Cruz-Aguado, Reyniel

The chapter, "Glutathione in the nervous system: Roles in neural function and health and implications for neurological disease" was written by the listed authors including Reyniel Cruz-Aguado (Douglas College Faculty). Glutathione (γ-l-glutamyl-l-cysteinylglycine, GSH) is the most abundant cellular antioxidant molecule in aerobic cells. In the nervous system, it is found in the millimolar range in both neuronal and nonneuronal cells, arising endogenously by synthesis from its precursor amino acids or taken up from the blood by means of specific transport mechanisms. Glutathione can participate as an antioxidant either as a substrate of glutathione peroxidase (GSHPx) or as an electron donor in spontaneous reactions with reactive oxygen species (ROS). Besides the well-established role of glutathione as an antioxidant, it serves other functions in the nervous system, including neutralization of xenobiotics, participation in amino acid transport, regulation of the activity and conformation of proteins, protection against cysteine and glutamate neurotoxicities, and modulation of glutamatergic transmission. In addition, several lines of evidence suggest that glutathione might act as a neurotransmitter on its own class of receptors. This latter possibility may have significant implications for the possible involvement of GSH in learning and memory processes. Given its ample range of functions in the nervous system, it is not surprising to find significant alterations in glutathione levels and/or glutathione-related enzymes during brain aging and in several neurological conditions including Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), schizophrenia, and chronic fatigue syndrome (CFS). -- From publisher description.

Bioaccumulation of 􏰁-methylamino-L-alanine (BMAA) through Cyanobacteria-contaminated food or water supplies has been suggested as a possible contributor to Parkinson-dementia complex (PDC) among the indigenous Chamorro of Guam as well as Alzheimer disease (AD) worldwide, a speculation that has been widely commented on in news and editorial sections of premier scientific and medical journals, and that has led to product recalls and government-sponsored assessments of public health in Europe. However, quantification of BMAA to date has been based on indirect high performance liquid chromatography methods. Given the potential global health significance, we developed a stable-isotope dilution assay for BMAA to more rigorously test its proposed bioaccumulation in cerebral cortex.

β-Methylamino- l-alanine (BMAA) has been proposed as a global contributor to neurodegenerative diseases, including Parkinson–dementia complex (PDC) of Guam and Alzheimer's disease (AD). The literature on the effects of BMAA is conflicting with some but not all in vitro data supporting a neurotoxic action, and experimental animal data failing to replicate the pattern of neurodegeneration of these human diseases, even at very high exposures. Recently, BMAA has been reported in human brain from individuals afflicted with PDC or AD. Some of the BMAA in human tissue reportedly is freely extractable (free) while some is protein-associated and liberated by techniques that hydrolyze the peptide bond. The latter is especially intriguing since BMAA is a non-proteinogenic amino acid that has no known tRNA. We attempted to replicate these findings with techniques similar to those used by others; despite more than adequate sensitivity, we were unable to detect free BMAA. Recently, using a novel stable isotope dilution assay, we again were unable to detect free or protein-associated BMAA in human cerebrum. Here we review the development of our new assay for tissue detection of BMAA and show that we are able to detect free BMAA in liver but not cerebrum, nor do we detect any protein-associated BMAA in mice fed this amino acid. These studies demonstrate the importance of a sensitive and specific assay for tissue BMAA and seriously challenge the proposal that BMAA is accumulating in human brain.