phosphorus-radioisotopes and propionic-acid

In this study we investigated the effects of methylmalonic acid (MMA) and propionic acid (PA) on the phosphorylation of cytoskeletal proteins of cerebral cortex of rats. Slices of tissue were incubated with 32P-orthophosphate in the presence or absence of glutamate, MMA, PA and ionotropic or metabotropic glutamate receptor agonists. The cytoskeletal fraction was isolated and the radioactivity incorporated into the cytoskeletal proteins was measured. Results demonstrated that the acids, glutamate and NMDA increased the phosphorylation of the proteins studied. However, this effect was not observed for non-NMDA ionotropic agonists or metabotropic agonists. Experiments using glutamate receptor antagonists confirmed that MMA and PA at the same concentrations as found in tissues from propionic or methylmalonic acidemic children increase the phosphorylation of cytoskeletal proteins, possibly via NMDA glutamate receptors. Therefore, it is feasible that these findings may be related to the neurological dysfunction characteristic of these disorders.

Topics: 2-Amino-5-phosphonovalerate; 6-Cyano-7-nitroquinoxaline-2,3-dione; Animals; Cerebral Cortex; Cytoskeletal Proteins; Glutamic Acid; In Vitro Techniques; Methylmalonic Acid; N-Methylaspartate; Phosphates; Phosphorus Radioisotopes; Phosphorylation; Propionates; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate

We studied the effects of acute and chronic administration of methylmalonic (MMA) and propionic (PA) acids on the in vitro incorporation of 32P into neurofilament subunits (NF-M and NF-L), alpha and beta tubulins, from cerebral cortex of rats. In the chronic treatment, drugs were administered subcutaneously from day 6-17 post-partum (MMA 0.76-0.89 micromol/g body weight and PA 0.93 micromol/g body weight). In the acute treatment MMA and PA were injected (MMA 3.78 micromol/g body weight and PA 3.90 micromol/g body weight). Control animals received saline in the same volumes. The Triton-insoluble cytoskeletal fraction of control in treated animals was isolated and incubated with 32P-ATP. Our results demonstrate that both drugs were able to inhibit 32P in vitro incorporation into neurofilaments and tubulins. The acute administration of MMA decreased the in vitro 32P incorporation into NF-L and alpha-tubulin subunit, whereas PA administration decreased the 32P in vitro incorporation into NF-M, NF-L, and tubulins. On the other hand, chronic MMA administration induced a decreased 32P in vitro incorporation into NF-M, while chronic treatment with propionate decreased the in vitro phosphorylation of NF-M and alpha-tubulin. This study provides consistent evidence that a decreased phosphorylation of cytoskeletal proteins is induced by MMA and PA metabolites which accumulate in methylmalonic and propionic acidemias respectively. Therefore, it is possible that an altered brain cytoskeletal metabolism could be related with the structural alterations of CNS observed in these disorders.

Topics: Animals; Autoradiography; Cerebral Cortex; Cytoskeletal Proteins; Methylmalonic Acid; Organ Size; Phosphorus Radioisotopes; Propionates; Rats; Rats, Wistar