Phosphodiesterase Type 4 Inhibition in CNS Diseases

Phosphodiesterases (PDEs) have been an interesting drug target for many diseases. Although a vast number of mainly preclinical studies demonstrates beneficial effects of PDE inhibitors for central nervous system (CNS) diseases, no drugs are currently available for CNS indications. In this review, we discuss the rationale of PDE4 inhibitors for different CNS diseases, including memory impairments, striatal disorders, multiple sclerosis (MS), and acquired brain injury (ABU). However, clinical development has been problematic due to mechanism-based adverse effects of these drugs in humans. Our increased understanding of factors influencing the conformational state of the PDE4 enzyme and of how to influence the binding affinity of PDE4 subtype inhibitors, holds promise for the successful development of novel selective PDE4 inhibitors with higher efficacy and fewer adverse effects

Antagonizing α7 nicotinic receptors with methyllycaconitine (MLA) potentiates receptor activity and memory acquisition

Abstract α7 nicotinic acetylcholine receptors (α7nAChRs) have been targeted to improve cognition in different neurological and psychiatric disorders. Nevertheless, no α7nAChR activating ligand has been clinically approved. Here, we investigated the effects of antagonizing α7nAChRs using the selective antagonist methyllycaconitine (MLA) on receptor activity in vitro and cognitive functioning in vivo. Picomolar concentrations of MLA significantly potentiated receptor responses in electrophysiological experiments mimicking the in vivo situation. Furthermore, microdialysis studies showed that MLA administration substantially increased hippocampal glutamate efflux which is related to memory processes. Accordingly, pre-tetanus administration of low MLA concentrations produced longer lasting potentiation (long-term potentiation, LTP) in studies examining hippocampal plasticity. Moreover, low doses of MLA improved acquisition, but not consolidation memory processes in rats. While the focus to enhance cognition by modulating α7nAChRs lies on agonists and positive modulators, antagonists at low doses should provide a novel approach to improve cognition in neurological and psychiatric disorders

Beta-amyloid interacts with and activates the longform phosphodiesterase PDE4D5 in neuronal cells to reduce cAMP availability

Inhibition of the cyclic-AMP degrading enzyme phosphodiesterase type 4 (PDE4) in the brains of animal models is protective in Alzheimer's disease (AD). We show for the first time that enzymes from the subfamily PDE4D not only colocalize with beta-amyloid (Aβ) plaques in a mouse model of AD but that Aβ directly associates with the catalytic machinery of the enzyme. Peptide mapping suggests that PDE4D is the preferential PDE4 subfamily for Aβ as it possesses a unique binding site. Intriguingly, exogenous addition of Aβ to cells overexpressing the PDE4D5 longform caused PDE4 activation and a decrease in cAMP. We suggest a novel mechanism where PDE4 longforms can be activated by Aβ, resulting in the attenuation of cAMP signalling to promote loss of cognitive function in AD

Role of Δ1-Pyrroline-5-Carboxylate Dehydrogenase Supports Mitochondrial Metabolism and Host-Cell Invasion ofTrypanosoma cruzi

Proline is crucial for energizing critical events throughout the life cycle of Trypanosoma cruzi, the etiological agent of Chagas disease. The proline breakdown pathway consists of two oxidation steps, both of which producereducing equivalents as follows: the conversion of proline to Δ1-pyrroline-5-carboxylate (P5C), and the subsequent conversion of P5C to glutamate. We have identified and characterized the Δ1-pyrroline-5-carboxylate dehydrogenase from T. cruzi (TcP5CDH) and report here on how this enzyme contributes to a central metabolic pathway in this parasite. Size-exclusionchromatography, two-dimensional gel electrophoresis, and small angle x-ray scattering analysis of TcP5CDH revealed an oligomericstate composed of two subunits of six protomers. TcP5CDH was found to complement a yeast strain deficient in PUT2 activity,confirming the enzyme's functional role; and the biochemical parameters (Km, kcat, and kcat/Km) of the recombinant TcP5CDH were determined, exhibiting values comparable with those from T. cruzi lysates. In addition, TcP5CDH exhibited mitochondrial staining during the main stages of the T. cruzi life cycle. mRNA and enzymatic activity levels indicated the up-regulation (6-fold change) of TcP5CDH during the infectivestages of the parasite. The participation of P5C as an energy source was also demonstrated. Overall, we propose that thisenzymatic step is crucial for the viability of both replicative and infective forms of T. cruzi

Selective PDE4 subtype inhibition provides new opportunities to intervene in neuroinflammatory versus myelin damaging hallmarks of multiple sclerosis.

Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS) characterized by focal inflammatory lesions and prominent demyelination. Even though the currently available therapies are effective in treating the initial stages of disease, they are unable to halt or reverse disease progression into the chronic progressive stage. Thus far, no repair-inducing treatments are available for progressive MS patients. Hence, there is an urgent need for the development of new therapeutic strategies either targeting the destructive immunological demyelination or boosting endogenous repair mechanisms. Using in vitro, ex vivo, and in vivo models, we demonstrate that selective inhibition of phosphodiesterase 4 (PDE4), a family of enzymes that hydrolyzes and inactivates cyclic adenosine monophosphate (cAMP), reduces inflammation and promotes myelin repair. More specifically, we segregated the myelination-promoting and anti-inflammatory effects into a PDE4D- and PDE4B-dependent process respectively. We show that inhibition of PDE4D boosts oligodendrocyte progenitor cells (OPC) differentiation and enhances (re)myelination of both murine OPCs and human iPSC-derived OPCs. In addition, PDE4D inhibition promotes in vivo remyelination in the cuprizone model, which is accompanied by improved spatial memory and reduced visual evoked potential latency times. We further identified that PDE4B-specific inhibition exerts anti-inflammatory effects since it lowers in vitro monocytic nitric oxide (NO) production and improves in vivo neurological scores during the early phase of experimental autoimmune encephalomyelitis (EAE). In contrast to the pan PDE4 inhibitor roflumilast, the therapeutic dose of both the PDE4B-specific inhibitor A33 and the PDE4D-specific inhibitor Gebr32a did not trigger emesis-like side effects in rodents. Finally, we report distinct PDE4D isoform expression patterns in human area postrema neurons and human oligodendroglia lineage cells. Using the CRISPR-Cas9 system, we confirmed that pde4d1/2 and pde4d6 are the key targets to induce OPC differentiation. Collectively, these data demonstrate that gene specific PDE4 inhibitors have potential as novel therapeutic agents for targeting the distinct disease processes of MS

Recent advances and perspectives on starch nanocomposites for packaging applications

Starch nanocomposites are popular and abundant materials in packaging sectors. The aim of this work is to review some of the most popular starch nanocomposite systems that have been used nowadays. Due to a wide range of applicable reinforcements, nanocomposite systems are investigated based on nanofiller type such as nanoclays, polysaccharides and carbonaceous nanofillers. Furthermore, the structures of starch and material preparation methods for their nanocomposites are also mentioned in this review. It is clearly presented that mechanical, thermal and barrier properties of plasticised starch can be improved with well-dispersed nanofillers in starch nanocomposites

Ecosystem process interactions between central Chilean habitats

AbstractUnderstanding ecosystem processes is vital for developing dynamic adaptive management of human-dominated landscapes. We focus on conservation and management of the central Chilean silvopastoral savanna habitat called “espinal”, which often occurs near matorral, a shrub habitat. Although matorral, espinal and native sclerophyllous forest are linked successionally, they are not jointly managed and conserved. Management goals in “espinal” include increasing woody cover, particularly of the dominant tree Acacia caven, improving herbaceous forage quality, and increasing soil fertility. We asked whether adjacent matorral areas contribute to espinal ecosystem processes related to the three main espinal management goals. We examined input and outcome ecosystem processes related to these goals in matorral and espinal with and without shrub understory. We found that matorral had the largest sets of inputs to ecosystem processes, and espinal with shrub understory had the largest sets of outcomes. Moreover, we found that these outcomes were broadly in the directions preferred by management goals. This supports our prediction that matorral acts as an ecosystem process bank for espinal. We recommend that management plans for landscape resilience consider espinal and matorral as a single landscape cover class that should be maintained as a dynamic mosaic. Joint management of espinal and matorral could create new management and policy opportunities

Computational investigation of the dynamic control of cAMP signaling by PDE4 isoform types

Cyclic adenosine monophosphate (cAMP) is a generic signaling molecule that, through precise control of its signaling dynamics, exerts distinct cellular effects. Consequently, aberrant cAMP signaling can have detrimental effects. Phosphodiesterase 4 (PDE4) enzymes profoundly control cAMP signaling and comprise different isoform types wherein enzymatic activity is modulated by differential feedback mechanisms. Because these feedback dynamics are non-linear and occur coincidentally, their effects are difficult to examine experimentally but can be well simulated computationally. Through understanding the role of PDE4 isoform types in regulating cAMP signaling, PDE4-targeted therapeutic strategies can be better specified. Here, we established a computational model to study how feedback mechanisms on different PDE4 isoform types lead to dynamic, isoform-specific control of cAMP signaling. Ordinary differential equations describing cAMP dynamics were implemented in the VirtualCell environment. Simulations indicated that long PDE4 isoforms exert the most profound control on oscillatory cAMP signaling, as opposed to the PDE4-mediated control of single cAMP input pulses. Moreover, elevating cAMP levels or decreasing PDE4 levels revealed different effects on downstream signaling. Together these results underline that cAMP signaling is distinctly regulated by different PDE4 isoform types and that this isoform specificity should be considered in both computational and experimental follow-up studies to better define PDE4 enzymes as therapeutic targets in diseases in which cAMP signaling is aberrant