Neurotoxic effects of the intrastriatal injection of spermine and spermidine: lack of involvement of NMDA receptors

Bourdiol, F.; Fage, Dominique; Serrano, A.; Carter, Christopher; Bénavidès, J.; Scatton, B.

doi:10.1016/0006-8993(92)91546-q

Cited by 26 publications

(10 citation statements)

References 34 publications

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“…Given a recovery of -25% across the dialysis membrane at this flow rate, extracellular spermidine concentrations in the parietal cortex following permanent MCA occlusion are within the low micromolar range. Spermidine (and spennine) are neurotoxic, per se, in hippocampal slices at micromolar concentrations (from 50 p M ) (Virgili et al, 1992), and are also neurotoxic following intrastriatal injection (Virgili et al, 1992;Bourdiol et al, 1992). Frank polyamine neurotoxicity, induced by high polyamine concentrations, in vitro or in vivo, is not sensitive to NMDA antagonists (Virgili el al, 1992;Bourdiol et al, 1992).…”

Section: Resultsmentioning

confidence: 99%

“…Spermidine (and spennine) are neurotoxic, per se, in hippocampal slices at micromolar concentrations (from 50 p M ) (Virgili et al, 1992), and are also neurotoxic following intrastriatal injection (Virgili et al, 1992;Bourdiol et al, 1992). Frank polyamine neurotoxicity, induced by high polyamine concentrations, in vitro or in vivo, is not sensitive to NMDA antagonists (Virgili el al, 1992;Bourdiol et al, 1992). Whether the spermidine concentrations attained in this study are sufficient to provoke NMDA receptor independent neurotoxicity is debateable.…”

Section: Resultsmentioning

confidence: 99%

“…Low concentrations of spermine or spermidine potentiate NMDA mediated neurotoxicity in vitro, probably via this modulatory site (Shalaby et al, 1992). However spermine and spermidine can also exert frank neurotoxic effects in tissue culture through NMDA receptor independent mechanisms (Virgili et al, 1992) and are also neurotoxic following intrastriatal injection again via NMDA independent mechanisms (Virgili et a1, 1992;Bourdiol et al, 1992). Overt polyamine neurotoxi-city in vitro or in vivo has not been well characterised.…”

Section: Introductionmentioning

confidence: 99%

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Release of spermidine from the rat cortex following permanent middle cerebral artery occlusion

Carter¹,

Poignet

Carboni

et al. 1995

Fundamemntal Clinical Pharma

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We have studied the effects of middle cerebral artery (MCA) occlusion in rats on polyamine efflux in the parietal cortex using the microdialysis technique. Dialysis probe implantation itself provoked a delayed, prolonged and vigorous release of spermidine and putrescine. Spermidine release returned to stable baseline levels within 48 hours. Putrescine release also returned to lower levels within this time period but putrescine levels in the dialysate fluctuated dramatically in individual animals. Because of the underlying effects of the dialysis probe (likely a reflection of traumatic cerebral damage and stimulation of polyamine metabolism and release within the immediate vicinity of the dialysis probe), MCA occlusion was performed 48 hours after probe implantation. MCA occlusion persistently (5/5 animals) resulted in a significant increase in cortical spermidine efflux, although the onset, magnitude and duration of this increased release was variable. Putrescine efflux was significantly increased in 2/5 animals with MCA occlusion but the increase in release was similar to the spontaneous fluctuations observed in control animals. Spermine was not detectable in cortical dialysates of control or MCA occluded groups. Spermidine, but not spermine or putrescine is consistently released from the parietal cortex following permanent focal ischaemia and may contribute to ischaemic neuropathology either through its effects at the N-methyl-D-aspartate (NMDA) receptor or via direct, and as yet uncharacterised, neurotoxic effects.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Release of spermidine from the rat cortex following permanent middle cerebral artery occlusion

Carter¹,

Poignet

Carboni

et al. 1995

Fundamemntal Clinical Pharma

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“…However, there are disparate reports in the literature concerning the involvement of NMDA receptor activation in polyamine‐induced neuronal toxicity. Thus, although many reports indicate that polyamine toxicity is mediated by an enhancement of NMDA receptor activation (Fahey et al, 1993; Munir et al, 1993; Otsuki et al, 1995; Sparapani et al, 1997), there are several investigations that have been unable to link NMDA receptor activation to polyamine toxicity (Bourdiol et al, 1992; Virgili et al, 1992; Doyle and Shaw, 1994). It is likely that different models (e.g., primary cell culture versus in vivo injections), cell types (e.g., striatal, hippocampal, cortical, or cerebellar granule), and experimental conditions all contribute to the apparent disparities among investigations.…”

Section: Discussionmentioning

confidence: 99%

Spermine‐Induced Toxicity in Cerebellar Granule Neurons Is Independent of Its Actions at NMDA Receptors

Segal

Skolnick

2000

Journal of Neurochemistry

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The neurotoxic actions of polyamines such as spermine have been linked to their modulation of NMDA receptors, resulting in an excitotoxic cell death. Here, we demonstrate that chronic exposure to the polyamine spermine and acute exposure to the combination of spermine and glutamate result in significant toxicity to primary cultures of cerebellar granule neurons (CGNs). However, in both cases this cell death (a) lacks the characteristic cell swelling associated with the necrotic cell death induced by glutamate and (b) is characterized by the widespread formation of apoptotic nuclei. Whereas dizocilpine (MK-801) blocks the synergistic cell death resulting from acute exposure to spermine plus glutamate, neither MK-801 nor the calcium chelator EGTA appreciably attenuates CGN death resulting from chronic exposure to spermine. Consistent with previous reports, glutamate, both acute and chronic, causes CGN death that is characterized by cell swelling, sensitivity to MK-801 and EGTA, and only small numbers of apoptotic nuclei. Spermine-induced toxicity is not blocked by either the protein synthesis inhibitor cycloheximide or the pancaspase inhibitor tert-butoxycarbonyl-Asp-(O-methyl) fluoromethyl ketone. However, the antioxidant butylated hydroxyanisole is an effective blocker of spermine-induced CGN death, suggesting a free-radical component to this cell death. The intact spermine molecule, rather than a catabolic by-product, is required for cell death because the amine oxidase inhibitors N1,N2-bis(2,3-butadienyl)-1,4-butanediamine and aminoguanidine fail to block this toxicity. Thus, in CGNs, spermine-induced toxicity does not occur by its modulation of NMDA receptors, although, under some circumstances, NMDA receptor activation can modulate spermine-induced toxicity.

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“…Putrescine (300 nmol) is without these effects, while previous administration of MK-801 (10 mg/kg i.p.) has no protective effect against the neuronal loss by spermine and spermidine (Bourdiol et al, 1992;Virgili et al, 1992). In contrast, Otsuki et al, have shown a significant reduction of the volume of damage by the administration of 60 nmol MK-801 together with 100 nmol spermine, or by pre-treatment of animals with pentobarbital (Otsuki et al, 1995).…”

Section: Cytotoxicity Of Polyamines and Rele-vant Oxidation Productsmentioning

confidence: 96%

Neuronal and Glial Responses to Polyamines in the Ischemic Brain

Takano¹,

Ogura²,

Nakamura³

et al. 2005

CNR

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The polyamines, putrescine, spermidine and spermine are present in most living cells, with the essentiality for normal cell function, cellular growth and differentiation. In the mammalian brain, polyamines are also present at relatively high concentrations with different regional distribution profiles. Cerebral ischemia is a leading cause of disability and mortality in humans, and believed to yield a cascade of cytotoxic molecules responsible for the death of viable cells in the brain. Polyamines have been implicated in the pathogenesis of ischemic brain damage. For example, polyamine biosynthesis is increased after the onset of cerebral ischemia through an induction of ornithine decarboxylase, a key enzyme in the polyamine biosynthetic pathway. The administration of a drug that inhibits ornithine decarboxylase activity prevents the development of ischemic brain damage, suggesting a critical role of the accumulation of polyamines in the ischemic brain in the pathogenesis of stroke. Both spermine and spermidine are linked to the development of glutamate-mediated neurotoxicity, for they can bind to the N-methyl-D-aspartate (NMDA)-sensitive subtype of glutamate receptors to potentiate cellular responses to glutamate. Moreover, polyamines are metabolized by polyamine oxidases after acetylation to produce different cytotoxic aldehydes and reactive oxygen species such as hydrogen peroxide, which possibly damage proteins, DNA and lipids. Polyamines have been extensively studied in the ischemic brain, particularly with respect to neuronal responses such as NMDA receptor-mediated excitotoxicity. However, little is known about glial responses to polyamines in the ischemic brain to date. In this review, we would summarize previous studies related to neuronal and glial responses to polyamines in the ischemic brain.

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Neurotoxic effects of the intrastriatal injection of spermine and spermidine: lack of involvement of NMDA receptors

Cited by 26 publications

References 34 publications

Release of spermidine from the rat cortex following permanent middle cerebral artery occlusion

Release of spermidine from the rat cortex following permanent middle cerebral artery occlusion

Spermine‐Induced Toxicity in Cerebellar Granule Neurons Is Independent of Its Actions at NMDA Receptors

Neuronal and Glial Responses to Polyamines in the Ischemic Brain

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