European Journal of Pharmacology 2012-06-05

Spermidine decreases Na+,K+-ATPase activity through NMDA receptor and protein kinase G activation in the hippocampus of rats

Fabiano B. Carvalho, Carlos F. Mello, Patricia C. Marisco, Raquel Tonello, Bruna A. Girardi, Juliano Ferreira, Mauro S. Oliveira, Maribel A. Rubin

文献索引：Eur. J. Pharmacol. 684(1-3) , 79-86, (2012)

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摘要

Spermidine is an endogenous polyamine with a polycationic structure present in the central nervous system of mammals. Spermidine regulates biological processes, such as Ca2+ influx by glutamatergic N-methyl-d-aspartate receptor (NMDA receptor), which has been associated with nitric oxide synthase (NOS) and cGMP/PKG pathway activation and a decrease of Na+,K+-ATPase activity in rats' cerebral cortex synaptosomes. Na+,K+-ATPase establishes Na+ and K+ gradients across membranes of excitable cells and by this means maintains membrane potential and controls intracellular pH and volume. However, it has not been defined whether spermidine modulates Na+,K+-ATPase activity in the hippocampus. In this study we investigated whether spermidine alters Na+,K+-ATPase activity in slices of hippocampus from rats, and possible underlying mechanisms. Hippocampal slices and homogenates were incubated with spermidine (0.05–10μM) for 30min. Spermidine (0.5 and 1μM) decreased Na+,K+-ATPase activity in slices, but not in homogenates. MK-801 (100 and 10μM), a non-competitive antagonist of NMDA receptor, arcaine (0.5μM), an antagonist of the polyamine binding site at the NMDA receptor, and L-NAME (100μM), a NOS inhibitor, prevented the inhibitory effect of spermidine (0.5μM). ODQ (10μM), a guanylate cyclase inhibitor, and KT5823 (2μM), a protein kinase G inhibitor, also prevented the inhibitory effect of spermidine on Na+,K+-ATPase activity. Spermidine (0.5 and 1.0μM) increased NO2 plus NO3 (NOx) levels in slices, and MK-801 (100μM) and arcaine (0.5μM) prevented the effect of spermidine (0.5μM) on the NOx content. These results suggest that spermidine-induced decrease of Na+,K+-ATPase activity involves NMDA receptor/NOS/cGMP/PKG pathway.