Familial ALS-superoxide dismutases associate with mitochondria and shift their redox potentials

Recent studies suggest that the toxicity of familial amyotrophic lateral sclerosis mutant Cu, Zn superoxide dismutase (SOD1) arises from its selective recruitment to mitochondria. Here we demonstrate that each of 12 different familial ALS-mutant SOD1s with widely differing biophysical properties are associated with mitochondria of motoneuronal cells to a much greater extent than wild-type SOD1, and that this effect may depend on the oxidation of Cys residues. We demonstrate further that mutant SOD1 proteins associated with the mitochondria tend to form cross-linked oligomers and that their presence causes a shift in the redox state of these organelles and results in impairment of respiratory complexes. The observation that such a diverse set of mutant SOD1 proteins behave so similarly in mitochondria of motoneuronal cells and so differently from wild-type SOD1 suggests that this behavior may explain the toxicity of ALS-mutant SOD1 proteins, which causes motor neurons to die

siRNA screen identifies QPCT as a druggable target for Huntington's disease.

Huntington's disease (HD) is a currently incurable neurodegenerative condition caused by an abnormally expanded polyglutamine tract in huntingtin (HTT). We identified new modifiers of mutant HTT toxicity by performing a large-scale 'druggable genome' siRNA screen in human cultured cells, followed by hit validation in Drosophila. We focused on glutaminyl cyclase (QPCT), which had one of the strongest effects on mutant HTT-induced toxicity and aggregation in the cell-based siRNA screen and also rescued these phenotypes in Drosophila. We found that QPCT inhibition induced the levels of the molecular chaperone αB-crystallin and reduced the aggregation of diverse proteins. We generated new QPCT inhibitors using in silico methods followed by in vitro screening, which rescued the HD-related phenotypes in cell, Drosophila and zebrafish HD models. Our data reveal a new HD druggable target affecting mutant HTT aggregation and provide proof of principle for a discovery pipeline from druggable genome screen to drug development

The role of setting in the oral self-administration of alcohol in the rat

RATIONALE We have previously found that rats that were kept at all times in the self-administration (SA) chambers (resident group) self-administered more heroin than rats that were transferred to the SA chambers immediately before testing (Non-Resident group). Alcohol resembles heroin in its ability to produce, at recreational doses, mood elevation, euphoria, drowsiness, and sedation. Furthermore, alcohol presents some similarities with the mechanisms of action of heroin at the levels of the mesostriatal circuitry. Therefore, we predicted that, as for heroin, alcohol intake would be greater in the Resident than in the Non-Resident group. MATERIALS AND METHODS In Experiment 1, oral self-administration of ethanol and wine solutions (2.5%, 5%, and 10%, v/v) was assessed in Resident and Non-Resident rats using both one-bottle (three sessions) and two-bottle (seven sessions) tests. In addition, we also assessed the intake of water (Experiment 2) and of 0.04% saccharin-0.003% quinine solution (Experiment 3). RESULTS During the one-bottle sessions, alcohol intake of Resident rats was up to two times that of Non-Resident rats. During the two-bottle sessions, Resident rats drank two times more 5% alcohol than water, whereas Non-Resident rats took equal amount of the two fluids. The average daily intake of pure ethanol for Resident rats given access to 5% solutions was 0.71 ± 0.076 vs. 0.46 ± 0.078 g/kg for Non-Resident rats. No group differences in the intake of water and of saccharin-quinine solution were found. CONCLUSION The present report demonstrates at a preclinical level the importance of setting for alcohol self-administration

Environmental modulation of cocaine self-administration in the rat

RATIONALE: Previous studies have shown that environmental context can powerfully modulate the induction of psychomotor sensitization to cocaine in the rat. Rats that receive repeated administrations of cocaine in association with environmental novelty exhibit greater psychomotor sensitization than animals that receive the same treatments in their home cages. OBJECTIVES: The goal of the present study was to investigate whether environmental context can exert its modulatory influence also on cocaine self-administration. MATERIALS AND METHODS: Independent groups of rats with intravenous catheters were given the possibility to self-administer different doses of cocaine (0.0, 0.2, 0.4, and 0.8 mg/kg per infusion) under two environmental conditions. Some animals were housed in the self-administration cages (home groups), whereas other rats were transported to the self-administration cages only for the test sessions (novelty groups). RESULTS: Environmental "novelty" facilitated the acquisition of cocaine self-administration at the doses of 0.2 and 0.4 mg/kg per infusion. When rats were given access to a higher dose of cocaine (0.8 mg/kg per infusion), there were no significant group differences in drug taking. Environmental context had no effect on the self-administration of the vehicle. Thus, it appears that environmental "novelty" produced a shift to the left in the dose-effect curve for cocaine self-administration. Furthermore, "novelty" enhanced the motivation of the rats to work for cocaine, as indicated by the results of a progressive ratio procedure. CONCLUSIONS: The present findings demonstrate for the first time that the environment surrounding drug taking can alter both the intake of and motivation for cocaine

Dissociation in the effects of the D2/D3 dopaminergic agonist quinpirole on drinking and on vasopressin levels in the rat

In the present study, we investigated the role of vasopressin in the development of quinpirole-induced hyperdipsia in the rat. We report that: (1), an acute intraperitoneal (i.p.) injection of 0.56 mg/kg of quinpirole increased plasma vasopressin (radioimmunoassay) at 15 min but not at 30 or 120 min; (2), nine daily injections of quinpirole (0.56 mg/kg, i.p.) progressively increased water intake and diuresis for a period of several hours after each treatment; (3), quinpirole hyperdipsia was associated with apparently normal levels of vasopressin (which might be considered inappropriately high in the presence of excessive drinking); (4), quinpirole reduced vasopressin and oxytocin, but not angiotensin, immunoreactivity in the supraoptic nucleus. These findings suggest that quinpirole hyperdipsia is a sound animal model of psychotic polydipsia. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved

Identification of 2-aminopyrimidine derivatives as inhibitors of the canonical Wnt signaling pathway

The canonical Wnt signaling pathway plays a fundamental role in embryonic as well as in adult development. Consequently, dysregulation of the pathway has been linked to a wide spectrum of pathological conditions. In a program aimed at the identification of small molecule inhibitors of the canonical Wnt pathway we identified a series of 2-aminopyrimidine derivatives which specifically inhibited the pathway with minimal or no sign of cellular toxicity. The hit molecules 1 and 2 showed promising inhibitory activity with IC50 values of approximately 10 microM, but low solubility and metabolic stability. During the early stage of the hit series exploration, the pyrimidine core was variously decorated to obtain active compounds with a better physico-chemical profile. In particular, compound 13 showed Wnt inhibition activity comparable to hit molecules 1 and 2, with improved physico-chemical properties. Therefore, this series of compounds may be considered a promising starting point for the design of novel small molecule inhibitors of the canonical Wnt pathway

<i>N</i>‑[5-(5-Fluoropyridin-3-yl)‑1<i>H</i>‑pyrazol-3-yl]-4-piperidin-1-ylbutyramide (SEN78702, WYE-308775): A Medicinal Chemistry Effort toward an α7 Nicotinic Acetylcholine Receptor Agonist Preclinical Candidate

α7 nicotinic acetylcholine receptors (α7 nAChR) represent promising therapeutic candidates for the treatment of cognitive impairment associated with Alzheimer’s disease (AD) and schizophrenia. A medicinal chemistry effort around previously reported compound <b>1</b> (SEN15924, WAY-361789) led to the identification of <b>12</b> (SEN78702, WYE-308775) a potent and selective full agonist of the α7 nAChR that demonstrated improved plasma stability, brain levels, and efficacy in behavioral cognition models