PDE9A is a cGMP-specific phosphodiesterase expressed in neurons throughout the brain that has attracted attention as a therapeutic target to treat cognitive disorders. Indeed, PDE9A inhibitors are ...under evaluation in clinical trials as a treatment for Alzheimer's disease and schizophrenia. However, little is known about the cGMP signaling cascades regulated by PDE9A. Canonical cGMP signaling in brain follows the activation of neuronal nitric oxide synthase (nNOS) and the generation of nitric oxide, which activates soluble guanylyl cyclase and cGMP synthesis. However, we show that in mice, PDE9A regulates a pool of cGMP that is independent of nNOS, specifically, and nitric oxide signaling in general. This PDE9A-regulated cGMP pool appears to be highly compartmentalized and independent of cGMP pools regulated by several PDEs. These findings provide a new foundation for study of the upstream and downstream signaling elements regulated by PDE9A and its potential as a therapeutic target for brain disease.
Huntington’s disease (HD) symptoms are driven to a large extent by dysfunction of the basal ganglia circuitry. HD patients exhibit reduced striatal phoshodiesterase 10 (PDE10) levels. Using HD mouse ...models that exhibit reduced PDE10, we demonstrate the benefit of pharmacologic PDE10 inhibition to acutely correct basal ganglia circuitry deficits. PDE10 inhibition restored corticostriatal input and boosted cortically driven indirect pathway activity. Cyclic nucleotide signaling is impaired in HD models, and PDE10 loss may represent a homeostatic adaptation to maintain signaling. Elevation of both cAMP and cGMP by PDE10 inhibition was required for rescue. Phosphoproteomic profiling of striatum in response to PDE10 inhibition highlighted plausible neural substrates responsible for the improvement. Early chronic PDE10 inhibition in Q175 mice showed improvements beyond those seen with acute administration after symptom onset, including partial reversal of striatal deregulated transcripts and the prevention of the emergence of HD neurophysiological deficits.
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•Q175 and R6/2 HD models exhibit reduced PDE10A equivalent to manifest HD patients•PDE10 inhibition restored striatal input and indirect pathway output in HD mice•Both cAMP and cGMP elevation were required for rescue•Chronic dosing of HD models from pre-symptomatic ages confers additional benefit
Beaumont et al. demonstrate that acute PDE10 inhibition boosts diminished corticostriatal input and indirect pathway output in symptomatic HD models, despite loss of PDE10. Their data provide rationale for a PDE10i clinical trial to assess symptom improvement in HD patients.
Predicting the potential distribution of invaders is informative for pre-emptive policy or management decisions and identifying suitable areas for establishment of new populations. Temporal ...projection of potential distributions is complicated by the magnitude and pace of changing climate, which could alter suitability under future conditions. The wetland invader,
Butomus umbellatus
is widespread in the northern US and southern Canada, but potential for invasion into new areas is unknown. We used environmental niche modeling to address our hypotheses for
B. umbellatus
: (1) a climatic niche shift has occurred between native and invasive ranges, (2) suitable areas in the invaded range have been colonized, and (3) climate suitability is likely to change in future climates. Environmental niche is highly conserved and stable (0.761) between ranges of
B. umbellatus
. Ensemble forecast revealed that nearly 60% of the invaded range is climatically suitable, including large areas in both the southern US and Alaska. Under future climates, there is a net decrease of suitable area, although two of three global circulation models predict range expansion of this species across gas emission scenarios. Given that the area is already invaded or at risk for future invasion, development of geographically adaptable long-term management strategies is prudent.
Large-scale patterns of plant invasions may reflect regional heterogeneity in biotic and abiotic factors and genetic variation within and between invading populations. Having information on how ...effects of biotic resistance vary spatially can be especially important when implementing biological control because introduced agents may have different impacts through interactions with host-plant genotype, local environment, or other novel enemies. We conducted a series of field surveys and laboratory studies to determine whether there was evidence of biotic resistance, as foliar fungal pathogens, in two introduced genotypes (triploid G1, diploid G4) of the Eurasian wetland weed,
Butomus umbellatus
L. in the USA. We tested whether genotypes differed in disease attack and whether spatial patterns in disease incidence were related to geographic location or climate for either genotype. We surveyed 27
B. umbellatus
populations (17 G1, 10 G4) to determine disease incidence and associated fungal pathogens. For a subset of plant populations, we isolated foliar fungi and tested pathogenicity of three isolates in laboratory assays. After accounting for location (latitude, climate), G1 plants had lower disease incidence than G4 plants in the field (38% vs. 70%) but similar pathogen richness. In contrast, bioassays revealed G1 plants consistently received a higher damage score and had larger leaf lesions regardless of pathogen. The seemingly contradictory results between the field and laboratory may be due to climatic differences between areas that limit the regional pool of pathogens or their effect on plant genotype. These results demonstrate that two widespread
B. umbellatus
genotypes exhibit different susceptibility to pathogens and effectiveness of pathogen biological controls may depend on local conditions.
Phosphodiesterase 10A (PDE10A) is a recently identified cyclic nucleotide phosphodiesterase expressed primarily in dopaminoreceptive medium spiny neurons of the striatum. We report that papaverine is ...a potent, specific inhibitor of PDE10A and use this compound to explore the role of PDE10A in regulating striatal function. Papaverine administration produces an increase in striatal tissue levels of cGMP and an increase in extracellular cAMP measured by microdialysis. These cyclic nucleotide changes are accompanied by increases in the phosphorylation of CREB and ERK, downstream markers of neuronal activation. In rats, papaverine potentiates haloperidol-induced catalepsy, consistent with the hypothesis that inhibition of PDE10A can increase striatal output and prompting a further evaluation of papaverine in models predictive of antipsychotic activity. Papaverine is found to inhibit conditioned avoidance responding in rats and mice and to inhibit PCP- and amphetamine-stimulated locomotor activity in rats. The effects of papaverine on striatal cGMP and CREB and ERK phosphorylation, as well as on conditioned avoidance responding, were absent in PDE10A knockout mice, indicating that the effects of the compound are the result of PDE10A inhibition. These results indicate that PDE10A regulates the activation of striatal medium spiny neurons through effects on cAMP- and cGMP-dependent signaling cascades. Furthermore, the present results demonstrate that papaverine has efficacy in behavioral models predictive of antipsychotic activity. Thus, inhibition of PDE10A may represent a novel approach to the treatment of psychosis.
Inhibition of phosphodiesterase 10A (PDE10A) promotes cyclic nucleotide signaling, increases striatal activation, and decreases behavioral activity. Enhanced cyclic nucleotide signaling is a well ...established route to producing changes in gene expression. We hypothesized that chronic suppression of PDE10A activity would have significant effects on gene expression in the striatum. A comparison of the expression profile of PDE10A knockout (KO) mice and wild-type mice after chronic PDE10A inhibition revealed altered expression of 19 overlapping genes with few significant changes outside the striatum or after administration of a PDE10A inhibitor to KO animals. Chronic inhibition of PDE10A produced up-regulation of mRNAs encoding genes that included prodynorphin, synaptotagmin10, phosphodiesterase 1C, glutamate decarboxylase 1, and diacylglycerol O-acyltransferase and a down-regulation of mRNAs encoding choline acetyltransferase and Kv1.6, suggesting long-term suppression of the PDE10A enzyme is consistent with altered striatal excitability and potential utility as a antipsychotic therapy. In addition, up-regulation of mRNAs encoding histone 3 (H3) and down-regulation of histone deacetylase 4, follistatin, and claspin mRNAs suggests activation of molecular cascades capable of neuroprotection. We used lentiviral delivery of cAMP response element (CRE)-luciferase reporter constructs into the striatum and live animal imaging of 2-{4--pyridin-4-yl-1-(2,2,2-trifluoro-ethyl)-1H-pyrazol-3-yl-phenoxymethyl}-quinoline succinic acid (TP-10)-induced luciferase activity to further demonstrate PDE10 inhibition results in CRE-mediated transcription. Consistent with potential neuroprotective cascades, we also demonstrate phosphorylation of mitogen- and stress-activated kinase 1 and H3 in vivo after TP-10 treatment. The observed changes in signaling and gene expression are predicted to provide neuroprotective effects in models of Huntington's disease.
Disasters pose a documented risk to mental health, with a range of peri- and post-disaster factors (both pre-existing and disaster-precipitated) linked to adverse outcomes. Among these, increasing ...empirical attention is being paid to the relation between disasters and violence.
This study examined self-reported experiences of assault or violence victimisation among communities affected by high, medium, and low disaster severity following the 2009 bushfires in Victoria, Australia. The association between violence, mental health outcomes and alcohol misuse was also investigated.
Participants were 1016 adults from high-, medium- and low-affected communities, 3-4 years after an Australian bushfire disaster. Rates of reported violence were compared by areas of bushfire-affectedness. Logistic regression models were applied separately to men and women to assess the experience of violence in predicting general and fire-related post-traumatic stress disorder, depression and alcohol misuse.
Reports of experiencing violence were significantly higher among high bushfire-affected compared with low bushfire-affected regions. Analyses indicated the significant relationship between disaster-affectedness and violence was observed for women only, with rates of 1.0, 0 and 7.4% in low, medium and high bushfire-affected areas, respectively. Among women living in high bushfire-affected areas, negative change to income was associated with an increased likelihood of experiencing violence (odds ratio, 4.68). For women, post-disaster violence was associated with more severe post-traumatic stress disorder and depression symptoms.
Women residing within high bushfire-affected communities experienced the highest levels of violence. These post-disaster experiences of violence are associated with post-disaster changes to income and with post-traumatic stress disorder and depression symptoms among women. These findings have critical implications for the assessment of, and interventions for, women experiencing or at risk of violence post-disaster.
The poor prognosis for pancreatic ductal adenocarcinoma (PDAC) patients is due in part to the highly fibrotic nature of the tumors that impedes delivery of therapeutics, including nanoparticles ...(NPs). Our prior studies demonstrated that proglumide, a cholecystokinin receptor (CCKR) antagonist, reduced fibrosis pervading PanIN lesions in mice. Here, we further detail how the reduced fibrosis elicited by proglumide achieves the normalization of the desmoplastic tumor microenvironment (TME) and improves nanoparticle uptake. One week following the orthotopic injection of PDAC cells, mice were randomized to normal or proglumide-treated water for 3-6 weeks. Tumors were analyzed ex vivo for fibrosis, vascularity, stellate cell activation, vascular patency, and nanoparticle distribution. The histological staining and three-dimensional imaging of tumors each indicated a reduction in stromal collagen in proglumide-treated mice. Proglumide treatment increased tumor vascularity and decreased the activation of cancer-associated fibroblasts (CAFs). Additionally, PANC-1 cells with the shRNA-mediated knockdown of the CCK2 receptor showed an even greater reduction in collagen, indicating the CCK2 receptors on tumor cells contribute to the desmoplastic TME. Proglumide-mediated reduction in fibrosis also led to functional changes in the TME as evidenced by the enhanced intra-tumoral distribution of small (<12 nm) Rhodamine-loaded nanoparticles. The documented in vivo, tumor cell-intrinsic anti-fibrotic effects of CCK2R blockade in both an immunocompetent syngeneic murine PDAC model as well as a human PDAC xenograft model demonstrates that CCK2R antagonists, such as proglumide, can improve the delivery of nano-encapsulated therapeutics or imaging agents to pancreatic tumors.
By utilizing structure-based drug design (SBDD) knowledge, a novel class of phosphodiesterase (PDE) 10A inhibitors was identified. The structure-based drug design efforts identified a unique ..."selectivity pocket" for PDE10A inhibitors, and interactions within this pocket allowed the design of highly selective and potent PDE10A inhibitors. Further optimization of brain penetration and drug-like properties led to the discovery of 2-4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl-quinoline (PF-2545920). This PDE10A inhibitor is the first reported clinical entry for this mechanism in the treatment of schizophrenia.
Abstract
Separate introductions or post-introduction evolution may lead to multiple invader genotypes or cytotypes that differ in growth rates, biomass or chemical profile responses (phenotype) to a ...range of environments. If the invader has high trait plasticity to a range of resource levels, then sediment N or P enrichment may enhance invasiveness. However, the ways in which ploidy, plasticity, and available N or P interact are unknown for most species despite the potential to explain spread and impacts by invaders with multiple introduced lineages. We conducted a common garden experiment with four triploid and six diploid populations of Butomus umbellatus, collected from across its invasive range in the USA. Plants were grown under different N or P nutrient levels (4, 40, 200, 400 mg L−1 N; 0.4, 4, 40 mg L−1 P) and we measured reaction norms for biomass, clonal reproduction and tissue chemistry. Contrary to our expectation, triploid B. umbellatus plants were less plastic to variation in N or P than diploid B. umbellatus in most measured traits. Diploid plants produced 172 % more reproductive biomass and 57 % more total biomass across levels of N, and 158 % more reproductive biomass and 33 % more total biomass across P than triploid plants. Triploid plants had lower shoot:root ratios and produced 30 % and 150 % more root biomass than diploid plants in response to increases in N and P, respectively. Tissue chemistry differed between cytotypes but plasticity was similar; N was 8 % higher and C:N ratio was 30 % lower in triploid than diploid plants across levels of N and plant parts, and N was 22 % higher and C:N ratio 27 % lower across levels of P and plant parts. Our results highlight differences in nutrient response between cytotypes of a widespread invader, and we call for additional field studies to better understand the interaction of nutrients and ploidy during invasion.
The ability to withstand and respond to a range of environmental conditions can vary among plants of varying ploidy levels and contribute to the success of invasive species in introduced areas. The authors undertook a greenhouse study of the wetland invader, flowering rush (Butomus umbellatus) to determine whether ploidy of introduced populations explained differences in biomass production and allocation, and chemical responses to increasing nitrogen or phosphorus availability. Diploid plants produced more biomass across levels of either nutrient but allocation to roots was higher in triploid plants. Overall, plasticity was higher in diploid plants which may contribute to B. umbellatus invasion in eutrophic systems.
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