SL 82.0715, an NMDA antagonist acting at the polyamine site, does not induce neurotoxic effects on rat cortical neurons

Duval, D.; Roome, Nigel; Gauffeny, Christiane; Nowick, J.P.; Scatton, B.

doi:10.1016/0304-3940(92)90402-s

Cited by 50 publications

(9 citation statements)

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“…Scatton and colleagues have shown that SL 82.0715, an NMDA antagonist acting at the polyamine site, does not evoke increased CMRgic nor induce neuromorphological changes in rat CNS (Scatton et al, 1991;Duval et al, 1992). These results, together with those from the present studies, suggest that the potential therapeutic window for NMDA receptor antagonists may depend upon the specific site within the NMDA receptor complex at which the compound acts to reduce activation.…”

Section: Discussionsupporting

confidence: 61%

Lack of effect of L‐687,414 ((+)‐cis‐4‐methyl‐HA‐966)₅ an NMDA receptor antagonist acting at the glycine site, on cerebral glucose metabolism and cortical neuronal morphology

Hargreaves

Rigby

Smith

et al. 1993

British J Pharmacology

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1 N-methyl-D-aspartate (NMDA) receptor ion channel antagonists have been reported to cause pronounced increases in cerebral glucose metabolism (CMRglc) and transient reversible vacuolation within pyramidal cortical neurones. The present studies examined in rats the effects of the NMDA receptor antagonist, L-687,414 (R-( + )-cis-4-methyl-3-amino-1-hydroxypyrolid-2-one; (+ )-cis-4-methyl-HA-966) on regional CMRg,c and cortical neuronal morphology.2 L-687,414 was given as a steady state intravenous infusion for 4 h in a neuroprotective dose regime of 17.5 mg free base kg-' bolus followed by 225 jtg kg' min-' (n = 8) or at the higher dose rate of 35 mg kg-' bolus followed by 440 jig kg-' min ' (n = 10). Data were compared to a parallel series of experiments in rats given the NMDA receptor ion channel antagonist, dizocilpine for 4 h in the optimum intravenous neuroprotective dose-regime of 0.12 mg kg-' bolus followed by 1.8 gg kg-' minm ' (n = 8) or at the higher dose rate of 0.4 mg kg'-bolus followed by 6 jig kg-' min-' (n = 4; morphology only studied). A saline-infused group of rats (n = 8) were used as controls.3 CMRglc was studied by use of ['4C]-2-deoxyglucose and autoradiography (n = 4 each group) whilst plasma drug levels were in a steady state during the final 45 min of the 4 h drug infusion. Effects on cortical neuronal morphology were assessed at the end of the 4 h infusion period using light microscopic techniques (n = 4-6 each group). 4 The results showed a selective activation of limbic CMRglc by dizocilpine at optimal neuroprotective dose levels and showed that this dose was at the threshold for the neuronal vacuolation response as I of 4 rats showed morphological changes in the pyramidal neurones in the posterior cingulate and retrosplenial cortices. At the higher dose rate of dizocilpine, all 4 animals showed extensive morphological changes in these cortical neurones. In contrast, L-687,414 did not increase limbic CMRg1, nor evoke vacuolation when given in the neuroprotective dose-regime or at the higher dosage rate. 5 The findings of the present study suggest that neuroprotection mediated through the NMDA receptor complex can be achieved without changes in CMRg,i or cortical neuronal morphology by antagonism at the glycine modulatory site.

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Section: Discussionsupporting

confidence: 61%

Lack of effect of L‐687,414 ((+)‐cis‐4‐methyl‐HA‐966)₅ an NMDA receptor antagonist acting at the glycine site, on cerebral glucose metabolism and cortical neuronal morphology

Hargreaves

Rigby

Smith

et al. 1993

British J Pharmacology

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“…Similar to CGP 61594, the neuroprotective agents ifenprodil and eliprodil, acting at the polyamine site of NMDA receptors, interact preferentially with NR1/2B receptors (60,61). They are characterized by a favorable side effect profile at neuroprotective doses compared with agents that inhibit NMDA receptors nonselectively (62)(63)(64). Thus, the glycine antagonist CGP 61594 may serve as a valuable tool for developing potential therapeutic agents targeted to the NR1/2B receptor.…”

Section: Electrophysiological Analysis Of Cgp 61594 On Recombinantmentioning

confidence: 99%

Differentiation of Glycine Antagonist Sites ofN-Methyl-d-aspartate Receptor Subtypes

Honer¹,

Benke²,

Laube³

et al. 1998

Journal of Biological Chemistry

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The binding site for the co-agonist glycine on N-methyl-D-aspartate (NMDA) receptors has been mapped to the NR1 subunit whereas binding of the principal agonist glutamate is mediated by the NR2 subunits. block, slow activation and inactivation kinetics, and the requirement for glycine as a co-agonist in channel gating (1-6). They play a crucial role in brain development, synaptic plasticity and the pathophysiology of major neurological disorders (7-11). NMDA receptors are assembled from the NR1 subunit in combination with at least one type of NR2 subunit (NR2A-2D) (12-15), giving rise to receptor subtypes with distinct electrophysiological and pharmacological properties (2, 16 -21).Inhibition of NMDA receptors by glycine site antagonists is of major interest for the therapeutic intervention in pathological central nervous system states like stroke, head injury, and epilepsy. At doses evoking remarkable anticonvulsant and neuroprotective effects, glycine site antagonists are less prone to psychotomimetic actions and exhibit less severe motoric and cognitive side effects than glutamate site antagonists (22). Further improvements are expected from the targeting of the glycine site of NMDA receptor subtypes.The NR1 subunit harbors main determinants of the glycine binding site in recombinant receptors as well as in situ. Recombinant homomeric NR1 receptors bind glycine agonists and antagonists (19,23,24), and various amino acid residues involved in high affinity binding have been identified by mutational analysis of the NR1 subunit (25-28). Similarly, in native receptors, the novel glycine antagonist and photoaffinity ligand [ 3 H]CGP 61594 labels exclusively the NR1 subunit of NMDA receptors in brain membranes.2 In contrast, the glutamate binding pocket is formed by the NR2 subunits (29). Interestingly, the properties of the glycine site are influenced by the type of NR2 subunit that is assembled with the NR1 subunit. Glycine displays an up to 10-fold lower potency at NR1/2A receptors than at NR1/2B, NR1/2C, or NR1/2D receptors, and a similar difference in affinity has also been observed for the glycine site agonists D-serine, 1-aminocyclobutanecarboxylic acid, D-alanine, 414 (16,19,21,[30][31][32][33]. However, glycine site antagonists (e.g. L-701,324, L-689,560, L-695,902, CKA) did not clearly differentiate between recombinant NMDA receptor subtypes (23,34). Mutational analysis of the NR1 subunit suggested structural differences in the binding domains of glycine site agonists and antagonists (25)(26)(27)(28). Some of the mutated residues affected the affinity for

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“…However, it has been demonstrated that these drugs produce a psychotomimetic action, impairment of learning and memory, and morphological damage in the posterior cingulate and retrosplenial cortex of the rat brain (Olney et al, 1989(Olney et al, , 1991Allen and Iversen, 1990;Fix et al, 1993). In addition, it has been reported that neuronal degeneration has been observed in the limbic structures, including the retrosplenial cortex, after the continuous administration of non-competitive NMDA receptor antagonists (dizocilpine and phencyclidine) and the competitive NMDA receptor antagonist LY 235959 (Ellison, 1994), and that CGS 19755 and CGP 37849, antagonists acting at the glutamate site of the NMDA receptor complex, cause neurotoxicity in the retrosplenial cortex (Hargreaves et al, 1993b). In contrast, it has been reported that SL 82.0715 (eliprodil), an antagonist acting at the polyamine site of the NMDA receptor complex, and L684,414, an antagonist acting at the glycine site of the NMDA receptor complex, do not induce Note the absence of HSP-70 immunoreactivity in the retrosplenial cortex 24 h after administration of vehicle (I m l k g , i.p.).…”

Section: Introductionmentioning

confidence: 99%

Rolipram, a Selective Phosphodiesterase Type‐IV Inhibitor, Prevents Induction of Heat Shock Protein HSP‐70 and hsp‐70 mRNA in Rat Retrosplenial Cortex by the NMDA Receptor Antagonist DizociIpine

Hashimoto

Tomitaka

et al. 1997

Eur J of Neuroscience

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The non-competitive NMDA receptor antagonists, such as (+)-MK-801 (dizocilpine), cause the expression of heat shock protein HSP-70 and pathomorphological damage in the retrosplenial cortex of the rat brain. However, the precise mechanism(s) underlying the neurotoxicity of NMDA receptor antagonists is unknown. The present study was undertaken to examine the role of phosphodiesterase type IV in the expression of heat shock genes induced by dizocilpine. Heat shock protein HSP-70, which is known as a sensitive marker of neuron injury, was induced in the retrosplenial cortex of the rat brain 24 h after a single administration of dizocilpine (1 mg/kg). Pretreatment with the specific phosphodiesterase type IV inhibitor rolipram (2.5, 5 or 10 mg/kg, 15 min before dizocilpine) attenuated the expression of HSP-70 and hsp-70 mRNA induced by dizocilpine (1 mg/kg) in a dose-dependent manner. Furthermore, another phosphodiesterase type IV inhibitor, Ro 20-1724 (5 or 10 mg/kg, 15 min before dizocilpine), and a non-selective phosphodiesterase inhibitor, 3-isobutyl-1-methylxanthine (IBMX) (5 or 10 mg/kg, 15 min before dizocilpine), significantly attenuated the expression of HSP-70 protein and hsp-70 mRNA induced in the retrosplenial cortex by dizocilpine. However, the induction of the immediate early gene c-fos and microglial activation in the retrosplenial cortex after administration of dizocilpine was not attenuated by pretreatment with rolipram (5 or 10 mg/kg, 15 min before dizocilpine). Moreover, histopathological study indicated that pretreatment with rolipram (5 or 10 mg/kg, 15 min before dizocilpine) did not prevent the formation of vacuoles caused by treatment with dizocilpine. The present findings suggest that phosphodiesterase type IV may play a significant role in the expression of HSP-70 protein and hsp-70 mRNA in the rat retrosplenial cortex after administration of dizocilpine, and that phosphodiesterase type IV may not play a role in the neurotoxicity of NMDA receptor antagonists such as dizocilpine.

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SL 82.0715, an NMDA antagonist acting at the polyamine site, does not induce neurotoxic effects on rat cortical neurons

Cited by 50 publications

References 13 publications

Lack of effect of L‐687,414 ((+)‐cis‐4‐methyl‐HA‐966)₅ an NMDA receptor antagonist acting at the glycine site, on cerebral glucose metabolism and cortical neuronal morphology

Lack of effect of L‐687,414 ((+)‐cis‐4‐methyl‐HA‐966)₅ an NMDA receptor antagonist acting at the glycine site, on cerebral glucose metabolism and cortical neuronal morphology

Differentiation of Glycine Antagonist Sites ofN-Methyl-d-aspartate Receptor Subtypes

Rolipram, a Selective Phosphodiesterase Type‐IV Inhibitor, Prevents Induction of Heat Shock Protein HSP‐70 and hsp‐70 mRNA in Rat Retrosplenial Cortex by the NMDA Receptor Antagonist DizociIpine

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SL 82.0715, an NMDA antagonist acting at the polyamine site, does not induce neurotoxic effects on rat cortical neurons

Cited by 50 publications

References 13 publications

Lack of effect of L‐687,414 ((+)‐cis‐4‐methyl‐HA‐966)5 an NMDA receptor antagonist acting at the glycine site, on cerebral glucose metabolism and cortical neuronal morphology

Lack of effect of L‐687,414 ((+)‐cis‐4‐methyl‐HA‐966)5 an NMDA receptor antagonist acting at the glycine site, on cerebral glucose metabolism and cortical neuronal morphology

Differentiation of Glycine Antagonist Sites ofN-Methyl-d-aspartate Receptor Subtypes

Rolipram, a Selective Phosphodiesterase Type‐IV Inhibitor, Prevents Induction of Heat Shock Protein HSP‐70 and hsp‐70 mRNA in Rat Retrosplenial Cortex by the NMDA Receptor Antagonist DizociIpine

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Lack of effect of L‐687,414 ((+)‐cis‐4‐methyl‐HA‐966)₅ an NMDA receptor antagonist acting at the glycine site, on cerebral glucose metabolism and cortical neuronal morphology

Lack of effect of L‐687,414 ((+)‐cis‐4‐methyl‐HA‐966)₅ an NMDA receptor antagonist acting at the glycine site, on cerebral glucose metabolism and cortical neuronal morphology