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PubMed1996

Inhibition of squalene synthase in vitro by 3-(biphenyl-4-yl)-quinuclidine.

Squalene synthase (SQS) catalyses a step following the final branch in the pathway of cholesterol biosynthesis. Inhibition of this enzyme, therefore, is an approach for the treatment of atherosclerosis with the potential for low side effects. We have characterised the inhibition of rat liver microsomal SQS by 3-(biphenyl-4-yl)quinuclidine (BPQ). BPQ follows slow binding kinetics in that the rate of accumulation of product decreases with time if the inhibitor is added when the assay is started. Preincubation of BPQ and SQS leads to a biphasic dose-response where accumulation of product is linear with time only for the sensitive phase. When the farnesyl pyrophosphate (FPP) substrate is present at 19.6 microM, approximately 77% of the SQS activity is sensitive to the inhibitor (vOs) and the remainder is insensitive (vOi). The apparent inhibition constants (K'i values) are respectively K'is = 4.5 nM and K'ii = 1300 nM. Similar biphasic behaviour is exhibited by other inhibitors and in microsomes prepared from human and marmoset liver. As the concentration of FPP is reduced below 19.6 microM, there is a decrease in the relative contribution from vOi. Conversely, the value of K'is for BPQ remains constant when the FPP concentration is changed, showing noncompetitive kinetics with respect to this substrate. Possible causes of the observed kinetics are discussed. Inhibition by BPQ is said to follow tight binding kinetics because the value of K'is is similar to the concentration of inhibitor binding sites. Thus, to avoid an artefactual variation in potency when the enzyme concentration is varied, it is necessary to allow for the effects of depletion of free inhibitor. Furthermore, estimates of potency that average activity across the two phases are influenced by the relative contributions of each phase. These contributions differ according to the FPP concentration and the species used as the source of microsomes. Thus, it is necessary to separate the phases to compare measurements made in different experiments. Our observations indicate that careful experimental design and data analysis are required to characterise the kinetics of SQS inhibitors.

Animals↗
PubMed1984

Selective focal inhibition of brain protein synthesis during generalized bicuculline seizures in newborn marmoset monkeys.

Generalized epileptic seizures, induced in 5-7 day-old marmoset monkeys with bicuculline (5 mg/kg) produce striking focal disruption of protein synthesis. Inhibition of protein synthesis was most severe in the neocortex and hippocampus but was completely absent in the lateral geniculate nuclei and in the optic tract. In the cortex, regions in which protein synthesis was most severely reduced alternated with areas in which it was relatively preserved creating a columnar pattern. With few exceptions, subcortical gray matter structures in the forebrain and brainstem were less severely affected than the cortex. In the cerebellum, seizures appeared to have little effect on the proliferating external granular layer while the closely adjacent internal granular layer showed clear-cut inhibition. The focal nature of protein synthesis inhibition in brain during seizures suggests that the systemic effects of convulsions (e.g. hypoxemia, acidosis or changes in arterial blood pressure) are not a major factor. More likely, protein synthesis inhibition is related to the extent to which various cerebral structures participate in seizure activity.

Amino Acids↗
PubMed1986

Preferential blood flow to brainstem during generalized seizures in the newborn marmoset monkey.

The effect of generalized seizures on local cerebral blood flow was studied autoradiographically in 21 immature marmoset monkeys, using either [123I]- or [131I]isopropyliodoamphetamine. Generalized convulsions were induced in ketamine-anesthetized and awake monkeys with bicuculline and continued for 4-59 min. During convulsions in marmosets less than 3 weeks of age, there was a striking rearrangement of blood flow in favor of the brainstem pontomedullary region. The ratios of blood flow in pons-medulla to blood flow in cerebral cortex, putamen, ventroposterior thalamic nuclei, lateral geniculate nuclei, cerebellum and hemispheric white matter increased 1 1/2 to 2 times compared to controls. In seizure animals 4-8 weeks of age, the redistribution of blood flow to brainstem did not occur. Although metabolic acidosis developed after 30 min of bicuculline-induced seizures, mean arterial blood pressure, temperature, arterial pO2 and pCO2 did not differ significantly from controls, indicating that hypoxemia, hypercapnia and hypotension cannot explain the altered cerebral blood flow pattern. The redistribution phenomenon could be explained by more pronounced vasodilatation in brainstem than many other brain regions during generalized seizures in newborn monkeys. Lack of significant vasodilatation in forebrain structures such as cerebral cortex could contribute to neuronal damage by limiting substrate supply at a time of increased metabolic activity.

Amphetamines↗
PubMed1991

Extensive loss of brain dopamine and serotonin induced by chronic administration of MPTP in the marmoset.

Common marmosets were given a subcutaneous injection of MPTP (1.25-2.5 mg/kg twice a week) for 5 or 10 consecutive months and were sacrificed after a survival time of 6 months or 15 days, respectively. The parkinsonian symptoms were not very marked at the time of sacrifice but there was a strong decrease of dopamine and, to a lesser extent, of its metabolites in the striatum and in some extrastriatal regions. There was also a profound loss of serotonin in the striatum and in all of the extrastriatal regions analyzed, which was still highly significant 6 months after discontinuation of MPTP treatment. The results suggest that the selected dosage schedule produces a widespread and lasting neuronal degeneration closely resembling the neurochemical pathology of Parkinson's disease.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1992

Chronic MPTP treatment reduces substance P and met-enkephalin content in the basal ganglia of the marmoset.

Common marmosets were treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP, 1.25-2.5 mg/kg s.c., twice a week) for 5-10 consecutive months. The initial doses of MPTP produced a severe parkinsonian syndrome but motor activity was partially recovered at the end of treatment. Fifteen days or 6 months after the last MPTP dose, monkeys were sacrificed. In addition to a strong decrease of dopamine in the striatum, there were significant reductions in substance P and Met-enkephalin content in the substantia nigra, caudate nucleus and putamen. In the globus pallidus, the reduction in peptide levels did not reach statistical significance as compared to controls. Neurotensin levels were also decreased in the caudate nucleus. The chronic administration of MPTP for 5-10 months induces changes in substance P and Met-enkephalin systems which resemble the degeneration found in brains from parkinsonian patients.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1993

Cognitive inflexibility after archicortical and paleocortical prefrontal lesions in marmosets.

The behaviour and cognitive abilities of marmosets with bilateral ablations of either the archicortex on the mediodorsal surface or the paleocortex on the ventrolateral surface of the frontal lobes were assessed in terms of the types of information being handled, the mode of action (inhibitory versus productive mechanisms), and the level of functioning of these frontal areas. Although there was a tendency for the ventrolateral ablation to produce a greater impairment on object than on spatial discrimination in comparison to the mediodorsal ablation, the differences between the two groups was not marked in this respect. The effect of ablations of either of these areas was more marked on tasks which required the inhibition of prepotent responses than on tasks where novel or arbitrary responses were appropriate. The major effect of both lesions was the production of perseverative behaviour which occurred at the level of motor output in the first few days after surgery but was then observed at the level of choice behaviour and attentional set in formal cognitive tests. Impairments were also seen on postoperative retention of tasks learnt prior to surgery. It is suggested that all these impairments arise from an inability to use or modify stored information.

Animals↗
PubMed1995

Functional implications of kappa opioid receptor-mediated modulation of glutamate transmission in the output regions of the basal ganglia in rodent and primate models of Parkinson's disease.

Parkinson's disease is characterized by an increased excitatory amino acid transmission in the internal segment of the globus pallidus and the substantia nigra pars reticulata. The effects of the kappa receptor agonist enadoline (CI-977) on glutamate transmission were investigated in vitro. Enadoline reduced the K(+)-evoked release of glutamate from slices of substantia nigra in a concentration-dependent manner (maximum effect: 78% inhibition at 200 microM). This effect was blocked by the selective kappa receptor antagonist nor-binaltorphimine. The endogenous ligand for kappa receptors is thought to be dynorphin. Dynorphin released from terminals of striato-pallidal and striato-nigral pathways might thus act as an endogenous modulatory agent on glutamatergic transmission in the basal ganglia. In vivo experiments were carried out in rodent and primate models of Parkinson's disease to assess the potential of manipulating kappa receptors as a potential treatment for Parkinson's disease. Enadoline reduced reserpine-induced akinesia when injected in the entopeduncular nucleus of the rat. Similarly, injections of CI-977 in the internal segment of globus pallidus (GPi) of the MPTP-treated marmoset alleviated parkinsonian symptoms and allowed the animal to recover its locomotor activity. This suggest that reducing the overactive glutamatergic transmission in the output regions of the basal ganglia by activating kappa receptors might potentially form the basis of a novel anti-parkinsonian therapy.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1996

Amphetamine induces Fos-like immunoreactivity in the striatum of primates.

Injections of D-amphetamine (5 mg/kg) three hours before sacrifice were found to elicit robust Fos-like immunoreactivity in the striatum of cynomolgus monkeys and of the common marmoset. Labeled cells were most frequently observed in the medial portion of the caudate nucleus and were distributed in a patchy fashion. Comparison with adjacent sections stained for the calcium binding protein calbindin indicated that the patches of amphetamine induced labeling corresponded to the calbindin-poor striosomes. These results are consistent with those reported in rats and thus suggest similarities in the basic organization of striatal mechanisms underlying the response to amphetamine in rodents and primates.

Amphetamine↗
PubMedDate not supplied

Specificity for homonymous pathways following repair of peripheral nerves with treated skeletal muscle autografts--in the primate.

While distal influences acting both tropically and trophically upon regenerating nerve fibres are not in doubt, the specificity of such influences is unresolved. The present experiments were designed to test whether pioneering axons regenerating through a large muscle graft showed specificity for their homonymous distal stumps if faced with a choice of pathways. Regeneration was assessed with respect to nerve conduction, the electromyograph, isometric tension and morphological indices of nerve regeneration in the median and ulnar nerves of non-human primates. Reinnervation of both distal stumps with functional neuromuscular transmission was found to take place by growth of nerve fibres from either proximal nerve into either distal stump. There was thus no evidence of specific homonymous reinnervation. The implications of this finding are discussed from a mechanistic and a clinical point of view.

Animals↗
PubMed1992

Terguride stimulates locomotor activity at 2 months but not 10 months after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine treatment of common marmosets.

The mixed dopamine (DA) agonist/antagonist terguride acts as a DA antagonist on normosensitive receptors but shows DA agonistic properties at supersensitive DA receptors. Such a compound could offer an alternative to the treatment of Parkinson's disease with indirect or direct DA agonists. The present study compares the actions of terguride, 4-12 mg/kg i.p., in naive common marmosets with its effects in animals rendered parkinsonian by administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), 2 months or 10 months previously, in order to test its antiparkinsonian efficacy. Terguride reduced locomotor activity in naive common marmosets, similar to its effects in rodents and in line with the DA antagonistic activity of the compound. In marmosets treated with MPTP 2 months previously and exhibiting pronounced behavioural motor deficits, terguride stimulated locomotor activity, showing DA agonistic properties under these conditions. In contrast, the locomotor activity of animals that had recovered from MPTP treatment 10 months previously was not altered by terguride. It is concluded that terguride has anti-akinetic efficacy in this primate model of Parkinson's disease. In addition, terguride offers a unique opportunity to differentiate, pharmacologically, the extent of dopaminergic recovery from MPTP treatment in this primate species.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1992

A-77636: a potent and selective dopamine D1 receptor agonist with antiparkinsonian activity in marmosets.

A-77636, ((1R,3S) 3-(1'-adamantyl)-1-aminomethyl-3,4-dihydro-5,6-dihydroxy-1H-2-benz opyran hydrochloride), is a selective dopamine D1 receptor agonist. In a battery of receptor binding assays, A-77636 shows the highest affinity (pKi = 7.40 +/- 0.09; Ki = 39.8 nM) for the dopamine D1 receptor. A-77636 is an agonist at the dopamine D1 receptors in the fish retina (pEC50 = 8.13; EC50 = 1.1 nM; intrinsic activity = 102% of dopamine) and the rat caudate-putamen (pEC50 = 8.97; intrinsic activity = 134% of dopamine). The compound is functionally inactive at dopamine D2 receptors (EC50 > 10 microM). In rats with unilateral 6-OHDA (6-hydroxydopamine) lesions of the nigro-striatal dopaminergic pathway, A-77636 elicits prolonged (> 20 h) contralateral turning that is blocked by SCH 23390, a D1 receptor antagonist, but not by haloperidol at doses selective for the dopamine D2 receptor. Higher doses of A-77636 produce forelimb clonus in rats and mice. When tested in marmosets treated with MPTP to induce a parkinsonian-like state, A-77636 increases locomotor activity and decreases the severity of the parkinsonian-like symptoms: the compound is active after either subcutaneous or oral administration. A-77641, the optical antipode of A-77636, has a lower affinity towards the dopamine D1 receptor (pKi = 5.14, Ki = 7200 nM), is less potent as a dopamine D1 receptor agonist (pEC50 = 5.65; EC50 = 2200 nM), fails to elicit turning in the 6-OHDA-lesioned rat, and lacks antiparkinsonian efficacy in the MPTP-treated marmoset.(ABSTRACT TRUNCATED AT 250 WORDS)

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1992

The distribution of 5-HT3 recognition sites in the marmoset brain.

The distribution of the binding of [3H]GR65630 (0.2 nM) to putative 5-HT3 recognition sites in the brain of the common marmoset was assessed using autoradiography. Specific binding was heterogeneously distributed with the highest densities found in discrete nuclei of the lower medulla (nucleus tractus solitarii, dorsal motor nucleus of the vagus nerve, nucleus of spinal trigeminal nerve tract and the area postrema). In forebrain areas, relatively high binding densities were located in the medial habenula nucleus and the hippocampus (CA3, CA4 and fascia dentata). Low levels of specific binding in the rest of the forebrain hindered quantification.

Animals↗
PubMed1992

Neurotoxic effect of prenatal exposure to MPTP on the dopaminergic systems of the marmoset brain.

MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) was incidentally administered to pregnant marmosets during the whole gestational period, except for the last 15 days before term. The infant monkeys were killed 5 months after birth, and dopamine and its metabolites were measured in the striatum and the nucleus accumbens. Prenatal exposure to MPTP produced a marked dopamine depletion in these brain regions of the offspring, showing that MPTP is able to cross the placental barrier in primates.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1993

The effect of the 5-HT3 receptor antagonist, RS-42358-197, in animal models of anxiety.

The S-isomer of the novel 5-HT3 receptor antagonist RS-42358 ((S)-N-(1-azabicyclo[2.2.2]oct-3-yl)-2,4,5,6-tetrahydro-1-H- benzo[de]isoquinolin-1-one, RS-42358-197) disinhibited behaviour in the mouse suppressed by the aversive situation of the light/dark test box. RS-42358-197 was effective at sub-ng/kg dose levels and the efficacy was maintained over a 100 million-fold dose range. In contrast, the R-isomer was ineffective at all doses studied. The S-isomer also disinhibited a suppressed behaviour in social interaction and elevated X-maze tests in the rat and reduced anxiety-related behaviours in a marmoset human threat test. RS-42358-197 prevented the exacerbation of the suppression of behaviour in the mouse light/dark test following withdrawal from treatment with alcohol, nicotine, cocaine and diazepam. Thus, the S-isomer of RS-42358 has a consistent non-sedating anxiolytic profile in rodent and primate models. It is exceptionally potent and a maintained efficacy at high doses distinguishes its actions from many other 5-HT3 receptor antagonists.

Animals↗
PubMed1993

Antidiuretic activity and release of factor VIII by vasopressin analogues.

Vasopressin and in particular its structural analogue dDAVP (1-deamino-8-D-arginine vasopressin) can increase plasma concentrations of Factor VIII and tissue plasminogen activator (tPA) in some species of animals and in humans. For this reason dDAVP is used therapeutically in the treatment of bleeding episodes in patients suffering from haemophilia A and Von Willebrand's disease. However, the high antidiuretic activity of dDAVP constitutes and unwanted effect in this context. In the present study, a large number of analogues of vasopressin were designed, synthesized and tested in monkeys with the aim of producing compounds in which the Factor VIII-releasing activity was selectively isolated from the vasopressor and antidiuretic actions of the peptide. The results indicate that it is possible to separate these biological activities; however, none of the analogues tested so far possessed Factor VIII potencies comparable to that of dDAVP.

Amino Acid Sequence↗
PubMed1993

Age-related effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine treatment of common marmosets.

The effect of treatment with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on juvenile (6-8 months), young adult (2-4 years) and aged (8-10 years) common marmosets were compared. Juvenile marmosets were more resistant to the actions of MPTP and required a greater cumulative dose over a longer period to induce the same degree of motor disability observed in older animals. Young adult and aged marmosets showed an equivalent motor recovery in the 4-5 weeks following cessation of MPTP treatment, but juvenile animals were less able to compensate for the motor impairments. Losses of putamen [3H]dopamine uptake and caudate nucleus dopamine content were equivalent in young adult and aged animals. However, juvenile animals showed a more marked degree of dopamine depletion and reduction in [3H]dopamine uptake. Histological analysis showed cell loss in the substantia nigra to be most prominent in juvenile animals although it was evident in all groups. No loss of cells in the locus coeruleus was apparent in any of the groups studied, and no intraneuronal eosinophilic inclusions were seen. Greater nigral cell loss and dopamine depletion were required in juvenile animals to impair motor function. The degree of behavioural recovery was less in juvenile animals than in young adult and aged marmosets. The extent of behavioural recovery appeared linked to the severity of cell loss and was not reduced in old age.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1993

Effects of talipexole on motor behavior in normal and MPTP-treated common marmosets.

Administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP, 0.5 mg/animal i.v. once or twice) to common marmosets induced persistent parkinsonian motor deficits. The postsynaptic dopamine D2 receptor agonist properties of talipexole (B-HT 920, 2-amino-6-allyl-5,6,7,8-tetrahydro-4H-thiazolo[4,5-d]-azepine), which is believed to be a dopamine autoreceptor agonist, were examined using normal and MPTP-treated marmosets and were compared to these properties of bromocriptine, a selective dopamine D2 receptor agonist. Talipexole (20-160 micrograms/kg i.p.) dose dependently increased motor activity and reversed the akinesia and incoordination of movement in MPTP-treated marmosets. In normal marmosets, higher doses of talipexole (80-160 micrograms/kg i.p.) produced a dose-dependent increase in motor activity, while the lowest dose (20 micrograms/kg i.p.) depressed this activity. These data for talipexole were very similar to those for bromocriptine. Talipexole had, however, several properties different from those of bromocriptine; it had a rapid onset of antiparkinsonian activity compared to bromocriptine; it had more than 25 times as much activity potency as bromocriptine; a dose of talipexole (80 micrograms/kg i.p.) sufficient to produce the activity did not induce emesis as strongly as an insufficient dose of bromocriptine (0.5 mg/kg i.p.). These results suggest that talipexole has postsynaptic dopamine D2 receptor agonist properties and that these properties of talipexole may be favorable in the treatment of Parkinson's disease.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗