Progressive Changes in Cortical Metabolites at Three Stages of Infantile Hydrocephalus Studied byIn VitroNMR Spectroscopy

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Abstract
Infantile hydrocephalus is most often caused by an obstruction in the cerebrospinal fluid flow pathway and results in ventricular dilatation and chronic trauma to the surrounding brain. Surgical treatment alleviates the condition but does not cure or prevent neurological deficits. The H-Tx rat has severe hydrocephalus due to a spontaneous aqueduct obstruction in late gestation. In order to determine how hydrocephalus affects brain metabolism in tissue adjacent to the expanded ventricles, cortical extracts have been made from groups of hydrocephalic and control littermates with early, intermediate, and advanced hydrocephalus at 4, 11, and 21 days after birth. Extracts were analyzed with 1H and 31P NMR spectroscopy and metabolite peaks were quantified using an external standard. Metabolite concentrations were calculated relative to tissue wet weight and subsequently expressed relative to tissue dry weight, using values for water content obtained from additional groups of rats. In early hydrocephalus there was a significant decrease in the phosphomonoester phosphorylcholine, and there were small, nonsignificant changes in other compounds. By 11 days, in addition to phosphomonoesters, there were significant decreases in ATP, phosphocreatine, and in inorganic phosphate, but with no change in lactate. By 21 days there were also substantial decreases in cholines, inositol, creatine, glutamate, glutamine, aspartate, N-acetylaspartate, alanine, and taurine. It is concluded that the sequence of pathological events starts with changes in membrane lipids. This is followed by reductions in energy metabolite which leads to cell swelling with loss of intracellular osmolytes and neurotransmitters. These changes are discussed in relation to hydrocephalus pathophysiology and to prevention and reversibility with shunt treatment. Key words: rat infantile hydrocephalus; NMR spectroscopy; cerebral cortex; membrane lipid metabolism; high-energy phosphates; amino acids; organic osmolytes