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The development of selective ligands targeting neuronal nicotinic acetylcholine receptors to alleviate symptoms associated with neurodegenerative diseases presents the advantage of affecting multiple deficits that are the hallmarks of these pathologies. TC-1734 is an orally active novel neuronal nicotinic agonist with high selectivity for neuronal nicotinic receptors. Microdialysis studies indicate that TC-1734 enhances the release of acetylcholine from the cortex. TC-1734, by either acute or repeated administration, exhibits memory enhancing properties in rats and mice and is neuroprotective following excitotoxic insult in fetal rat brain in cultures and against alterations of synaptic transmission induced by deprivation of glucose and oxygen in hippocampal slices. At submaximal doses, TC-1734 produced additive cognitive effects when used in combination with tacrine or donepezil. Unlike (-)-nicotine, behavioral sensitization does not develop following repeated administration of TC-1734. Its pharmacokinetic (PK) profile (half-life of 2 h) contrasts with the long lasting improvement in working memory (18 h) demonstrating that cognitive improvement extends beyond the lifetime of the compound. The very low acute toxicity of TC-1734 and its receptor activity profile provides additional mechanistic basis for its suggested potential as a clinical candidate. TC-1734 was very well tolerated in acute and chronic oral toxicity studies in mice, rats and dogs. Phase I clinical trials demonstrated TC-1734's favorable pharmacokinetic and safety profile by acute oral administration at doses ranging from 2 to 320 mg. The bioavailability, pharmacological, pharmacokinetic, and safety profile of TC-1734 provides an example of a safe, potent and efficacious neuronal nicotinic modulator that holds promise for the management of the hallmark symptomatologies observed in dementia.

The authors have described the effect of TC-1734, a brain-selective nicotinic acetylcholine receptor (nAChR) agonist, on acetylcholine (ACh) release in the frontoparietal cortex of rats and on cognitive function in mice. Oral administration of TC-1734 (5, 10 and 20 mg/kg) stimulated ACh release in a dose-dependent manner, as measured by transversal microdialysis. The maximal effect on the amplitude of ACh release was observed at a dose of 10 mg/kg (about 70% above baseline), whereas the maximal effect on the duration of ACh release was observed at the dose of 20 mg/kg. By contrast, oral administration of nicotine (1, 2.5 and 5 mg/kg) did not stimulate ACh release in a dose-dependent manner but produced the same maximal effect on the amplitude of ACh release (about 50% above baseline) at all the doses tested. The ability of both TC-1734 (10 mg/kg) and nicotine (1 mg/kg) to increase ACh levels was antagonized by mecamylamine (1 mg/kg s.c.), suggesting a specific nicotine receptor-mediated effect of both agonists. No tolerance to TC-1734- and nicotine-stimulated ACh release was observed after repeated treatment with TC-1734 (10 mg/kg) or nicotine (1 mg/kg) for 4 days. TC-1734 (1 mg/kg p.o.) improved memory in the object recognition test in mice, and this effect was antagonized by mecamylamine (2.5 mg/kg i.p.). Taken together, these results show that TC-1734 stimulates nAChR in the brain to induce an increase of ACh release in the cortex of rats and enhance memory in mice.

Our study aimed to determine whether riluzole, which has shown efficacy as a disease-modifying agent in amyotrophic lateral sclerosis (ALS), is neuroprotective in a marmoset model of Parkinson's disease (PD). Reduction of energy demand by riluzole could be a rational neuroprotective strategy with good tolerability. The efficacy of riluzole was evaluated in marmosets by testing its ability to reduce MPTP-induced behavioral deficits and loss of dopaminergic nigral neurons. Marmosets were divided into two groups of four animals each: animals in Group 1 were injected twice with MPTP (2 mg/kg subcutaneous) and treated with riluzole (10 mg/kg per os b.i.d.), animals in Group 2 (controls) were injected with MPTP and with the vehicle of riluzole. A third group of marmosets which did not receive MPTP or riluzole drug was introduced for neurohistopathological studies (normal animals). Marmosets treated with riluzole preserved a better motor function and neurological performance through the 26 days of assessment when compared with the controls. Histologically, there was sparing of TH- and Nissl-stained nigral neurons and of TH-stained terminals in the striatum and the putamen in the group treated with riluzole compared to the controls. We conclude that riluzole protects dopaminergic neurons and reduces behavioral deficits in a marmoset model of PD., (Copyright 2001 Movement Disorder Society.)

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), via its major metabolite 1-methyl-4-phenylpyridinium (MPP(+)), produces in primates including humans clinical, biochemical, and neuropathological changes similar to those which occur in idiopathic Parkinson's disease. Ebselen is an antioxidant drug with glutathione peroxidase-like activity and a proven neuroprotective action in stroke patients. Here we show that Ebselen, when administered before, during, and after MPTP injections, prevents both neuronal loss and clinical symptoms in a primate MPTP model of Parkinson's disease. Ebselen also prevents peroxide radical overproduction induced by serum withdrawal in cultured PC12 cells and hydroxyl radical generation induced by the mitochondrial toxin, MPP(+), in vivo in rat brain. Moreover, Ebselen inhibits MPP(+)-induced toxicity in PC12 cells, without interacting with the dopamine uptake system. Our results demonstrate that compounds which prevent mitochondrial dysfunction and free radical production may be useful as preventive treatment of Parkinson's disease., (Copyright 2000 Academic Press.)

We have used cannabinoid CB knock-out mice in a two-trial object recognition test to assess the role of cannabinoid CB receptors in memory. Cannabinoid CB1 knock-out mice are able to retain memory for at least 48 h after the first trial whereas the wild-type controls lose their capacity to retain memory after 24 h. These results suggest that endogenous cannabinoid CB receptors play a crucial role in the process of memory storage and retrieval.

Delta9-tetrahydrocannabinol (delta9-THC), cannabinol and cannabidiol are three important natural cannabinoids from the Marijuana plant (Cannabis sativa). Using [35S]GTP-gamma-S binding on rat cerebellar homogenate as an index of cannabinoid receptor activation we show that: delta9-THC does not induce the maximal effect obtained by classical cannabinoid receptor agonists such as CP55940. Moreover at high concentration delta9-THC exhibits antagonist properties. Cannabinol is a weak agonist on rat cerebellar cannabinoid receptors and cannabidiol behaves as an antagonist acting in the micromolar range.

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.

Axonal transport of the vesicular monoamine transporter was assayed in the rat brain by in vivo binding of the specific ligand [3H]reserpine. Because of the marked localization of reserpine binding sites in dopaminergic cell bodies and nerve terminals, the dopaminergic nigrostriatal pathway was chosen for the study of the axonal transport of the monoamine carrier present in the membrane of synaptic vesicles. When labelled reserpine was injected into the substantia nigra, a delayed accumulation of radioactivity in the ipsilateral striatum was observed approximately 4 h after the injection. Similarly, injection into the right striatum was followed by a substantial accumulation of radioactivity in the ipsilateral substantia nigra, which was prevented by peripheral injection of unlabelled reserpine or tetrabenazine. This process was rapid and dependent on microtubules. In senescent rats, the amount of retrogradely transported [3H]reserpine was significantly reduced. These results demonstrate that labelled reserpine may be used to monitor in vivo fast axonal transport in central neurons.

We present the pharmacological properties of two cyclopyrrolones, zopiclone as a hypnotic and suriclone as an anxiolytic, and examine their mechanism of action. The effects of zopiclone on the amount of time spent at each vigilance level have been studied in freely moving rats. Zopiclone from 2.5 mg/kg i.p. extends the duration of slow wave sleep (SWS), concomitantly shortening the periods awake. This SWS inducing effect of zopiclone was more potent after 10 mg/kg i.p.; moreover, zopiclone did not depress REM sleep and no rebound of activity in wakefulness or REM sleep were observed the day after zopiclone treatment. In rats, at the cortical level, zopiclone increases the spectral energy in the delta band (0.5 to 4 hertz). This rise in energy appears at doses starting from 1.25 mg/kg p.o. and can also reach the fast frequencies (beta band: 12 to 16 hertz). This power spectrum is characteristic of a compound having tranquilizing-hypnotic potential. Taken together these EEG results corroborate the clinical studies. In man, zopiclone increased SWS, decreased SWS latency and respected sleep architecture in both healthy volunteers and insomniacs. This respect of sleep structure and the relative short duration of action of zopiclone minimized the residual effects seen upon waking (drowsiness, impairment of psychomotor performance). In the Geller-Seifter test, an operant conflict procedure, the minimal effective dose (MED) of suriclone in reversing the conflict-induced inhibition of drinking behavior was 2.5 mg.kg-1 p.o. in rats. Depression of unpunished responding is only seen at higher doses (20 mg.kg-1 p.o.).(ABSTRACT TRUNCATED AT 250 WORDS)

Based on the results of the in vitro metabolism of CCK8 by various peptidases, we have synthesized three CCK analogs: Boc-Tyr(SO3H)-Nle-Gly-Trp-(N- Me)Nle-Asp-Phe-NH2 (compound I), Boc-Tyr(SO3H)-gNle-mGly-Trp-Nle-Asp-Phe-Nh2 (compound II), Boc-Tyr(SO3H)-gNle-mGly-Trp-(N-Me)Nle-Asp-Phe-NH2 (compound III). In in vitro enzymatic degradation studies, these compounds showed a high stability toward either enkephalinase or the enzymes present in crude rat brain membranes preparations. Moreover, in binding studies on guinea pig tissues, these CCK-related peptides were characterized by high apparent affinities for brain CCK receptors and by a broader range of affinities for pancreatic CCK receptors. This broad range of affinities was reflected by their pharmacological potencies in the guinea pig pancreatic amylase release and ileum contraction assays. These enzyme-resistant CCK analogs provide therefore valuable tools to investigate the pharmacology of CCK.

Bilateral injections of 6-OHDA in the ventral mesencephalic tegmentum (VMT) destroy the DA afferents of the nucleus accumbens but do not induce any denervation supersensitivity of the D1 receptors in the nucleus accumbens. Because other non-DA afferent fibers might also regulate D1 receptors in that structure, bilateral ablations of the prefrontal cortex were performed. This lesion induced a 55% decrease of [3H]glutamic acid high-affinity uptake activity in the nucleus accumbens. When the prefronto-cortical ablation was performed simultaneously with the bilateral injection of 6-OHDA in the VMT, a marked hypersensitivity of DA-sensitive adenylate cyclase activity was observed in the nucleus accumbens (+52% increase of Vmax and a two-fold decrease of the Kapp for DA) while the ablation of the prefrontal cortex alone induced only a +14% (P less than 0.01) increase of D1 receptors in that structure. These results indicate that the regulation of D1 receptors in the nucleus accumbens is not solely dependent on the presynaptic DA innervation and that other non-DA fibers, such as those of the cortico-nucleus accumbens pathway, might contribute to it.