The PDE10A Inhibitor TAK-063 Reverses Sound-Evoked EEG Abnormalities in a Mouse Model of Fragile X Syndrome.

Fragile X syndrome (FXS) is a genetic neurodevelopmental syndrome characterized by increased anxiety, repetitive behaviors, social communication deficits, delayed language development, and abnormal sensory processing. Recently, we have identified electroencephalographic (EEG) biomarkers that are conserved between the mouse model of FXS (Fmr1 KO mice) and humans with FXS. In this study, we test a specific candidate mechanism for engagement of multielectrode array (MEA) EEG biomarkers in the FXS mouse model. We administered TAK-063, a potent, selective, and orally active phosphodiesterase 10A (PDE10A) inhibitor, to Fmr1 KO mice, and examined its effects on MEA EEG biomarkers. We demonstrate significant dose-related amelioration of inter-trial phase coherence (ITPC) to temporally modulated auditory stimuli by TAK-063 in Fmr1 KO mice. Our data suggest that TAK-063 improves cortical auditory stimulus processing in Fmr1 KO mice, without significantly depressing baseline EEG power or causing any noticeable sedation or behavioral side effects. Thus, the PDE10A inhibitor TAK-063 has salutary effects on normalizing EEG biomarkers in a mouse model of FXS and should be pursued in further translational treatment development.

The role of vitamin D in asthma.

OBJECTIVE: To review the current literature on vitamin D and asthma, discussing the possible roles of vitamin D on asthma pathogenesis and the potential consequences of vitamin D deficiency. DATA SOURCES: PubMed database was searched from 1950 to 2009. Keywords used included asthma, vitamin D, inflammation, airway smooth muscle and cytokines. STUDY SELECTION: Articles were selected based on relevance to the subject. RESULTS: Vitamin D deficiency has been associated with epidemiologic patterns observed in the asthma epidemic. Vitamin D deficiency is more common with obesity, African American ethnicity, and westernization of countries with higher-risk populations for asthma. Evidence suggests that vitamin D deficiency is associated with increased airway hyperresponsiveness, lower pulmonary functions, worse asthma control, and possibly steroid resistance. Lung epithelial cells express high baseline levels of 1alpha-hydroxylase. This allows the conversion of inactive calcidiol to active calcitriol locally within the lung. Calcitriol has been shown to inhibit the synthesis and release of certain cytokines, such as RANTES, platelet-derived growth factor, and matrix metalloproteinases, from bronchial smooth muscle cells, thereby leading to decreased lung inflammation and smooth muscle cell proliferation. Vitamin D also increases synthesis of interleukin 10 by CD4+CD25+Foxp3+ T-regulatory cells and dendritic cells, while concurrently inhibiting dendritic cell activation by downregulating expression of costimulatory molecules CD40 and CD80/86. Vitamin D is also capable of inducing the expression of several anti-infective molecules, such as cathelicidin. Thus, vitamin D has a number of biologic effects that are likely important in regulating key mechanisms in asthma. CONCLUSIONS: We hypothesize that vitamin D supplementation may lead to improved asthma control by inhibiting the influx of inflammatory cytokines in the lung and increasing the secretion of interleukin 10 by T-regulatory cells and dendritic cells.