Proteolytical processing of mutated human amyloid precursor protein in transgenic mice.

The evidence that betaA4 is central to the pathology of Alzheimer's disease (AD) came from the identification of several missense mutations in the amyloid precursor protein (APP) gene co-segregating with familial AD (FAD). In an attempt to study the proteolytical processing of mutated human APP in vivo, we have created transgenic mice expressing the human APP695 isoform with four FAD-linked mutations. Expression of the transgene was controlled by the promoter of the HMG-CR gene. Human APP is expressed in the brain of transgenic mice as shown by Western blot and immunohistology. The proteolytic processing of human APP in the transgenic mice leads to the generation of C-terminal APP fragments as well as to the release of betaA4. Despite substantial amounts of betaA4 detected in the brain of the transgenic mice, neither signs of Alzheimer's disease-related pathology nor related behavioural deficits could be demonstrated.

Neuroprotective effects of riluzole on a model of Parkinson's disease in the rat.

The aim of the present study was to analyse whether riluzole, a compound that interacts with the voltage-dependent sodium channel and impairs glutamatergic transmission, would exhibit a neuroprotective activity in a model of Parkinson's disease in the rat. Impaired skilled forelimb use, circling behavior, and altered dopaminergic metabolism of the mesotelencephalic system were evaluated in unilaterally 6-hydroxydopamine-lesioned rats. Riluzole was administered twice 15 min before, and 24 h after, the lesion. Riluzole reduced both the contralateral rotations induced by apomorphine and the ipsilateral ones elicited by amphetamine. Moreover, the decreased dopaminergic metabolism seen after 6-hydroxydopamine injection was attenuated in the riluzole-treated animals, at both the striatal and nigral levels. These biochemical and behavioral results demonstrate the ability of riluzole partially to protect the degeneration of the nigrostriatal dopaminergic neurons induced by the toxin 6-hydroxydopamine. Perhaps, the most striking evidence for the protective effect of riluzole was that this compound improved the skilled paw use, a complex sensorimotor behavior which is not easily ameliorated by palliative therapies such as dopaminergic grafts. These results extend previous data showing that riluzole counteracts the toxicity induced by 1-methyl-4-1,2,3,6-tetrahydropyridine and 1-methyl-4-phenylpyridinium in rodent dopaminergic neurons. The use of riluzole may be considered of potential interest for the neuroprotective therapy of Parkinson's disease.

Effects of complete and partial lesions of the dopaminergic mesotelencephalic system on skilled forelimb use in the rat.

This study compares certain behavioural consequences of partial and complete unilateral lesions of the dopaminergic mesotelencephalic system. We investigated skilled forelimb use, rotations induced by apomorphine and amphetamine, and dopaminergic metabolism of the nigrostriatal system of rats that had received a unilateral injection of 6-hydroxydopamine into the medial forebrain bundle. The rats classified Apo(+), that rotated after the administration of apomorphine, had a complete lesion of the nigrostriatal system, whereas those classified Apo(-), that did not rotate after the administration of apomorphine, had a partial lesion of the nigrostriatal system. In the Apo(+) rats, 99.8% of the dopamine in the striatum was depleted, as was 85% of that in the substantia nigra. For the Apo(-) rats, 72% of the dopamine in the striatum was depleted as was 56% of that in the substantia nigra. When investigated with the staircase test, the animals with the most severe dopamine depletions were those most impaired in the paw reaching task. Complete and partial unilateral depletions of the dopaminergic mesotelencephalic system impaired the hierarchic phases of paw reaching differently. A complete dopamine depletion, but not a partial one, decreased the number of attempts made with the contralateral paw, and induced a bias towards the ipsilateral paw. A partial dopamine lesion impaired the sensorimotor co-ordination of both paws, whereas the complete dopamine lesion had a greater effect on the contralateral paw than on the ipsilateral paw. The mild paw reaching impairments observed in animals with moderate depletions of dopamine are proposed as a model of the early symptoms of Parkinson's disease that may be useful for the development of protective or restorative therapies.

2-Amino-6-trifluoromethoxy benzothiazole, a possible antagonist of excitatory amino acid neurotransmission--I. Anticonvulsant properties.

2-Amino-6-trifluoromethoxy benzothiazole (PK 26124) prevented convulsions induced in rodents by maximal electroshock, inhibitors of the synthesis of gamma-aminobutyric acid (GABA) and ouabain, but was inactive against seizures provoked by GABA antagonists, unlike diazepam, chlordiazepoxide, phenobarbital and valproic acid. 2-Amino-6-trifluoromethoxy benzothiazole prevented seizures induced by sound stimuli in DBA/2 mice (ED50 = 0.66; 2.1 and 4.1 mg/kg, i.p. according to the seizure component), postural seizures in El mice (ED50 = 7.5 mg, i.p.) and seizures induced by photic stimulation in the baboon, Papio papio, at 4 and 8 mg/kg (i.v.). This spectrum of anticonvulsant activity closely resembles that reported previously for dicarboxylic amino acid antagonists. Indeed, PK 26124 prevented seizures induced by L-glutamate (ED50 = 8.5 mg/kg, i.p.) or by kainate (ED50 = 9.25 mg/kg, i.p.) and tremors induced by harmaline (ED50 = 2.5 mg/kg, i.p.) In these tests diazepam was inactive (L-glutamate) or as potent as PK 26124 (kainate, harmaline), whereas it was 10-20 times more potent than PK 26124 against seizures induced by inhibitors of the synthesis of GABA. Together, these data suggest that PK 26124 possesses antagonistic properties of excitatory dicarboxylic amino acids, which may contribute to its anticonvulsant action.

Pharmacological evidence that PK 8165 behaves as a partial agonist of brain type benzodiazepine receptors.

PK 8165, a new quinoline derivative, has a good affinity for brain type benzodiazepine binding sites and an anticonflict activity in the Vogel Test. However, contrarily to classical benzodiazepines (BZ) this compound is devoid of anticonvulsant and sedative properties. As biochemical studies suggested that PK 8165 is a partial agonist for BZ receptors, its interactions with convulsant, sedative and muscle relaxant properties of diazepam (DZ) were investigated. PK 8165 potentiates (12.5 to 50 mg/kg i.p.) the antagonistic effect of DZ on M.E.S.-induced seizures and footshock-induced fighting in mice. Moreover, PK 8165 potentiates in the same dose range the muscle relaxant and hypnotic effects of DZ in mice. These potentiations are specific since PK 8165 does not interfere with phenobarbital and mebubarbital effects in M.E.S. and righting reflex in mice. Also, PK 8165's anticonflict activity (punished drinking in thirsty rats) is antagonized by RO15-1788, a specific antagonist of centrally active BZ.