Activation of neuronal adenosine A1 receptors causes hypothermia through central and peripheral mechanisms

Extracellular adenosine, a danger signal, can cause hypothermia. We generated mice lacking neuronal adenosine A1 receptors (A1AR, encoded by the Adora1 gene) to examine the contribution of these receptors to hypothermia. Intracerebroventricular injection of the selective A1AR agonist (Cl-ENBA, 5'-chloro-5'-deoxy-N6-endo-norbornyladenosine) produced hypothermia, which was reduced in mice with deletion of A1AR in neurons. A non-brain penetrant A1AR agonist [SPA, N6-(p-sulfophenyl) adenosine] also caused hypothermia, in wild type but not mice lacking neuronal A1AR, suggesting that peripheral neuronal A1AR can also cause hypothermia. Mice expressing Cre recombinase from the Adora1 locus were generated to investigate the role of specific cell populations in body temperature regulation. Chemogenetic activation of Adora1-Cre-expressing cells in the preoptic area did not change body temperature. In contrast, activation of Adora1-Cre-expressing dorsomedial hypothalamus cells increased core body temperature, concordant with agonism at the endogenous inhibitory A1AR causing hypothermia. These results suggest that A1AR agonism causes hypothermia via two distinct mechanisms: brain neuronal A1AR and A1AR on neurons outside the blood-brain barrier. The variety of mechanisms that adenosine can use to induce hypothermia underscores the importance of hypothermia in the mouse response to major metabolic stress or injury.

Pharmacokinetics of Darolutamide, its Diastereomers and Active Metabolite in the Mouse: Response to Saini NK et al. (2020)

Background: Saini et al. recently investigated the pharmacokinetics of darolutamide and its diastereomers in vitro and in vivo in Balb/c mice, reporting higher levels of (S,S)-darolutamide than (S,R)-darolutamide following intravenous or oral dosing, and interconversion of (S,R)-darolutamide to (S,S)-darolutamide. Objective: To present our in vitro and in vivo studies of darolutamide pharmacokinetics in mice, which contrast with the findings of Saini et al. Methods: Nude male Balb/c mice were orally dosed for 7 days with 25, 50, or 100 mg/kg of darolutamide twice daily. Pharmacokinetic parameters in plasma and tissue samples were assessed by liquid chromatography-tandem mass spectrometry. Metabolism and interconversion of darolutamide and diastereomers was investigated in cryopreserved Balb/c mouse hepatocytes. Protein binding was determined in plasma samples by equilibrium dialysis. Results and Discussion: At day 7, Cmax was reached 30 min after last dose. Rapid formation and greater exposure of ketodarolutamide versus darolutamide were observed. Plasma exposure of (S,R)-darolutamide was 3–5-fold higher than that of (S,S)-darolutamide. The fraction of unbound keto-darolutamide was almost 6-fold lower than for darolutamide. In mouse hepatocytes, conversion of (S,S)- to (S,R)-darolutamide was observed but conversion of (S,R)- to (S,S)- darolutamide was not detectable. Back-formation of keto-darolutamide to both diastereomers occurred at low levels. Conclusion: The darolutamide diastereomer ratio changes upon administration in mice and other species, due to interconversion through keto-darolutamide. This is not considered clinically relevant since both diastereomers and ketodarolutamide are pharmacologically similar in vitro. Based on the high protein binding of keto-darolutamide, its contribution in vivo in humans is considered low.

The life of an XPA-mouse. A posthumanist approach to becoming with humans in laboratory and law

This article is about mice. More specifically about several generations of transgenic mice, XPA-mice, that were born, lived and died in a Dutch laboratory where they were exposed to carcinogens to test if they were more sensitive to these substances than ‘regular’ mice. Taking a posthumanist approach, I analyze the daily lives of these mice as a multispecies choreography. This choreography involves mice, humans and technologies such as cages, performing together to produce ‘the XPA-mouse’ as laboratory mouse. The focus is on daily doings and bodily entanglement, rather than linguistics, making it more inclusive of human bodies, nonhuman animals and materials. However, for the different phrases of this choreography, I do not only discuss what is included but also which moves have been foreclosed, which worlds and accompanying mouse response-abilities have been excluded? This focus on exclusion will show how interspecies power relations both within the lab and within social and legal discourse have greatly constraint the meaning of agency for these particular mice.

The Core Mouse Response to Infection by Neospora Caninum Defined by Gene Set Enrichment Analyses

In this study, the BALB/c and Qs mouse responses to infection by the parasite Neospora caninum were investigated in order to identify host response mechanisms. Investigation was done using gene set (enrichment) analyses of microarray data. GSEA, MANOVA, Romer, subGSE and SAM-GS were used to study the contrasts Neospora strain type, Mouse type (BALB/c and Qs) and time post infection (6 hours post infection and 10 days post infection). The analyses show that the major signal in the core mouse response to infection is from time post infection and can be defined by gene ontology terms Protein Kinase Activity, Cell Proliferation and Transcription Initiation. Several terms linked to signaling, morphogenesis, response and fat metabolism were also identified. At 10 days post infection, genes associated with fatty acid metabolism were identified as up regulated in expression. The value of gene set (enrichment) analyses in the analysis of microarray data is discussed.

Pyruvate kinase deficiency confers susceptibility to Salmonella typhimurium infection in mice

The mouse response to acute Salmonella typhimurium infection is complex, and it is under the influence of several genes, as well as environmental factors. In a previous study, we identified two novel Salmonella susceptibility loci, Ity4 and Ity5, in a (AcB61 × 129S6)F2 cross. The peak logarithm of odds score associated with Ity4 maps to the region of the liver and red blood cell (RBC)–specific pyruvate kinase (Pklr) gene, which was previously shown to be mutated in AcB61. During Plasmodium chabaudi infection, the Pklr mutation protects the mice against this parasite, as indicated by improved survival and lower peak parasitemia. Given that RBC defects have previously been associated with resistance to malaria and susceptibility to Salmonella, we hypothesized that Pklr is the gene underlying Ity4 and that it confers susceptibility to acute S. typhimurium infection in mice. Using a fine mapping approach combined with complementation studies, comparative studies, and functional analysis, we show that Pklr is the gene underlying Ity4 and that it confers susceptibility to acute S. typhimurium infection in mice through its effect on the RBC turnover and iron metabolism.

A comparative study of renal function in the desert-adapted spiny mouse and the laboratory-adapted C57BL/6 mouse: response to dietary salt load

The desert-adapted spiny mouse has a significantly lower glomerular number, increased glomerular size, and a more densely packed renal papillae compared with the similar-sized laboratory-adapted C57BL/6 mouse. In the present study we examined the functional consequences of these structural differences in young adult male spiny and C57BL/6 mice and detailed the impact of 1 wk of a high-salt (10% wt/wt NaCl) diet. Basal food and water intake, urine and feces production, and urinary electrolyte concentrations were not different between species, although urinary urea concentrations were higher in spiny mice ( P < 0.05). On normal salt, MAP of the anesthetized spiny mouse was ∼18 mmHg lower, effective renal plasma flow (ERPF) was 40% lower ( P < 0.001), and glomerular filtration rate (GFR) tended to be lower than in the C57BL/6 mouse. On the high-salt diet, both species had similar 24-h NaCl excretions; but C57BL/6 mice required a significantly increased amount of water (lower urine NaCl concentration) than the spiny mice. Filtration fraction was greater in both species on the high-salt diet. Spiny mice had greater GFR and ERPF after the high-salt diet, whereas the C57BL/6 mouse showed little change in GFR. The ability of the spiny mouse to tolerate a significantly higher plasma osmolality after salt, measured by a decreased drinking response, and the ability to increase ERPF at a lower MAP are features that allow this species to conserve water more efficiently than can be done in the C57BL/6 mouse. These features are important, particularly since the desert mouse has a smaller kidney, with fewer nephrons.