The PET imaging agent CuII(atsm) improves motor and cognitive function in Parkinson’s disease.

Background:Cu II (atsm) [(diacetylbis(N(4)-methylthiosemicarbazonato) copper(II)] was orally administrated to transgenic SOD1 G93A mice. Results: Treatment significantly prolonged lifespan with preservation of motor neurons. Reduced protein oxidation, attenuated astrocyte, and microglial activation also resulted from treatment. Conclusion:Cu II (atsm) is neuroprotective in this model even when treatment begins after the onset of disease symptoms. Significance: The drug has therapeutic potential for amyotrophic lateral sclerosis.

Alzheimer's disease is the most common form of age-related neurodegenerative dementia. The disease is characterised by the presence of plaques in the cerebral cortex. The major constituent of these plaques is aggregated amyloid-β peptide. This review focuses on the molecular aspects of metal complexes designed to bind to amyloid-β. The development of radioactive metal-based complexes of copper and technetium designed as diagnostic imaging agents to detect amyloid burden in the brain is discussed. Separate sections of the review discuss the use of luminescent metal complexes to act as non-conventional probes of amyloid formation and recent research into the use of metal complexes as inhibitors of amyloid formation and toxicity.

Radiolabeleddiacetylbis4-methylthiosemicarbazonatocopper II [Cu II atsm] is an effective positron-emission tomography imaging agent for myocardial ischemia, hypoxic tumors, and brain disorders with regionalized oxidative stress, such as mitochondrial myopathy, encephalopathy, and lactic acidosis with stroke-like episodes (MELAS) and Parkinson's disease. An excessively elevated reductive state is common to these conditions and has been proposed as an important mechanism affecting cellular retention of Cu from Cu II atsm. However, data from whole-cell models to demonstrate this mechanism have not yet been provided. The present study used a unique cell culture model, mitochondrial xenocybrids, to provide whole-cell mechanistic data on cellular retention of Cu from Cu II atsm. Genetic incompatibility between nuclear and mitochondrial encoded subunits of the mitochondrial electron transport chain (ETC) in xenocybrid cells compromises normal function of the ETC. As a consequence of this impairment to the ETC we show xenocybrid cells upregulate glycolytic ATP production and accumulate NADH. Compared to control cells the xenocybrid cells retained more Cu after being treated with Cu II atsm. By transfecting the cells with a metal-responsive element reporter construct the increase in Cu retention was shown to involve a Cu II atsminduced increase in intracellular bioavailable Cu specifically within the xenocybrid cells. Parallel experiments using cells grown under hypoxic conditions confirmed that a compromised ETC and elevated NADH levels contribute to increased cellular retention of Cu from Cu II atsm. Using these cell culture models our data demonstrate that compromised ETC function, due to the absence of O 2 as the terminal electron acceptor or dysfunction of individual components of the ETC, is an important determinant in driving the intracellular dissociation of Cu II atsm that increases cellular retention of the Cu.sodium arsenite | energy metabolism | radiopharmaceutical P