Neurotoxicity of polyamines and pharmacological neuroprotection in cultures of rat cerebellar granule cells
- PMID: 9398458
- DOI: 10.1006/exnr.1997.6627
Neurotoxicity of polyamines and pharmacological neuroprotection in cultures of rat cerebellar granule cells
Abstract
We have studied in a well-characterized in vitro neuronal system, cultures of cerebellar granule cells, the toxicity of polyamines endogenously present in the brain: spermine, spermidine, and putrescine. Twenty-four-hour exposure of mature (8 days in vitro) cultures to 1-500 microM spermine resulted in a dose-dependent death of granule cells, with the half-maximal effect being reached below 50 microM concentration. Putrescine was moderately toxic but only at 500 microM concentration. Spermidine was tested at 50 and 100 microM concentration and its toxicity was evaluated to be about 50% that of spermine. Neuronal death caused by spermine occurred, at least in part, by apoptosis. Spermine toxicity was completely prevented by competitive (CGP 39551) and noncompetitive (MK-801) antagonists of the NMDA receptor, but was unaffected by a non-NMDA antagonist (NBQX) or by antagonists of the polyamine site present on the NMDA receptor complex, such as ifenprodil. A partial protection from spermine toxicity was obtained through the simultaneous presence of free radical scavengers or through inhibition of the free radical-generating enzyme nitric oxide synthase, known to be partially effective against direct glutamate toxicity. The link between spermine toxicity and glutamate was further strengthened by the fact that, under culture conditions in which glutamate toxicity was ineffective or much reduced, spermine toxicity was absent or very much decreased. Exposure to spermine was accompanied by a progressive accumulation of glutamate in the medium of granule cell cultures. This was attributed to glutamate leaking out from dying or dead cells and was substantially prevented by the simultaneous presence of MK-801 or CGP 39551. The present results demonstrate that polyamines are toxic to granule cells in culture and that this toxicity is mediated through the NMDA receptor by interaction of exogenously added polyamines with endogenous glutamate released by neurons in the medium. The involvement of brain polyamines, in particular spermine and spermidine, in excitotoxic neuronal death is strongly supported by our present results.
Similar articles
-
Modulation of learning and memory by natural polyamines.Pharmacol Res. 2016 Oct;112:99-118. doi: 10.1016/j.phrs.2016.03.023. Epub 2016 Mar 22. Pharmacol Res. 2016. PMID: 27015893 Review.
-
Spermine induces cell death in cultured human embryonic cerebral cortical neurons through N-methyl-D-aspartate receptor activation.J Neurosci Res. 2008 Mar;86(4):861-72. doi: 10.1002/jnr.21538. J Neurosci Res. 2008. PMID: 17941054
-
Excitotoxic death induced by released glutamate in depolarized primary cultures of mouse cerebellar granule cells is dependent on GABAA receptors and niflumic acid-sensitive chloride channels.Eur J Neurosci. 2005 Jan;21(1):103-12. doi: 10.1111/j.1460-9568.2004.03848.x. Eur J Neurosci. 2005. PMID: 15654847
-
The inhibition of peroxide formation as a possible substrate for the neuroprotective action of dihydroergocryptine.J Neural Transm Suppl. 1995;45:297-305. J Neural Transm Suppl. 1995. PMID: 8748638 Review.
-
Death of septal cholinergic neurons produced by chronic exposure to glutamate is prevented by the noncompetitive NMDA receptor/channel antagonist, MK-801: role of nerve growth factor and nitric oxide.J Neurosci Res. 1995 Apr 15;40(6):764-75. doi: 10.1002/jnr.490400608. J Neurosci Res. 1995. PMID: 7629890
Cited by
-
The Potential Role of Polyamines in Epilepsy and Epilepsy-Related Pathophysiological Changes.Biomolecules. 2022 Oct 29;12(11):1596. doi: 10.3390/biom12111596. Biomolecules. 2022. PMID: 36358946 Free PMC article. Review.
-
Altered Brain Arginine Metabolism and Polyamine System in a P301S Tauopathy Mouse Model: A Time-Course Study.Int J Mol Sci. 2022 May 27;23(11):6039. doi: 10.3390/ijms23116039. Int J Mol Sci. 2022. PMID: 35682712 Free PMC article.
-
Alzheimer's disease as a chronic maladaptive polyamine stress response.Aging (Albany NY). 2021 Apr 3;13(7):10770-10795. doi: 10.18632/aging.202928. Epub 2021 Apr 3. Aging (Albany NY). 2021. PMID: 33811757 Free PMC article. Review.
-
Prevention of multiple system atrophy using human bone marrow-derived mesenchymal stem cells by reducing polyamine and cholesterol-induced neural damages.Stem Cell Res Ther. 2020 Mar 4;11(1):63. doi: 10.1186/s13287-020-01590-1. Stem Cell Res Ther. 2020. PMID: 32127052 Free PMC article.
-
Arginase Inhibition Supports Survival and Differentiation of Neuronal Precursors in Adult Alzheimer's Disease Mice.Int J Mol Sci. 2020 Feb 8;21(3):1133. doi: 10.3390/ijms21031133. Int J Mol Sci. 2020. PMID: 32046281 Free PMC article.
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources