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Neurotoxicity of polyamines and pharmacological neuroprotection in cultures of rat cerebellar granule cells.
Exp Neurol. 1997 Nov; 148(1):157-66.EN

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.

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Authors+Show Affiliations

Sparapani M
Department of Biology, University of Bologna, Italy.
Dall'Olio R
No affiliation info available
Gandolfi O
No affiliation info available
Ciani E
No affiliation info available
Contestabile A
No affiliation info available

MeSH

2-Amino-5-phosphonovalerateAnimalsApoptosisAspartic AcidButylated HydroxytolueneCells, CulturedCerebellar CortexDizocilpine MaleateEnzyme InhibitorsExcitatory Amino Acid AntagonistsFemaleFree Radical ScavengersGlutamic AcidL-Lactate DehydrogenaseMaleNerve Tissue ProteinsNeuronsNeuroprotective AgentsNitric Oxide SynthaseNitroargininePiperidinesPutrescineQuinoxalinesRatsRats, WistarReceptors, N-Methyl-D-AspartateSpermidineSpermineVitamin E

Pub Type(s)

Comparative Study
Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

9398458

Citation

Sparapani, M, et al. "Neurotoxicity of Polyamines and Pharmacological Neuroprotection in Cultures of Rat Cerebellar Granule Cells." Experimental Neurology, vol. 148, no. 1, 1997, pp. 157-66.
Sparapani M, Dall'Olio R, Gandolfi O, et al. Neurotoxicity of polyamines and pharmacological neuroprotection in cultures of rat cerebellar granule cells. Exp Neurol. 1997;148(1):157-66.
Sparapani, M., Dall'Olio, R., Gandolfi, O., Ciani, E., & Contestabile, A. (1997). Neurotoxicity of polyamines and pharmacological neuroprotection in cultures of rat cerebellar granule cells. Experimental Neurology, 148(1), 157-66.
Sparapani M, et al. Neurotoxicity of Polyamines and Pharmacological Neuroprotection in Cultures of Rat Cerebellar Granule Cells. Exp Neurol. 1997;148(1):157-66. PubMed PMID: 9398458.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Neurotoxicity of polyamines and pharmacological neuroprotection in cultures of rat cerebellar granule cells. AU - Sparapani,M, AU - Dall'Olio,R, AU - Gandolfi,O, AU - Ciani,E, AU - Contestabile,A, PY - 1997/12/17/pubmed PY - 1997/12/17/medline PY - 1997/12/17/entrez SP - 157 EP - 66 JF - Experimental neurology JO - Exp Neurol VL - 148 IS - 1 N2 - 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. SN - 0014-4886 UR - https://www.unboundmedicine.com/medline/citation/9398458/Neurotoxicity_of_polyamines_and_pharmacological_neuroprotection_in_cultures_of_rat_cerebellar_granule_cells_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0014-4886(97)96627-9 DB - PRIME DP - Unbound Medicine ER -
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