Jeremy Pratt

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.

Glutamate uptake is decreased tardively in the spinal cord of FALS mice.

THIS study examined high affinity Na+-dependent uptake of glutamate in synaptosomal preparations from spinal cord in mice that express a dominant mutation of human copper/zinc superoxide dismutase (SOD1) and represent an animal model of amyotrophic lateral sclerosis (ALS). Their muscle strength was also monitored by a grip traction test throughout their lifespan. The high affinity Na+-dependent uptake of [3H]glutamate was decreased between 120 and 150 days of age. A marked and significant decrease in Vmax (−40.2%; p < 0.001) on whole spinal cord synaptosomes was observed at 150 days, with no change in Km. This significant decrease was reached a week before the animals died (157.2 ± 2.2 days) and corresponded to a considerable fall in muscle strength (25% loss between 120 and 140 days, p < 0.001). The FALS mouse model therefore reproduces the decrease in glutamate uptake reported in humans suffering from sporadic or familial ALS. These results are discussed in terms of a possible tardive involvement of glutamate uptake deficiency in human ALS.

The effect of riluzole on post-traumatic spinal cord injury in the rat.

THIS study evaluated treatment with riluzole, a neuroprotective agent, following thoracic spinal cord compression in the rat. Animals received riluzole (2 mg kg−1) or vehicle twice daily for 10 days following the trauma. Motor deficits, somatosensory evoked potentials (SEP) and lesion histology were evaluated. Although paralysis was seen following trauma, seven of 10 animals receiving riluzole recovered motor function and nearly normal behaviour, unlike animals receiving vehicle. Trauma dramatically disturbed SEPs with falls in amplitude and increases in latency. After riluzole SEP returned towards pre-injury levels, while untreated animals showed no recovery. Morphological studies revealed significant (53%) reduction in the degree of spinal cord infarcted after riluzole treatment.

Enoxaparin Reduces Cerebral Edemaafter Photothrombotic Injury in the Rat

This study investigates the effect of enoxaparin (Lovenox, Klexane), a low-molecular-weight heparin, on edema following a photothrombotic lesion using rose bengal dye in the rat. An area of cerebral ischemia was provoked in the right hemisphere of rats. Edema developed over 24 h after the lesion, as seen comparing water content of a core sample from the right hemisphere to that of a similar sample from the left hemisphere of each rat. Enoxaparin at 0.5 mg/kg i.v. plus 2 mg/kg s.c. reduced edema 24 h after lesion induction by 32% (p < 0.01) when the treatment was started 2 h after photothrombotic insult, with maintenance doses of 2 mg/kg s.c. enoxaparin at 6 and 18 h. When the same initial treatment with enoxaparin was started 18 h after insult, there was still a significant reduction of 20% (p < 0.01) in cerebral edema. Administration of enoxaparin 18 h after insult reduced cerebral edema in a dose-dependent manner. There was no evidence of intracranial hemorrhages in any of the animal groups and when the hemoglobin content of the brain samples was assayed by the method of Drabkin, no increase in hemoglobin content was seen compared to sham-operated animals.

Acute effects of irradiation on the rat brain: protection by glutamate blockade

Riluzole (2-amino-6-trifluorothethoxy benzothiazole), dizocilpine (MK-801; (+)-5-methyl-10,11-dihydro-5H-dibenzo(a,d)-cyclohepten-5,10-imine maleate), and lamotrigine (3,5-diamino-6-(2,3-dichlorophenyl)-1,2-triazine), agents reported to have neuroprotective actions, and WR2721 (S-2-(3-aminopropylamino)-ethylphosphorothioic acid), a radioprotector, were evaluated in 15-day-old rats that underwent a 2.5 Gray (Gy) irradiation from a cobalt 60 source. 20 min after irradiation, riluzole (0.5-8 mg/kg), dizocilpine (0.1-1 mg/kg), lamotrigine (25 mg/kg), WR 2721 (75 mg/kg) or vehicle, were injected intraperitoneally. 6 h after irradiation, behavioural and histological evaluations revealed that exposure to 2.5 Gy caused hypolocomotion, stumbling gait and somnolence, which was significantly reduced, from the dose of 4 mg/kg i.p. of riluzole. A dose-dependent protection of neurones in the dentate gyrus, starting from the dose of 1 mg/kg i.p. was also seen. Dizocilpine caused behavioral modifications but significantly reduced neuronal damage. Lamotrigine significantly increased neuronal damage while WR 2721 conferred no protection. In conclusion, two blockers of glutamatergic neurotransmission conferred significant protection against brain damage caused by ionizing irradiation when administered subsequent to exposure.

Spiro-imidazo[1,2-a]indeno[1,2-e]pyrazine-4-one derivatives are mixed AMPA and NMDA glycine-site antagonists active in vivo.

Original spiro-imidazo[1,2-a]indeno[1,2-e]pyrazine-4-one derivatives were synthesised and led to the identification of 3e which showed good affinities for both the AMPA and the NMDA glycine-site receptors, and displayed good anticonvulsant effects after i.p. and i.v. administrations in the electroshock-induced convulsion assay in mice. The corresponding dextrorotatory isomer (+)-3e was notably more potent than the levorotatory isomer (-)-3e in in vitro and in vivo assays.

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.

Synthesis and pharmacological properties of 5H, 10H-imidazo[1,2-a]indeno[1,2-e]pyrazine-4-one, a new competitive AMPA/KA receptor antagonist

The excessive release of glutamate, a potent excitatory neurotransmitter, is thought to play an important role in a variety of acute and chronic neurological disorders. Consequently, excitatory amino acid antagonists may have an important therapeutic potential in the treatment of these diseases. Glutamate interacts with at least three types of receptor: 1) NMDA (N‐methyl‐D‐aspartic acid) receptors; 2) AMPA [2‐amino‐3‐(3‐hydroxy‐5‐methylisoxazol‐4‐yl)propionic acid]/kainic acid (KA) receptors; and 3) metabotropic receptors. Blockade of ionotropic AMPA/KA receptors has been shown to prevent cerebral ischemia insult in experimental models. This article describes the synthesis, pharmacological activity, and neuroprotective properties of 5H,10H‐imidazo[1,2‐a]indeno[1,2‐e]pyrazine‐4‐one (1), a novel AMPA/KA antagonist which showed micromolar affinity at AMPA/KA receptors and competitively inhibited functional responses mediated by these receptors. In mice, 1 had significant anticonvulsive properties and conferred protection against hypobaric hypoxia and KCN intoxication. In rats and gerbils, 1 possesses significant activity in models of global or focal cerebral ischemia, as well as in a model of neurotrauma. Compound 1 was prepared from 2‐bromo‐indanone using two synthetic pathways in two or three steps with moderate (30%) or good (70%) yields, respectively. Drug Dev. Res. 48:121–129, 1999.

8-Methylureido-4,5-dihydro-4-oxo-10H-imidazo[1,2-a]indeno[1,2-e]pyrazines: highly potent in vivo AMPA antagonists.

A novel series of readily water soluble 8-methylureido-4,5-dihydro-4-oxo-10H-imidazo[1,2-a]indeno[1,2-e]++ +pyrazines were synthesized. The -10-yl acetic acid ((+)-3) and -10-carboxylidene (4) derivatives exhibit potent affinities (IC50=4 and 19 nM, respectively) and antagonist properties (IC50 = 2 and 3 nM, respectively) at the ionotropic AMPA receptor. These compounds also display anticonvulsant properties against both electrically and sound-induced convulsions in mice after ip, sc and iv administration with ED50 values between 0.9 and 11 mg/kg, thus suggesting adequate brain penetration.