ABSTRACT
Neurological dysfunction is common in patients with methylmalonic and propionic acidemias. However, the mechanisms underlying the neuropathology of these disorders are far from understood. In the present study we investigated the in vitro effects of methylmalonic (MMA) and propionic (PA) acids at various concentrations (1 microM-5 mM) on three parameters of the glutamatergic system, namely the basal and potassium-induced release of L-[3H]glutamate by synaptosomes, Na+-dependent L-[3H]glutamate uptake by synaptosomes and Na+-independent L-[3H]glutamate uptake by synaptic vesicles from cerebral cortex of male adult Wistar rats. The results showed that MMA significantly increased potassium-induced but not basal L-[3H]glutamate release from synaptosomes with no alteration in synaptosomal L-[3H]glutamate uptake. A significant reduction of L-[3H]glutamate incorporation into vesicles caused by MMA was also detected. In contrast, PA had no effect on these parameters. These findings indicate that MMA alters the glutamatergic system. Although additional studies are necessary to evaluate the importance of these observations for the neuropathology of methylmalonic acidemia, it is possible that the effects elicited by MMA may lead to excessive glutamate concentrations at the synaptic cleft, a fact that may explain previous in vivo and in vitro findings associating MMA with excitotoxicity.
Subject(s)
Cerebral Cortex/metabolism , Glutamic Acid/metabolism , Methylmalonic Acid/pharmacology , Propionates/pharmacology , Synaptic Vesicles/metabolism , Synaptosomes/metabolism , Animals , Cerebral Cortex/drug effects , Cerebral Cortex/enzymology , L-Lactate Dehydrogenase/metabolism , Male , Nerve Tissue Proteins/metabolism , Potassium/pharmacology , Rats , Rats, Wistar , Synaptic Vesicles/drug effects , Synaptic Vesicles/enzymology , Synaptosomes/drug effects , Synaptosomes/enzymologyABSTRACT
Application of single transient forebrain ischemia (ISC) in adult Wistar rats, lasting 2 or 10 min, caused inhibition of Na+,K+-ATPase activity in cytoplasmic membrane fractions of hippocampus and cerebral cortex immediately after the event. In the 2-min ISC group followed by 60 min of reperfusion, the enzyme inhibition was maintained in the cortex, while there was an increase in hippocampal enzyme activity; both effects were over 1 day after the event. However, in the 10-min ISC group enzyme inhibition had been maintained for 7 days in both cerebral structures. Interestingly, ischemic preconditioning (2-min plus 10-min ISC, with a 24-hour interval in between) prevented the inhibitory effect of ischemia/reperfusion on Na+,K+-ATPase activity observed either after a single insult of 2 min or 10 min ischemia. We suggest that the maintenance of Na+,K+-ATPase activity afforded by preconditioning be related to cellular neuroprotection.
