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

Abstract

Spermidine is an endogenous polyamine with a polycationic structure present in the central nervous system of mammals. Spermidine regulates biological processes, such as Ca(2+) 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 (0.05-10 μM) for 30 min. Spermidine (0.5 and 1 μM) decreased Na(+),K(+)-ATPase activity in slices, but not in homogenates. MK-801 (100 and 10 μM), 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 (0.5 μM). ODQ (10 μM), a guanylate cyclase inhibitor, and KT5823 (2 μM), a protein kinase G inhibitor, also prevented the inhibitory effect of spermidine on Na(+),K(+)-ATPase activity. Spermidine (0.5 and 1.0 μM) increased NO(2) plus NO(3) (NOx) levels in slices, and MK-801 (100 μM) and arcaine (0.5 μM) prevented the effect of spermidine (0.5 μM) on the NOx content. These results suggest that spermidine-induced decrease of Na(+),K(+)-ATPase activity involves NMDA receptor/NOS/cGMP/PKG pathway.

Protective Effect of Spermidine Against Excitotoxic Neuronal Death Induced by Quinolinic Acid in Rats: Possible Neurotransmitters and Neuroinflammatory Mechanism

“…Treatment with spermidine at a dose of 5 and 10 mg/kg significantly inhibited the QAmediated excitotoxicity and prevented the loss of GABAergic MSNs. The preventive effect of spermidine against 3-NP mediated excitotoxicity is attributed to antagonistic action of spermidine on NMDA receptor mediated through NR2B subunit (Rock and Macdonald 1995;Carvalho et al 2012). Dysfunction of dopaminergic system is well implicated in HD animals as well as patients.…”

“…Spermidine has been reported to regulate biological processes, such as Ca 2? influx by glutamatergic NMDAR, which has been associated with nitric oxide synthase (NOS) and cGMP/PKG pathway activation (Carvalho et al 2012). Exogenous supply of spermidine has been reported to prolong the life span of several model organisms including yeast (Saccharomyces cerevisiae), nematodes (Caenorhabditis elegans), and flies (Drosophila melanogaster) and significantly reduces age-related oxidative protein damage in mice, indicating that this agent may act as a universal antiaging drug (Madeo et al 2010).…”

“…Recent evidences have suggested that polyamines play important role in cell re-programming and autophagy regulation. Polyamines have been reported to modulate the NMDA receptor in a concentration-dependent manner, i.e., at low concentrations, polyamines increase NMDA-evoked currents, while at high concentrations they decrease such currents (Carvalho et al 2012). In addition to this, it has been reported that polyamine (spermidine or high-polyamine diet) supplementation increases life span in model organisms (Minois et al 2011).…”

Tabernaemontana catharinensis ethyl acetate fraction presents antinociceptive activity without causing toxicological effects in mice

“…The cerebral cortex was immediately dissected and used for the preparation of slices (400 μm thick, with a Mcllwain tissue chopper) according Carvalho et al (2012) with modifications.…”

Supramolecular Fmoc-valyl based nanoassemblies for delivery of mitoxantrone into HeLa cells

“…Furthermore, endogenous polyamines such as putrescine, spermidine and spermine have been used as crosslinkers as they are prone to interact with negatively charged compounds and can function as nanoparticulate drug delivery vehicles [18][19][20].…”