Pavlos Alexakos

The effects of different types of individually ventilated caging systems on growing male mice.

Ventilation rate and turnover rate of dry air vary among different types of ventilation systems used with individually ventilated cages (IVCs) and can affect the well-being of rodents housed in these cages. The authors compared the effects of two types of IVC systems, forced-air IVCs and motor-free IVCs, on 4-week-old C57Bl/6J male mice. The mice were acclimatized to the cages for 8 d and then monitored for 87 d. Their body weights, food and water consumption and preferred resting areas were recorded. Mice that were housed in motor-free IVCs had a significantly greater increase in body weight than those housed in forced-air IVCs, despite having similar food consumption. Mice in forced-air IVCs had greater water consumption than mice in motor-free IVCs. In addition, mice in forced-air IVCs were more frequently located in the front halves of their cages, whereas mice in motor-free IVCs were located with similar frequency in the front and back halves of their cages, perhaps because of the higher ventilation rate or the location of the air inlets and outlets in the rear of the cage. These results suggest that body weight, food and water consumption and intracage location of growing male mice are influenced by the type of ventilation system used in the cages in which the mice are housed.

Assessing the exploratory and anxiety-related behaviors of mice. Do different caging systems affect the outcome of behavioral tests?

Ample studies have shown that housing can affect the health, welfare and behavior of mice and therefore, the outcomes of certain experiments. The aim of this study was to investigate if three widely used housing systems, Open Top Cages (OTC), Motor Free Ventilated Cages (MFVC) and Individually Ventilated Cages (IVC) may affect exploratory and anxiety-related behaviors in mice. Subjects were 8week-old male C57Bl/6J mice (n=36) divided into three groups, OTC, IVC and MFVC groups, respectively. The experimental procedure consisted of two behavioral tests: the open field and the elevated plus maze test. Although there were no differences in the open field test, the results from the elevated plus maze showed that animals housed in the MFVCs exhibited increased exploratory and less anxiety-like behavior. It is concluded that the different caging systems may have an impact on the outcome of behavioral tests used to assess exploratory and anxiety like behavior in mice. Therefore, it is essential to take into consideration housing conditions when reporting, analyzing, and/or systematically reviewing the results of behavioral testing in mice.

Nurr1:RXRα heterodimer activation as monotherapy for Parkinson’s disease

Significance In Parkinson’s disease (PD), dopamine (DA)-producing neurons gradually degenerate, leading to DA deficiency and to the main symptoms of PD. Current medications do not impede neurodegeneration, but relieve symptoms by replenishing DA; however, their chronic use causes serious side effects. We targeted a protein required for the development and function of DA neurons by designing a chemical compound that, by activating this protein, increases DA and improves symptoms without current treatment side effects while simultaneously preventing neuron loss in PD mice. Our findings point to a monotherapy that can both impede PD progression and concurrently improve symptoms of PD. Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopaminergic (DAergic) neurons in the substantia nigra and the gradual depletion of dopamine (DA). Current treatments replenish the DA deficit and improve symptoms but induce dyskinesias over time, and neuroprotective therapies are nonexistent. Here we report that Nuclear receptor-related 1 (Nurr1):Retinoid X receptor α (RXRα) activation has a double therapeutic potential for PD, offering both neuroprotective and symptomatic improvement. We designed BRF110, a unique in vivo active Nurr1:RXRα-selective lead molecule, which prevents DAergic neuron demise and striatal DAergic denervation in vivo against PD-causing toxins in a Nurr1-dependent manner. BRF110 also protects against PD-related genetic mutations in patient induced pluripotent stem cell (iPSC)-derived DAergic neurons and a genetic mouse PD model. Remarkably, besides neuroprotection, BRF110 up-regulates tyrosine hydroxylase (TH), aromatic l-amino acid decarboxylase (AADC), and GTP cyclohydrolase I (GCH1) transcription; increases striatal DA in vivo; and has symptomatic efficacy in two postneurodegeneration PD models, without inducing dyskinesias on chronic daily treatment. The combined neuroprotective and symptomatic effects of BRF110 identify Nurr1:RXRα activation as a potential monotherapeutic approach for PD.