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Methylmalonate administration decreases Na+,K+-ATPase activity in cerebral cortex of rats
A T Wyse1, E L Streck, S V Barros
1Departamento de Bioquímica, ICBS, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
Abstract:
Buffered methylmalonate (MMA) was injected s.c. into rats twice a day at 8 h intervals from 5 to 25 days of age (chronic treatment), or into 10-day-old rats three times a day at 1 h intervals (acute treatment). Control rats received saline in the same volumes. Na+,K+-ATPase and Mg2+-ATPase activities were determined in the synaptic plasma membranes from cerebral cortex of rats. Na+,K+-ATPase activity was reduced by 30-40% in MMA-treated rats, whereas Mg2+-ATPase activity was not. In contrast, MMA at final concentrations ranging from 0.1 to 2.0 mM had no in vitro effect on these enzyme activities. However, when brain homogenates were incubated with 2 mM MMA before membrane preparation, Na+,K+-ATPase activity was decreased by 44%. Furthermore, this reduction was totally prevented by the simultaneous addition of glutathione and MMA, suggesting that oxidation of thiol groups or other oxidative damage to the enzyme could be responsible for this effect.
Insights
Methylmalonate (MMA) exposure in rats reduced Na+,K+-ATPase activity in brain membranes. This effect appears linked to oxidative damage, as glutathione prevented the enzyme inhibition.
Area of Science:
- Neuroscience
- Biochemistry
- Toxicology
Background:
- Methylmalonate (MMA) is a metabolite implicated in certain metabolic disorders.
- The impact of MMA on specific neuronal enzyme functions, particularly Na+,K+-ATPase, requires detailed investigation.
Purpose of the Study:
- To investigate the in vivo and in vitro effects of methylmalonate (MMA) on Na+,K+-ATPase and Mg2+-ATPase activities in rat cerebral cortex.
- To explore the potential mechanisms underlying MMA-induced alterations in enzyme activity.
Main Methods:
- Chronic and acute subcutaneous administration of buffered methylmalonate (MMA) or saline to rats at different ages and intervals.
- Biochemical assays to determine Na+,K+-ATPase and Mg2+-ATPase activities in isolated synaptic plasma membranes from rat cerebral cortex.
- In vitro incubation of brain homogenates with MMA, with and without glutathione, prior to enzyme activity assessment.
Main Results:
- Subcutaneous MMA administration significantly reduced Na+,K+-ATPase activity by 30-40% in rat cerebral cortex synaptic membranes.
- Mg2+-ATPase activity remained unaffected by MMA treatment.
- In vitro incubation of brain homogenates with MMA decreased Na+,K+-ATPase activity, an effect mitigated by glutathione, suggesting oxidative damage.
Conclusions:
- In vivo methylmalonate exposure impairs Na+,K+-ATPase activity in the rat brain.
- The observed reduction in Na+,K+-ATPase activity is likely mediated by oxidative stress or damage to enzyme thiol groups.
- These findings highlight a potential neurotoxic mechanism of methylmalonate relevant to conditions involving its accumulation.