Motor actions of eliprodil in the normal and monoamine-depleted mouse: A role in the treatment of Parkinson's disease?

Abstract

The non-competitive NMDA polyamine site antagonist, eliprodil, was examined for its effects on exploratory activity in non-habituated mice and for its antiakinetic potential in reserpine-treated mice. A low dose of eliprodil (5 mg/kg) weakly stimulated locomotion in naive animals, whilst higher doses depressed rearing (20-40 mg/kg) and grooming (40 mg/kg), consistent with a sedative action. At no dose did eliprodil cause ataxia. In 24 h reserpine-treated mice, eliprodil (10-40 mg/kg) reversed akinesia, but this effect was subject to considerable inter-animal variation and was not statistically significant. Eliprodil did not alter the motor recovery elicited by the dopamine D1 agonist SKF 38393, or the dopamine D2 agonist RU 24213, and suppressed the motor stimulation induced by L-DOPA. These results indicate that eliprodil displays a far lower propensity than many other NMDA receptor antagonists for disturbing posture and gait, but lacks the essential motor stimulant action required to make it a safe and effective antiparkinsonian agent, at least in the reserpine-treated mouse model of Parkinson's disease.

Targeting Sigma Receptors for the Treatment of Neurodegenerative and Neurodevelopmental Disorders

“…In the same study of reserpine-treated mice, eliprodil reversed akinesia, although this was not statistically significant. Furthermore, eliprodil failed to improve motor recovery from the DA D1 agonist SKF38393, or the DA D2 agonist RU24213, and inhibited the motor stimulation induced by L-DOPA [ 295 ]. Eliprodil has been clinically trialled for movement disorders, including PD (NCT00001929), although the data were never published.…”

Targeting Sigma Receptors for the Treatment of Neurodegenerative and Neurodevelopmental Disorders

“…In the same study of reserpine-treated mice, eliprodil reversed akinesia, although this was not statistically significant. Furthermore, eliprodil failed to improve motor recovery from the DA D1 agonist SKF38393, or the DA D2 agonist RU24213, and inhibited the motor stimulation induced by L-DOPA [ 295 ]. Eliprodil has been clinically trialled for movement disorders, including PD (NCT00001929), although the data were never published.…”

Effect of N1-dansylspermine and Ro25,6981 on locomotor activity in naive mice and in the reserpinized mouse model of Parkinson’s disease

“…Spermine and spermidine levels are raised in red blood cells of patients with Parkinson's Disease [12]. Reserpine-induced monoamine depletion in rodents allows the rapid assessment of anti-akinetic potential of drugs, and was previously shown to detect the antiparkinsonian potential of ifenprodil [7] but the limited effect of its sister drug eliprodil [13]. The aim of this study was to assess the effect of N 1 Dansylspermine, a polyamine analogue and competitive polyamine antagonist [14,15] and Ro25,6981, a non-competitive polyamine antagonist with good affinity and selectivity for the…”

Targeting Sigma Receptors for the Treatment of Neurodegenerative and Neurodevelopmental Disorders

“…In the same study of reserpine-treated mice, eliprodil reversed akinesia, although this was not statistically significant. Furthermore, eliprodil failed to improve motor recovery from the DA D1 agonist SKF38393, or the DA D2 agonist RU24213, and inhibited the motor stimulation induced by L-DOPA [ 295 ]. Eliprodil has been clinically trialled for movement disorders, including PD (NCT00001929), although the data were never published.…”

Effect of N1-dansylspermine and Ro25,6981 on locomotor activity in naive mice and in the reserpinized mouse model of Parkinson’s disease

“…Spermine and spermidine levels are raised in red blood cells of patients with Parkinson's Disease [12]. Reserpine-induced monoamine depletion in rodents allows the rapid assessment of anti-akinetic potential of drugs, and was previously shown to detect the antiparkinsonian potential of ifenprodil [7] but the limited effect of its sister drug eliprodil [13]. The aim of this study was to assess the effect of N 1 Dansylspermine, a polyamine analogue and competitive polyamine antagonist [14,15] and Ro25,6981, a non-competitive polyamine antagonist with good affinity and selectivity for the…”

Targeting Sigma Receptors for the Treatment of Neurodegenerative and Neurodevelopmental Disorders

“…In the same study of reserpine-treated mice, eliprodil reversed akinesia, although this was not statistically significant. Furthermore, eliprodil failed to improve motor recovery from the DA D1 agonist SKF38393, or the DA D2 agonist RU24213, and inhibited the motor stimulation induced by L-DOPA [ 295 ]. Eliprodil has been clinically trialled for movement disorders, including PD (NCT00001929), although the data were never published.…”

Effect of N1-dansylspermine and Ro25,6981 on locomotor activity in naive mice and in the reserpinized mouse model of Parkinson’s disease

“…Spermine and spermidine levels are raised in red blood cells of patients with Parkinson's Disease [12]. Reserpine-induced monoamine depletion in rodents allows the rapid assessment of anti-akinetic potential of drugs, and was previously shown to detect the antiparkinsonian potential of ifenprodil [7] but the limited effect of its sister drug eliprodil [13]. The aim of this study was to assess the effect of N 1 Dansylspermine, a polyamine analogue and competitive polyamine antagonist [14,15] and Ro25,6981, a non-competitive polyamine antagonist with good affinity and selectivity for the…”