Oxygen consumption deficit in Huntington disease mouse brain under metabolic stress.

In vivo evidence for brain mitochondrial dysfunction in animal models of Huntington disease (HD) is scarce. We applied the novel 17O magnetic resonance spectroscopy (MRS) technique on R6/2 mice to directly determine rates of oxygen consumption (CMRO2) and assess mitochondrial function in vivo Basal respiration and maximal CMRO2 in the presence of the mitochondrial uncoupler dinitrophenol (DNP) were compared using 16.4 T in isoflurane anesthetized wild type (WT) and HD mice at 9 weeks. At rest, striatal CMRO2 of R6/2 mice was equivalent to that of WT, indicating comparable mitochondrial output despite onset of motor symptoms in R6/2. After DNP injection, the maximal CMRO2 in both striatum and cortex of R6/2 mice was significantly lower than that of WT, indicating less spare energy generating capacity. In a separate set of mice, oligomycin injection to block ATP generation decreased CMRO2 equally in brains of R6/2 and WT mice, suggesting oxidative phosphorylation capacity and respiratory coupling were equivalent at rest. Expression levels of representative mitochondrial proteins were compared from harvested tissue samples. Significant differences between R6/2 and WT included: in striatum, lower VDAC and the mitochondrially encoded cytochrome oxidase subunit I relative to actin; in cortex, lower tricarboxylic acid cycle enzyme aconitase and higher protein carbonyls; in both, lower glycolytic enzyme enolase. Therefore in R6/2 striatum, lowered CMRO2 may be attributed to a decrease in mitochondria while the cortical CMRO2 decrease may result from constraints upstream in energetic pathways, suggesting regionally specific changes and possibly rates of metabolic impairment.

Sh-I-048A, an in vitro non-selective super-agonist at the benzodiazepine site of GABAA receptors: the approximated activation of receptor subtypes may explain behavioral effects.

Enormous progress in understanding the role of four populations of benzodiazepine-sensitive GABAA receptors was paralleled by the puzzling findings suggesting that substantial separation of behavioral effects may be accomplished by apparently non-selective modulators. We report on SH-I-048A, a newly synthesized chiral positive modulator of GABAA receptors characterized by exceptional subnanomolar affinity, high efficacy and non-selectivity. Its influence on behavior was assessed in Wistar rats and contrasted to that obtained with 2mg/kg diazepam. SH-I-048A reached micromolar concentrations in brain tissue, while the unbound fraction in brain homogenate was around 1.5%. The approximated electrophysiological responses, which estimated free concentrations of SH-I-048A or diazepam are able to elicit, suggested a similarity between the 10mg/kg dose of the novel ligand and 2mg/kg diazepam; however, SH-I-048A was relatively more active at α1- and α5-containing GABAA receptors. Behaviorally, SH-I-048A induced sedative, muscle relaxant and ataxic effects, reversed mechanical hyperalgesia 24h after injury, while it was devoid of clear anxiolytic actions and did not affect water-maze performance. While lack of clear anxiolytic actions may be connected with an enhanced potentiation at α1-containing GABAA receptors, the observed behavior in the rotarod, water maze and peripheral nerve injury tests was possibly affected by its prominent action at receptors containing the α5 subunit. The current results encourage further innovative approaches aimed at linking in vitro and in vivo data in order to help define fine-tuning mechanisms at four sensitive receptor populations that underlie subtle differences in behavioral profiles of benzodiazepine site ligands.

Haloperidol: towards further understanding of the structural contributions of its pharmacophoric elements at D2-like receptors.

An attempt to understand the pharmacophore-relevant position of the alcoholic moiety in haloperidol and the contributions of other pharmacophoric elements led to the re-synthesis of its tropane analogue (compound 2). An analysis of the binding data suggests that haloperidol binds to the DA receptors with the OH group in the axial position and the OH group, while not essential for binding, enhances binding especially at the D2 receptor. It also became clear that shortening the butyrophenone chain not only reduces binding affinity at the DA receptors but eliminates subtype selectivity.

Examination of physical and regulatory variables leading to small dam removal in Wisconsin.

The decision to remove or repair a dam depends on multiple variables, many of which encompass both physical and social factors. In Wisconsin, the Department of Natural Resources is mandated to inspect small dams every ten years. A safety inspection often acts as a trigger event to a dam removal or repair decision. Although the issues surrounding a dam removal decision are often couched as ecological, these decisions are influenced by their social and regulatory context. In this work, we examine descriptive variables of Wisconsin dams that were inspected and consequently removed or maintained between 1985 and 1990. We hypothesize that geographic location, height of dam, size of impoundment, age of dam, and type of ownership determine the likelihood of a safety inspection, and the subsequent likelihood of removal. Using a logistic model, we find that publicly owned dams had the greatest probability of inspection after 1985. Of these dams, older dams and those with smaller impoundments were most likely to be removed. We were unable to build a strong predictive model for dam removal with our suite of variables, suggesting that a community's decision to remove or maintain a dam is complex and heterogeneous.