Current Brain Research with NMR Spectroscopy
Studies of metabolism of glyceraldehyde in mice by 13C NMR spectroscopy
About the project
The brain’s handling of glyceraldehyde (2,3-dihydroxypropanal) is of interest, since glyceraldehyde is one of several glycating agents that non-enzymatically form sugar-protein adducts. Glyceraldehyde-protein adducts have been detected in the brain of Alzheimer’s patients, in normally aged human brains, and in the brains of diabetic rats.
It is therfore of value to know whether brain cells are capable of metabolizing glyceraldehyde and thus eliminate or detoxify this compound. Further, metabolism of 13C labeled glyceraldehyde may illustrate the metabolic activity of several biochemical pathways. Detection of 13C-labeled metabolites by 13C nuclear magnetic resonance (NMR) spectroscopy after exposure of the brain to a 13C-labeled substrate shed light on the metabolic pathways traveled by that substrate. Importantly, the relative 13C labeling of certain amino acids indicate the type of brain cell that is involved in the metabolism.
We currently administer 13C labeled glyceraldehyde intravenously to mice and analyze brain, blood, and liver extracts by 13C NMR spectroscopy. We also investigate the expression of various enzymes related to glyceraldehyde metabolism in rat brain by micro array methodology, measure the activity of some of these enzymes in mouse brain homogenates.
Deficiency or lack of the enzyme propionyl-CoA carboxylase leads to impairment of propionyl-CoA metabolism and accumulation of propionic acid in blood, so-called propionic acidemia. Propionic acidemia is a rare disorder inherited from both parents. Neither parent shows symptoms, but both carry a defective gene responsible for this disease. It takes two faulty genes to cause the disease. Symptoms include poor feeding, vomiting, dehydration, acidosis (blood pH falls below 7.35), seizures, and lethargy. The effects of propionic acid quickly become deadly. More than 90% of striatal neurons are neurons producing GABA = γ-amino butyric acid. It is known that two propionic acid derivatives, 3-nitropropionic acid and 3-mercaptopropionic acid interfere with two different enzymes in the metabolism of these neurons. On this background the researchers hypothesize that propionic acid targets GABAergic neurons selectively. Such an effect of propionic acid will shed light on the vulnerability of the striatum of the brain in propionic acidemia and might have future clinical importance.
The research involves intravenous administration of propionic acid with the stable isotope 13C to mice to see if propionic acid cross the blood brain barrier and to see if it can be converted in brain – studied by 13C NMR. A variety of enzyme activity tests are exploited to see if the enzymes necessary for the metabolism of propionic acid are present in the brain and which enzyme(s) is/are inhibited by propionic acid.
NMR instruments from University of Oslo NMR Center are used in these studies.