Effects of sigma ligands on mouse cerebellar cyclic guanosine monophosphate (cGMP) levels in vivo: further evidence for a functional modulation ofN-methyl-d-aspartate (NMDA) receptor complex-mediated events by sigma ligands

Rao, Tadimeti S.; Mick, Steve J.; Cler, Julie A.; Emmett, Mark R.; Dilworth, Vickie M.; Contreras, Patricia C.; Gray, Nancy M.; Wood, Paul L.; Iyengar, Smriti

doi:10.1016/0006-8993(91)90747-j

Cited by 29 publications

(7 citation statements)

References 35 publications

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“…Polyamine NMDA antagonists were able to inhibit completely the NMDA-mediated, NO-dependent production of cyclic GMP with ifenprodil being more potent than the heterocyclic aminoalcohols. These data thus support an older body of work that ifenpiodil blocked NMDA-stimulated production of cyclic GMP in' cerebellar slices (Carter et al, 1988) and attenuated NMDA-dependent, cerebellar cyclic GMP responses in vivo (Rao et al, 1991). This inhibition probably occurs subsequent to the blockade of the NMDA receptorgated calcium channel (Reynolds & Miller, 1989) as the enzyme for NO biosynthesis, NO synthase, is known to be calcium-dependent (Garthwaite, 1991).…”

Section: Nmda-induced Leakage Of Ldhsupporting

confidence: 72%

Blockade by polyamine NMDA antagonists related to ifenprodil of NMDA‐induced synthesis of cyclic GMP, increases in calcium and cytotoxicity in cultured neurones

Beart

Schousboe²,

Frandsen³

1995

British J Pharmacology

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1 Antagonists acting at the polyamine site of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor, including a number of heterocyclic aminoalcohols related to ifenprodil, were investigated to establish their functional interaction at the NMDA receptor and their neuroprotective profile.2 In murine cultured neocortical neurones, NMDA (100 jiM)-stimulated production of guanosine 3':5'-cyclic monophosphate (cyclic GMP) was blocked by N-l([thienyl]-cyclohexyl)-piperidine (1 tiM) and by the nitric oxide (NO) synthase inhibitor N0-nitro-L-arginine (100 iM). Ifenprodil and structurally related heterocyclic aminoalcohols inhibited in a concentration-dependent manner the NMDAstimulated, NO-dependent production of cyclic GMP; rank potency order was: ifenprodil > 2309 BT > tibalosine > threo-tibalosine > 840S.3 All of the polyamine NMDA antagonists blocked NMDA (300 fiM)-stimulated increases in intracellular calcium concentrations as measured by changes in the fluorescence of pre-loaded fluo-3-acetoxy methyl ester. Rank potency order was: ifenprodil > 2309 BT > 840S > tibalosine > threotibalosine. 4 In a series of experiments to evaluate the effectiveness of the polyamine NMDA antagonists as blockers of NMDA-induced cytotoxicity, all of the drugs were found to inhibit the leakage of lactate dehydrogenase after the exposure of the murine neocortical cultures to NMDA (100 JM, 5 h). Rank potency order was: 2309 BT > ifenprodil > tibalosine > threo-tibalosine > 840S. 5 These results provide direct evidence that polyamine NMDA antagonists produce a functional blockade of the NMDA receptor complex. The heterocyclic aminoalcohols described herein, like ifenprodil, block NMDA-mediated elevation of intracellular NO and calcium, two key events in the excitotoxic cascade, and are cytoprotective.

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Section: Nmda-induced Leakage Of Ldhsupporting

confidence: 72%

Blockade by polyamine NMDA antagonists related to ifenprodil of NMDA‐induced synthesis of cyclic GMP, increases in calcium and cytotoxicity in cultured neurones

Beart

Schousboe²,

Frandsen³

1995

British J Pharmacology

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“…Rimcazole by itself at low doses (15-30 mg/kg) did not induce increases in cGMP levels, but at higher doses (50-100 mg/kg) cGMP levels were increased (119). This finding correlates with the clinical observations that high dose rimcazole produces convulsions (19,28,38).…”

Section: Neuroprotective Effectssupporting

confidence: 85%

“…In the original clinical trials, rimcazole caused convulsions when given at high doses (19,28,38), and a similar effect has also been reported in animals (21). Several lines of evidence suggest that the role of ó receptors in convulsions might be to regulate the activity of glutamatergic systems via the modulation of NMDA receptors (97,98,119). Borowicz et al investigated the effects of rimcazole against maximal electroshock, an effective generalized tonic-clonic seizure model for the study of NMDA receptor-related antiepileptic drugs (10).…”

Section: Convulsive Effectsmentioning

confidence: 99%

Review of the Pharmacological and Clinical Profile of Rimcazole

2004

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Rimcazole is a carbazole derivative that acts in part as a sigma receptor antagonist. Wellcome Research Laboratories introduced this compound during the 1980s when it was hypothesized to be a novel antipsychotic with an improved side effect profile. However, subsequent clinical trials demonstrated that rimcazole lacked efficacy in schizophrenic patients and it is now primarily used as an experimental tool. In addition to its actions as a sigma receptor antagonist, rimcazole also has high affinity for dopamine transporters, and in recent years it has served as a lead compound for the development of novel dopamine transporter ligands. Although rimcazole cannot be considered a selective ligand for sigma receptors, the recent development of other selective agonists and antagonists for sigma receptors have aided in clarifying the involvement of these receptors in the actions of rimcazole. Many of the physiological and behavioral effects of rimcazole can in fact be ascribed to its action as a sigma receptor antagonist, although there are exceptions. Rimcazole is likely to have a continued role in elucidating sigma receptor function in either in vitro or in vivo systems where sigma receptor-mediated effects can be studied independently of the influence of dopamine and serotonin transporters.

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“…1). Their capacity to modulate N-methyl-D-aspartate (NMDA)-mediated glutamatergic neurotransmission (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13) has been emphasized and proposed to play a crucial role in major neuroadaptative phenomena, such as long-term potentiation, learning and memory, seizures, acute neuronal death, and neurodegeneration (14). Using the in vitro model of NMDA-evoked [3H]norepinephrine ([3H]NE) release from preloaded rat hippocampal slices (15,16), we have shown that the selective cr ligands (+)-N-cyclopropylmethyl-N-methyl-1,4-diphenyl-1-ethylbut-3-en-1-ylamine hydrochloride (JO-1784; ref.…”

mentioning

confidence: 99%

Neurosteroids, via sigma receptors, modulate the [3H]norepinephrine release evoked by N-methyl-D-aspartate in the rat hippocampus.

Monnet

Mahé

Röbel

et al. 1995

Proc. Natl. Acad. Sci. U.S.A.

399

230

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N-Methyl-D-aspartate (NMDA, 200 pzM) evokes the release of [3H]norepinephrine ([3H]NE) from preloaded hippocampal slices. This effect is potentiated by dehydroepiandrosterone sulfate (DHEA S), whereas it is inhibited by pregnenolone sulfate (PREG S) and the highaffinity r inverse agonist 1,3-di(2-tolyl)guanidine, at concentrations of .100 nM. Neither 3a-hydroxy-5a-pregnan-20-one nor its sulfate ester modified NMDA-evoked [3H] NE overflow. Eighty-four female Sprague-Dawley rats (180-225 g), purchased from Iffa Credo, were kept at 21°C on a 12 hr:12 hr light/dark cycle with free access to water and Purina chow. At least 4 weeks prior to the release experiments, rats were anesthetized under ether and bilateral ovariectomy was carried out by lateral access. In a subgroup of 16 rats, anesthetized with chloral hydrate (400 mg/kg, i.p.) 3-11 days prior to the experiments, PTX (1 ,g/2 ,ul of physiological saline) was injected (using a 10-uAl Hamilton syringe) bilaterally into the dorsal hippocampus at A: 4.5, L: 4, and D: 4, according to the atlas of Paxinos and Watson (25) as described (3). Twelve control rats received an equal volume of the vehicle. When appropriate, the rats were killed by decapitation and their brains were rapidly dissected. Coronal slices (0.4-mm thick) of the hippocampus were prepared with a McIlwain tissue chopper. The slices were incubated in Krebs' solution containing[3H]NE (0.1 ,uM) and bubbled with a mixture of 95% 02/5% CO2 at 37°C for 30 min. The composition of the Krebs' solution (in mM) was NaCl 118, KCl 4.7, CaCl2 1.3, MgCl2 1.2, NaH2PO4 1, NaHCO3 25, glucose 11.1, Na2EDTA 0.04, and ascorbic acid 0.06. At the end of the incubation period, each glass chamber received two slices that were superfused continuously at a rate of 0.5 ml/min with oxygenated Mg2+-free Krebs' solution at 37°C for 68 min. As indicated in Results, one steroid and/or one of the cr ligands DTG, haloperidol, BD-1063, or spiperone were added in Mg2+-free Krebs' solution throughout the superfusion period. The prototypic a-ligand DTG was chosen since it acts on both a-i and o'2 receptors (3, 26). The universal o-antagonist haloperidol also binds to dopaminergic, serotoninergic, adrenergic, and cholinergic sites Abbreviations: 3a,5a-THP, 3a-hydroxy-Sa-pregnan-20-one; CNS, central nervous system; DHEA, dehydroepiandrosterone; DTG, 1,3-di(2-tolyl)guanidine; Gi/o protein, guanine nucleotide-binding pro-

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Effects of sigma ligands on mouse cerebellar cyclic guanosine monophosphate (cGMP) levels in vivo: further evidence for a functional modulation ofN-methyl-d-aspartate (NMDA) receptor complex-mediated events by sigma ligands

Cited by 29 publications

References 35 publications

Blockade by polyamine NMDA antagonists related to ifenprodil of NMDA‐induced synthesis of cyclic GMP, increases in calcium and cytotoxicity in cultured neurones

Blockade by polyamine NMDA antagonists related to ifenprodil of NMDA‐induced synthesis of cyclic GMP, increases in calcium and cytotoxicity in cultured neurones

Review of the Pharmacological and Clinical Profile of Rimcazole

Neurosteroids, via sigma receptors, modulate the [3H]norepinephrine release evoked by N-methyl-D-aspartate in the rat hippocampus.

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