Propionic and methylmalonic acids increase cAMP levels in slices of cerebral cortex of young rats via adrenergic and glutamatergic mechanisms.
We have previously described that propionic (PA) and methylmalonic (MMA) acids increased the in vitro phosphorylation of cytoskeletal proteins through cAMP-dependent protein kinase and glutamate. In the present study we investigated the in vitro effects of 1 mM glutamate, 2.5 mM MMA and 2.5 mM PA on cAMP levels in the slices of cerebral cortex of young rats. Results showed that PA, MMA and glutamate increased cAMP levels after 30 min of incubation, while the beta-adrenergic agonist epinephrine elicited a similar effect only at a shorter incubation time. Then effects were prevented by the beta-adrenergic antagonist propranolol, rather than by glutamate antagonists (AP5, CNQX and MCPG), suggesting that they were mediated by beta-adrenergic receptors. In addition, glutamate antagonists per se induced increased cAMP levels; however propranolol prevented only the effect elicited by the metabotropic glutamate antagonist MCPG. Taken together, it is feasible that PA and MMA increase cAMP synthesis via a beta-adrenergic/G protein coupled pathway, in a glutamate-dependent manner. Although additional studies will be necessary to evaluate the importance of these observations for the neuropathology of propionic and methylmalonic acidemias, it is possible that high brain cAMP levels may contribute to a certain extent to the neurological dysfunction of the affected individuals.
Loureiro
Samanta Oliveira
SO
Universidade Federal do Rio Grande do Sul, Instituto de Ciências Básicas da Saúde, Departamento de Bioquímica, Porto Alegre, RS, Brasil.
de Lima Pelaez
Priscila
P
Heimfarth
Luana
L
Souza
Diogo Onofre
DO
Wajner
Moacir
M
Pessoa-Pureur
Regina
R
D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000704:Analysis of Variance; D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism*; D004837:Epinephrine / Q000494:pharmacology; D018698:Glutamic Acid / Q000494:pharmacology; D005998:Glycine / Q000031:analogs & derivatives* / Q000494:pharmacology; D008764:Methylmalonic Acid / Q000494:pharmacology*; D011422:Propionates / Q000494:pharmacology*; D011433:Propranolol / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar
D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D011422:Propionates; C474696:methyl-(4-carboxyphenyl)glycine; D018698:Glutamic Acid; D008764:Methylmalonic Acid; D011433:Propranolol; D000242:Cyclic AMP; C029658:propionic acid; D005998:Glycine; D004837:Epinephrine