Spermine induces cell death in cultured human embryonic cerebral cortical neurons through N‐methyl‐D‐aspartate receptor activation

Abstract

The polyamines putrescine, spermidine and spermine play important roles in cell proliferation, differentiation and the modulation of ion channel receptors. However, the function of increased concentrations of these compounds in brain injury and disease is unclear since they have been proposed as being both neuroprotective and neurotoxic. The effects of spermine and putrescine were studied in human primary cerebral cortical cultures containing both neurons and glia. No toxic effects were induced at 8 days in vitro (DIV) by either of the two polyamines at concentrations ranging from 0.3 µM to 2 mM. However, when the oxidative metabolisation of spermine that generates toxic by-products was induced by the presence of foetal calf serum, spermine caused cellular death with a LC 50 of approximately 50 μM. At 14 DIV, the coapplication of spermine 2 mM and glutamate 5 mM induced neuron cell death, but the effect of applying both components separately was null. Both spermine and glutamate were toxic to older neurons (26 to 42 DIV cultures), and here the coapplication of glutamate was found always to intensify the effect of spermine. Spermine showed greater toxicity than glutamate in neurons. Another effect observed is that glutamate, but not spermine, induced astrocyte swelling. Spermine toxicity was inhibited by both MK801 and ifenprodil, indicating a mechanism involving NMDA-receptor activation. Moreover, a strong spermine modulation of the NMDA receptor was demonstrated by the inhibition of glutamate toxicity by ifenprodil. Putrescine induced minor effects also as a neurotoxic agent. In conclusion, neuronal death by spermine can be induced by its toxic by-products as well as through NMDA-receptor action. The present results confirm the potentially harmful role of the polyamines in excitotoxicity-related human disorders.

AMD1 is essential for ESC self-renewal and is translationally down-regulated on differentiation to neural precursor cells

“…Manipulation of polyamine levels have been linked to differentiation of F9 teratocarcinoma cells and the enhancement of cardiac differentiation (Frostesjo et al 1997;Sasaki et al 2008). There have been reports of both neuroprotective and neurotoxic effects of all three polyamines on neurons (de Vera et al 2008;Igarashi and Kashiwagi 2010), and disruption of polyamine homeostasis has been linked to a number of neurological disorders (Casero and Pegg 2009). The role of polyamines in ESC self-renewal and differentiation is clearly complex, and it is likely that they function in different ways depending on the developmental window and the cellular context.…”

Suicide and the Polyamine System

“…The major rate-limiting enzymes of this pathway are ornithine decarboxylase (ODC), spermidine/spermine N 1 -acetyl transferase (SAT1), and S-adenosylmethionine decarboxylase (AMD1), whose activities are influenced by numerous regulatory proteins as well as the polyamine levels [9]. In addition, not only are polyamines known to influence neurotransmitter systems, such as catecholamines [10,11], gamma-aminobutyric acid (GABA) [12], glutamate [13], and nitric oxide [14], but agmatine is also believed to act as a neurotransmitter [15]. Finally, polyamines are also able to influence the properties of several transmembrane channels, thereby affecting cell excitability [16].…”

Agonists and Allosteric Modulators of the Calcium-Sensing Receptor and Their Therapeutic Applications

“…Polyamines are found in a wide variety of tissues and are involved in stabilizing nucleic acid helical structure, having a role in cellular metabolism, growth, and differentiation. Polyamines also play a role in neurotransmission, producing their effects through modulation of the N-methyl-D-aspartic acid and ␣-amino-3-hydroxyl-5-methyl-4-isoxazolepropionate receptors and by blocking inwardly rectifying potassium channels (Shin et al, 2005;Kurata et al, 2007;de Vera et al, 2008).…”