS, 180 ppm) diet. Additional rats in each dietary group (ZA or ZS) were given a single intraperitoneal (ip) injection of zinc (30 mg/kg) 1 hour following injury. Results Brain injury resulted in significant increases in anxiety-like and depression-like behaviors as well as impairments in learning and memory. None of the zinc treatments (dietary or ip zinc) improved TBI-induced anxiety. The 2-bottle saccharin preference test for anhedonia revealed that dietary ZS also did not improve depression-like behaviors. However, dietary ZS combined with an early ip zinc injection significantly reduced anhedonia (P < .001). Dietary supplementation after injury, but not zinc injection, significantly improved (P < .05) cognitive behavior as measured by the time spent finding the hidden platform in the Morris water maze test compared with injured rats fed a ZA diet. Conclusions These data suggest that zinc supplementation may be an effective treatment option for improving behavioral deficits such as cognitive impairment and depression following TBI.
Traumatic brain injury is associated with a wide variety of behavioral deficits, including memory loss, depression, and anxiety. While treatments for these outcomes are currently limited, human clinical data suggest that supplemental zinc can be used during recovery to improve cognitive and behavioral deficits associated with brain injury. Additionally, pre-clinical models suggest that zinc may increase resilience to traumatic brain injury, making it potentially useful in populations at risk for injury.
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