Polyamine-enhanced NMDA receptor activity: effect of ethanol (original) (raw)
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Role of Polyamines and NMDA Receptors in Ethanol Dependence and Withdrawal
Alcoholism: Clinical and Experimental Research, 2001
This article represents the proceedings of a symposium at the 2000 ISBRA Meeting in Yokohama, Japan. The chair was John M. Littleton. The presentations were (1) Examination of ethanol spermine and acamprosate actions on native and recombinant NMDA receptors, by David Lovinger; (2) Ethanol inhibition of NMDA neurotoxicity on the polyamine site in cerebellar granule cells, by Sture Liljequist; (3) Alterations in expression of NMDA receptor subunits during ethanol exposure and withdrawal, by Raj Ticku; (4) Alterations in polyamine synthesis and release as a potential mechanism for ethanol dependence and withdrawal, by Izuru Matsumoto; (5) The role of polyamines in neurotoxicity induced by alcohol withdrawal in vitro, by John Littleton; and (6) Agmatine reduces some of the effects of "third trimester" alcohol exposure using a rodent model, by Susan Barron.
Alcoholism: Clinical & Experimental Research, 2003
Several reports demonstrate that withdrawal from long-term ethanol exposure is associated with significant central nervous system neurotoxicity, produced at least in part by increased activity of N-methyl-d-aspartate receptors (NMDARs). Recent evidence suggests that elevations in the synthesis and release of the polyamines spermidine and spermine, which are known modulators of NMDARs, contribute to the increased activity of the receptor during ethanol withdrawal. Therefore, the goal of this investigation was to examine what role, if any, spermidine and spermine have in the generation of ethanol withdrawal-induced neurotoxicity. Neurotoxicity (measured as fluorescence of the cell death indicator propidium iodide, PI), glutamate release (measured by high-performance liquid chromatography analysis), and polyamine concentrations (by high-performance liquid chromatography) were measured in rat hippocampal slice cultures undergoing withdrawal from chronic (10 day) ethanol exposure (100 mM). In addition, the effects of the polyamine synthesis inhibitor di-fluoro-methyl-ornithine (DFMO, 0.1-100 nM) and NMDAR polyamine-site antagonists ifenprodil, arcaine, and agmatine (1 nM-100 microM) on ethanol withdrawal- and NMDA-induced neurotoxicity were measured. Ethanol withdrawal significantly increased glutamate release (peaking at 18 hr with a 53% increase), increased concentrations of putrescine and spermidine (136% and 139% increases, respectively, at 18 hr), and produced significant cytotoxicity in the CA1 hippocampal region (56% increase in PI staining relative to controls) of the cultures. The cell death produced by ethanol withdrawal was significantly inhibited by ifenprodil (IC(50) = 14.9 nM), arcaine (IC(50) = 37.9 nM), agmatine (IC(50) = 41.5 nM), and DFMO (IC(50) = 0.6 nM). NMDA (5 microM) significantly increased PI staining in the CA1 region of the hippocampal cultures (365% relative to controls), but ifenprodil, arcaine, agmatine, and DFMO all failed to significantly affect this type of toxicity. These data implicate a role for polyamines in ethanol withdrawal-induced neurotoxicity and suggest that inhibiting the actions of polyamines on NMDARs may be neuroprotective under these conditions.
Regional Heterogeneity of Polyamine Effects on the N-Methyl-D-Aspartate Receptor in Rat Brain
Journal of Neurochemistry, 1993
Abstract: Polyamines have pronounced effects on N-methyl-D-aspartate (NMDA) receptors in vitro and may be important modulators of NMDA receptor activity in vivo. There is considerable regional heterogeneity in the effects of polyamines on [3H]MK-801 binding in rat brain sections. For example, spermidine enhances the binding of [3H]MK-801 to a much greater extent in the striatum than in the cortex. To further explore the basis for this regional heterogeneity, the effects of polyamines on [3H]MK-801 binding were measured in well-washed membranes prepared from frontal cortex and striatum. There was no difference in the concentration-response relationship for spermidine or the KD for [3H]MK-801 in the presence of 75 μM spermidine, suggesting that the regional difference seen in tissue sections is due to an endogenous factor that is either removed or inactivated during the preparation of membranes. Comparison of spermidine concentration-response curves in washed and unwashed tissue sections revealed that washing selectively enhanced the Emax value in the ventromedial caudate putamen without changing the EC50. This is consistent with the possibility that a noncompetitive polyamine antagonist is being removed from this region during washing. There was no regional variability in the effects of the putative inverse agonist 1, 10-diaminodecane, consistent with recent suggestions that this polyamine inhibits the NMDA receptor at a site distinct from the one at which polyamines act to enhance NMDA receptor function. Agents that modulate the redox state of the NMDA receptor did not eliminate the regional heterogeneity of polyamine effects. Furthermore, the stimulatory effect of glycine in these regions did not correlate with that of spermidine. These results suggest the existence of one or more endogenous factors that noncompetitively influence the effects of polyamines in a regionspecific manner.
Brain Research, 1991
Polyamines such as spermidine potentiate activation of the N-methyl-D-aspartate (NMDA)-type excitatory amino acid receptor. The goal of the present study was to investigate interactions between the putative polyamine binding site and previously described sites for glutamate and glycine. Binding of the high-potency PCP receptor ligand [3H]MK-801 to well-washed rat brain membranes was used as an in vitro probe of NMDA receptor activation. Spermidine concentration-response studies were performed in the absence and presence of both glutamate and glycine, with and without D-(-)-2-amino-5-phosphonovaleric acid (D(-)AP-5) or 7-chiorokynurenic acid (7C1-KYN). Incubation in the presence of spermidine alone induced a 20.4-fold increase in [3H]MK-801 binding with an ECs0 value of 13.3/~M. The mean concentration of spermidine which induced maximal stimulation of binding was 130/~M (n = 10, S.E.M. = 24.66, range = 25-250 ktM). Glutamate (10 /zM) decreased the ECs0 value for spermidine-induced stimulation of [3H]MK-801 binding to 3.4/~M. Glycine (10 ktM) did not significantly alter either maximum spermidine-induced [3H]MK-801 binding or the ECso value for spermidine-induced stimulation of [3H]MK-801 binding. Incubation in the presence of the specific glutamate antagonist D(-)AP-5 attenuated [3H]MK-801 binding in a glutamate-reversible fashion. The competitive glycine antagonist 7CI-KYN decreased maximum spermidine-induced [ 3H]MK-801 binding in a glycine-reversible fashion. In addition, 7CI-KYN increased the ECso value for spermidine-induced stimulation of [3H]MK-801 binding while D(-)AP-5 was without effect. These findings suggest that glutamate and glycine regulate the polyamine binding site differentially. PCP-like agents induce a psychotomimetic state closely resembling schizophrenia by inhibiting NMDA receptor-mediated neurotransmission. The ability of polyamines to modulate NMDA receptor functioning suggests a potential site for pharmacological intervention.
Polyamines modulate the neurotoxic effects of NMDA in vivo
Brain Research, 1993
The ability of polyamines to alter NMDA-induced neurotoxicity in neonatal rats was examined to determine whether polyamines modulate NMDA receptor activity in vivo. Unilateral injections of NMDA and/or polyamines were made into the striatum of 7-day-old rats. After 5 days, the brains were removed and 20/.~m thick coronal sections were cut and stained with Cresyl violet. A computer-based image analysis system was used to densitometrically measure the cross-sectional area of intact tissue in the control and injected hemispheres. Administration of NMDA (5-40 nmol) produced a dose-dependent tissue damage that ranged from 7 to 52% of the area of the uninjected hemisphere. The polyamine agonist spermine (10-500 nmol) dose-dependently exacerbated the toxicity of a 15 nmol dose of NMDA, increasing the size of the lesion by up to 50%. Administration of spermine alone produced dose-dependent tissue damage that ranged from 9 to 52%. The damage produced by both NMDA and spermine could be completely inhibited by co-administration of the NMDA antagonist MK-801. The polyamine inverse agonist 1,10-diaminodecane (DA-10, 50-400 nmol) inhibited the damage produced by NMDA in a dose-dependent manner, with a maximal inhibition of 50%. Administration of DA-10 alone produced limited damage at doses above 100 nmol. The weak partial agonist diethylenetriamine had no effect by itself or on NMDA-induced toxicity at the doses tested. These results indicate that polyamines can modulate the activity of NMDA receptors in vivo and suggest that polyamines or related compounds may have important therapeutic potential as neuroprotective agents.
Neuroscience Letters, 1996
The amino-1-oxy-and amino-8-oxy-analogues of spermidine (1-O-SPD and 8-O-SPD) were tested in vitro with rat hippocampal membranes as potential modulators of the N-methyl-D-aspartate (NMDA) receptor complex via the polyamine regulatory site. In the presence of 1/~M glutamate and glycine, the binding of the NMDA channel ligand [3H]MK-801 was stimulated by 8-O-SPD (ECs0 = 50ktM); 1-O-SPD was without significant influence at concentrations up to 1 mM. Addition of 2 and 4/~M of the polyamine agonist spermine eliminated the stimulatory property of 8-O-SPD, whereas 1-O-SPD was inhibitory under these conditions (IC5o = 274 and 481 ktM, respectively). At higher concentrations of spermine, both compounds were inhibitory. Inhibition of [3H]MK-801 binding by the inverse polyamine agonists 1,10-diaminodecane, 1,12-diaminododecane, and arcaine was attenuated by 1 mM 1-O-SPD. The data are compatible with the notion that 8-O-SPD is a partial polyamine agonist and that I-O-SPD is an antagonist without intrinsic activity.
Hydroxycinnamic acid amide derivatives of polyamines reverse spermine-induced CNS excitation
Pharmacology Biochemistry and Behavior, 2015
The aim of this study was to examine the acute effect of a range of novel hydroxycinnamic acid derivatives of spermine on the development of spermine-induced CNS excitation and convulsions in female Laca mice, and to assess the chronic adverse behavioural effect profile of these compounds over a 5 day period. Four of the six novel polyamine analogues dose-dependently inhibited body tremor and tonic convulsions caused by spermine, when administered centrally (icv) or peripherally (ip). BU43b was the most potent analogue tested, but BU31b, 33b, and 36b were also effective (p b 0.01, Mann-Whitney U test). A similar profile of effectiveness was seen with peripheral and central administration, indicating that the analogues may cross the blood brain barrier. More chronic investigation of the adverse effects of the compounds administered alone over 5 days of observation indicated that the drugs were well tolerated, only causing reduced locomotor activity on the first day of the study and mild changes in behaviours linked to CNS and ANS function. It is likely that NMDA receptor NR2B subunit inhibition is involved in the anticonvulsant effect of these novel analogues, but other mechanisms may also be involved. These novel polyamine derivatives warrant further investigation of their therapeutic potential in treating epilepsy and CNS disorders where excitotoxicity is implicated.
Journal of Medical Biochemistry, 2007
Spermine and L-Name Pretreatment Effects on Polyamine and Nitric Oxide Metabolism in Rat Brain During SeizuresIn the CNS polyamines can exert opposite effects, depending on the concentration and conditions in the cell. Protective or neurotoxic polyamine effects were documented during seizures and repeated CNS excitation. Intensive research of exogenous polyamines effects during seizures induced by numerous agents did not clear up confusions about the duality of effects and the role of polyamines in seizures. In order to understand polyamine modulatory effects in seizures, the importance of NO and polyamine metabolism interdependence and the possible implication of changes of postulated NO and polyamine equillibrium in seizures, the effects of spermine alone and in combination with L-NAME (NOS inhibitor) on seizures induced by pentazol (PTZ) were investigated. To compare the obtained results, the effects of anticonvulsant midazolam on NO production during seizures were also investiga...
Neuroscience Letters, 1992
In the present study, we have examined by light and electron microscopy whether SL 82.0715, a polyamine site-directed N-methyl-D-aspartate (NMDA) antagonist, causes pathological changes in cerebrocortical neurons similar to those observed with NMDA receptor channel blockers in the rat brain. Dizocilpine (1, 2 and 5 mg.kg-1, s.c.) induced a dose-dependent vacuolization of the neuronal cytoplasm in specific neurons of the retrosplenial and posterior cingulate cortices (layers III and IV) even at the lowest dose studied, at 6 h post-injection. In contrast, SL 82.0715 (10 and 30 mg.kg-1 i.p., 6 h post-injection) did not induce such morphological alterations. These results indicate that NMDA receptor blockade is not necessarily associated with alterations of cortical neuronal morphology.
Brain Research, 1991
The intrastriatal injection of N-methyl-D-aspartate (NMDA) (250 nmol) produced a delayed and marked increase in striatai ornithine decarboxylase (ODC) activity and putrescine levels which peaked 6-15 h following the injection of NMDA. Striatai ODC activity subsequently returned to normal values while putrescine levels remained significantly elevated for up to 4 days following the lesion. NMDA produced an early and progressive decline in striatal spermine and spermidine levels, preceding the increase in ODC activity, with a maximum effect 2 h following injection. Spermidine levels returned to normal 6 h post-NMDA infusion, and subsequently increased to above normal levels 36 h and 4 days after the infusion of NMDA. This late increase in striatal spermidine levels paralleled an increase in the binding of the glial cell/macrophage marker [3H]PK 11195. Spermine levels tended to return to normal values 6 h after the injection of NMDA but may be further depressed at later intervals (15 h to 4 days). The intrastriatal injection of saline also resulted in a delayed increase in striatal ODC activity and putreseine levels, but these changes were minor compared to those produced by NMDA. Intrastriatal saline injection provoked no consistent change in striatal spermine or spermidine levels. The changes in polyamine metabolism produced by the intrastriatal injection of kainic acid (4 nmol) were only analysed at 6 and 15 h following injection but were qualitatively similar to those produced by NMDA although perhaps following a slightly more delayed time-course. Neurotoxic lesions of the striatum thus provoke changes in ODC activity and increased levels of putrescine that follow closely the time-course of similar events in the ischaemic brain. The initial early changes in spermine and spermidine levels induced by NMDA could perhaps alter the functioning of the NMDA receptor itself via its polyamine-sensitive modulatory site and contribute to a feed-forward activation of NMDA receptors and prolonged NMDA receptor-mediated toxicity.