Metalloneurochemistry

Several projects have been launched in a relatively new area that we term metalloneurochemistry. Novel sensors for zinc have been prepared that append metal-chelating units to fluorescein and to a fluorescein/rhodamine framework that designated as rhodafluors. Zinc has been imaged in the dentate gyrus cells of the hippocampus in rat brain slices, and collaborative studies in progress have associated that release of zinc with long-term potentiation. The design and utilization of novel zinc-specific extracellular chelating agents have facilitated these experiments. Sensors programmed to visualize extracellular zinc or zinc in damaged neuronal cells have revealed selectively damaged neurons in the brains of animals that suffered blunt head trauma or drug-induced seizures. These same probes have identified new zinc-rich cells in brain. Work in progress includes several strategies to synthesize ratioable zinc sensors, which shift their wavelength upon zinc binding, and programmable sensors that can be attached to specific extra- and intracellular compartments and organelles. Experiments are being conducted with live brain slices to use zinc release to track neural network formation and communication. The ultimate goal is to understand zinc release in brain and to use it to investigate neural networks, including both hippocampal and olfactory bulb loci. Sensors capable of quantitating mobile zinc have also been devised and are being applied to study both prostate and pancreatic functions. In vivo microscopic imaging has revealed the loss of zinc during prostate cancer formation in the TRAMP, or transgenic adenocarcinoma of the mouse prostate model, mouse. Related sensors based on fundamental transition metal chemistry have been devised to detect biological nitric oxide. The focus is currently on the synthesis and characterization of transition metal complexes containing a ligand that becomes fluorescent and is released upon addition of NO to signal the presence of this neurotransmitter by light emission. We also study biomimetic chemistry of metal-sulfur clusters with nitric oxide to guide the interpretation of biological experiments in which NO released in cells signals a function or evokes pathology. Included are iron-sulfur cluster reactions with nitric oxide, the chemistry of zinc thiolates with NO and its metabolites, and nitrosation reactions involving metal-carbon and metal-nitrogen bonds.