Jean Rataud

Neuroprotective actions of riluzole in rodent models of global and focal cerebral ischaemia

Riluzole (2 amino 6-trifluoromethoxybenzothiazole), when administered at 4 and 8 mg/kg i.p., 0.5, 4.5, 24 and 28 h after the initiation of ischaemia, significantly reduced the prevalence of slow wave, and increased the proportion of higher frequency activity seen in the quantified electrocorticogram (ECoG), during the weeks that followed a 6 min bilateral occlusion of the common carotid arteries in the Mongolian gerbil. In focal ischaemia, provoked in Fischer rats following the occlusion of the middle cerebral artery, administration of riluzole (8 mg/kg) at 30 min and 24.5 h post occlusion significantly reduced the volume of infarcted cortex. These activities of riluzole could be related to its inhibition of sodium channel activity, which in turn inhibits glutamate release.

Comparative study of voltage-sensitive sodium channel blockers in focal ischaemia and electric convulsions in rodents

This study evaluates the neuroprotective properties of some voltage-sensitive sodium channel blockers in a model of focal ischaemia. After curative treatment (0.5 and 24.5 h after insult), well known voltage-sensitive sodium channel blockers, phenytoin (2 x 100 mg/kg i.p.), carbamazepine (2 x 50 mg/kg i.p.), lamotrigine (2 x 50 mg/kg i.p.) and RP 66055 (2 x 8 mg/kg i.p.) were found to protect rats against brain damage induced by occlusion of the middle cerebral artery, by 40%, 24%, 28% and 44% respectively. These compounds were also active in protecting both mice and rats against tonic convulsions induced by electroshock, Intraperitoneal ED50 values in mice and rats respectively were of 5.2 and 12.5 mg/kg for phenytoin, 8.4 and 3.6 mg/kg for carbamazepine, 4.4 and 3.1 mg/kg for lamotrigine, 3.9 and 0.22 mg/kg for RP 66055. In contrast, lifarizine was totally devoid of activity in these three tests. This study extends an accumulation of data in the literature pointing to a therapeutic potential for voltage-dependent sodium channel blockers which penetrate the blood brain barrier. Such compounds as phenytoin, carbamazepine, lamotrigine or RP 66055 may act at sodium channels to prevent depolarization, inhibit release of neurotransmitters such as glutamate and thus protects the cortex against cellular damage induced by focal ischaemia by both pre- and post-synaptic inhibition of abnormal neurotransmission.

Are 5-HT2 antagonists endowed with anxiolytic properties in rodents?

The precise role of serotonin (5-HT) in anxiety remains unclear. We report here on the effects of RP 62203, a new 5-HT2 antagonist, and ritanserin in different animal models of anxiety. In the elevated plus-maze in mice, RP 62203 increased dose-dependently the percentage of entries onto, and time spent on open arms, over the dose range 0.25-4 mg.kg-1 p.o. By contrast, ritanserin was ineffective up to the dose of 4 mg.kg-1 p.o. In addition, both compounds were tested against the anxiogenic compound FG 7142 (20 mg.kg-1, i.p.) in the plus-maze test in mice and via electrocorticographic recordings (ECoG) in rats. The anxiolytic effect of RP 62203 is antagonized by FG 7142 at a dose devoid of anxiogenic properties. A similar interaction between RP 62203 and FG 7142 is observed in ECoG studies. In contrast, ritanserin seemed to potentiate the anxiogenic and awakening activities of FG 7142. These results demonstrate that RP 62203, a selective 5-HT2 antagonist, possesses anxiolytic properties in rodents suggesting that 5-HT2 receptors are involved in the control of anxiety.

Pharmacological evidence of a possible tryptaminergic regulation of opiate receptors by using indalpine, a selective 5-HT uptake inhibitor

Abstract Indalpine or LM 5008 (4-[2-(3-indolyl)ethyl]piperidine), a selective and potent inhibitor of the uptake of 5-hydroxytryptamine, showed analgesic properties in the hot plate test in mice. It enhanced the analgesic effect of morphine and pethidine. This activity could not be explained by alterations of the pharmacokinetics of morphine since the brain morphine level was not changed by pretreatment with indalpine. This drug also antagonized the development of tolerance to morphine in mice. Morphine was 3–7 times more potent in competing for [3H]-naloxone (−NaCl), [3H]-metenkephalin or [3H]-leu-enkephalin binding when animals were pretreated in vivo with indalpine although indalpine itself had no effect on opiate receptor binding sites. In vitro addition of indalpine or 5-HT did not change the activity of morphine on opiate receptor binding sites. In vivo administration of indalpine sensitized the agonist state of opiate receptor binding sites, as measured by [3H]-naloxone (−NaCl) for example, to enkephalin without changing the antagonist state, as measured by [3H]-naloxone (+NaCl). The effect of indalpine was antagonized by the 5-HT synthesis inhibitor PCPA. Moreover, indalpine antagonized the depletion of opioid peptides induced by cyclophosphamide. All these results could suggest a tryptaminergic regulation of opiate receptors.

Synthesis, anticonvulsant and neuroprotective activities of RP 66055, a riluzole derivative

Abstract RP 66055, a riluzole derivative, has been characterized as a potent anticonvulsant and in vivo neuroprotective agent.

The effect of riluzole and mannitol on cerebral oedema after cryogenic injury in the mouse

A cryogenic lesion was produced under halothane anaesthesia in the mouse by placing a cotton swab soaked in liquid nitrogen onto the surface of the cranium. This provoked an oedematous lesion which developed within the hour after the insult and evolved over the following week. Treatment with mannitol at 3 g/kg i.v. caused a significant 22% reduction in oedema 1 h later, when administered immediately after lesion, but not when administered 23-h post lesion. Likewise riluzole (16 mg/kg, i.v.) significantly reduced oedema by 17% when administered immediately after lesion, or 13% (P < 0.05) when administered 23 h after lesion. Repeated doses (2 x 16 mg/kg, i.p.) of riluzole were also able to reduce oedema significantly (24%, P < 0.05) at 24 h post lesion. Riluzole, in four repeated doses of 8 mg/kg i.p. was also able to reduce lesion surface size by 16% (P < 0.05) 48 h after lesion.

Optical isomers of RP 64406: New potent antiglutamate agents

Abstract Optical isomers of the riluzole derivative, sulfoxide RP 64406, were prepared in pure forms. No significant difference was found between the (+) and (−) isomers in their powerful antiglutamate activity.