Haploinsufficiency of phosphodiesterase 10A activates PI3K/AKT signaling independent of PTEN to induce an aggressive glioma phenotype.

Glioblastoma is universally fatal and characterized by frequent chromosomal copy number alterations harboring oncogenes and tumor suppressors. In this study, we analyzed exome-wide human glioblastoma copy number data and found that cytoband 6q27 is an independent poor prognostic marker in multiple data sets. We then combined CRISPR-Cas9 data, human spatial transcriptomic data, and human and mouse RNA sequencing data to nominate PDE10A as a potential haploinsufficient tumor suppressor in the 6q27 region. Mouse glioblastoma modeling using the RCAS/tv-a system confirmed that Pde10a suppression induced an aggressive glioma phenotype in vivo and resistance to temozolomide and radiation therapy in vitro. Cell culture analysis showed that decreased Pde10a expression led to increased PI3K/AKT signaling in a Pten-independent manner, a response blocked by selective PI3K inhibitors. Single-nucleus RNA sequencing from our mouse gliomas in vivo, in combination with cell culture validation, further showed that Pde10a suppression was associated with a proneural-to-mesenchymal transition that exhibited increased cell adhesion and decreased cell migration. Our results indicate that glioblastoma patients harboring PDE10A loss have worse outcomes and potentially increased sensitivity to PI3K inhibition.

Effects of the Phosphodiesterase 10A Inhibitor MR1916 on Alcohol Self-Administration and Striatal Gene Expression in Post-Chronic Intermittent Ethanol-Exposed Rats.

Alcohol use disorder (AUD) requires new neurobiological targets. Problematic drinking involves underactive indirect pathway medium spiny neurons (iMSNs) that subserve adaptive behavioral selection vs. overactive direct pathway MSNs (dMSNs) that promote drinking, with a shift from ventromedial to dorsolateral striatal (VMS, DLS) control of EtOH-related behavior. We hypothesized that inhibiting phosphodiesterase 10A (PDE10A), enriched in striatal MSNs, would reduce EtOH self-administration in rats with a history of chronic intermittent ethanol exposure. To test this, Wistar rats (n = 10/sex) with a history of chronic intermittent EtOH (CIE) vapor exposure received MR1916 (i.p., 0, 0.05, 0.1, 0.2, and 0.4 µmol/kg), a PDE10A inhibitor, before operant EtOH self-administration sessions. We determined whether MR1916 altered the expression of MSN markers (Pde10a, Drd1, Drd2, Penk, and Tac1) and immediate-early genes (IEG) (Fos, Fosb, ΔFosb, and Egr1) in EtOH-naïve (n = 5-6/grp) and post-CIE (n = 6-8/grp) rats. MR1916 reduced the EtOH self-administration of high-drinking, post-CIE males, but increased it at a low, but not higher, doses, in females and low-drinking males. MR1916 increased Egr1, Fos, and FosB in the DLS, modulated by sex and alcohol history. MR1916 elicited dMSN vs. iMSN markers differently in ethanol-naïve vs. post-CIE rats. High-drinking, post-CIE males showed higher DLS Drd1 and VMS IEG expression. Our results implicate a role and potential striatal bases of PDE10A inhibitors to influence post-dependent drinking.

Targeting Striatal Glutamate and Phosphodiesterases to Control L-DOPA-Induced Dyskinesia.

A large body of work during the past several decades has been focused on therapeutic strategies to control L-DOPA-induced dyskinesias (LIDs), common motor complications of long-term L-DOPA therapy in Parkinson's disease (PD). Yet, LIDs remain a clinical challenge for the management of patients with advanced disease. Glutamatergic dysregulation of striatal projection neurons (SPNs) appears to be a key contributor to altered motor responses to L-DOPA. Targeting striatal hyperactivity at the glutamatergic neurotransmission level led to significant preclinical and clinical trials of a variety of antiglutamatergic agents. In fact, the only FDA-approved treatment for LIDs is amantadine, a drug with NMDAR antagonistic actions. Still, novel agents with improved pharmacological profiles are needed for LID therapy. Recently other therapeutic targets to reduce dysregulated SPN activity at the signal transduction level have emerged. In particular, mechanisms regulating the levels of cyclic nucleotides play a major role in the transduction of dopamine signals in SPNs. The phosphodiesterases (PDEs), a large family of enzymes that degrade cyclic nucleotides in a specific manner, are of special interest. We will review the research for antiglutamatergic and PDE inhibition strategies in view of the future development of novel LID therapies.

Magnetic resonance imaging detects white adipose tissue beiging in mice following PDE10A inhibitor treatment.

Weight gain is a common harmful side effect of atypical antipsychotics used for schizophrenia treatment. Conversely, treatment with the novel phosphodiesterase-10A (PDE10A) inhibitor MK-8189 in clinical trials led to significant weight reduction, especially in patients with obesity. This study aimed to understand and describe the mechanism underlying this observation, which is essential to guide clinical decisions. We hypothesized that PDE10A inhibition causes beiging of white adipose tissue (WAT), leading to weight loss. Magnetic resonance imaging (MRI) methods were developed, validated, and applied in a diet-induced obesity mouse model treated with a PDE10A inhibitor THPP-6 or vehicle for measurement of fat content and vascularization of adipose tissue. Treated mice showed significantly lower fat fraction in white and brown adipose tissue, and increased perfusion and vascular density in WAT versus vehicle, confirming the hypothesis, and matching the effect of CL-316,243, a compound known to cause adipose tissue beiging. The in vivo findings were validated by qPCR revealing upregulation of Ucp1 and Pcg1-α genes, known markers of WAT beiging, and angiogenesis marker VegfA in the THPP-6 group. This work provides a detailed understanding of the mechanism of action of PDE10A inhibitor treatment on adipose tissue and body weight and will be valuable to guide both the use of MK-8189 in schizophrenia and the potential application of the target for weight loss indication.

Expanding the genotype-phenotype landscape of PDE10A-associated movement disorders.

BACKGROUND: Phosphodiesterase 10A (PDE10A) controls body movements by regulating cyclic adenosine monophosphate signaling in the basal ganglia. Two classes of PDE10A variants are reported with distinctive genotype-phenotype correlation. The autosomal recessive mutations in the GAF-A and catalytic domains are associated with compromised membrane localization, and manifest with infantile onset chorea, developmental, and cognition delay with normal brain MRI. Conversely, autosomal dominant mutations in the GAF-B domain cause protein aggregates which results in childhood onset chorea in the context of normal cognition and development, with striatal lesions. METHODS: Phenotypic characteristics of affected individuals with PDE10A mutations belonging to a single family were recorded. In addition, Sanger sequencing and in silico analysis were used to identify the mutations. Homozygosity mapping was applied together with whole exome sequencing. RESULTS: Four individuals from a consanguineous family affected with PDE10A mutations were observed for up to 40 years. Although these individuals displayed a clinical phenotype attributed to the recessive GAF-A mutations, they revealed a bi-allelic GAF-B mutation (c.883G > A:p. D295 N; p.Asp295Asn) that was segregated with all affected individuals. In addition to chorea, we observed peculiar foot deformities and pronounced social phobia, with normal brain MRI. In silico structural analysis suggested that the GAF-B mutation blocked allosteric PDE10A activation. The resulting lack of PDE10A activity likely phenocopies GAF-A mutations, and this is achieved through a distinct mechanism. CONCLUSIONS: Collectively, our findings demonstrate the association of recessive and dominant phenotypes of known variants, and further expands the genotype-phenotype landscape of PDE10A-associated movement disorders.

Positron Emission Tomography Assessments of Phosphodiesterase 10A in Patients With Schizophrenia.

BACKGROUND AND HYPOTHESIS: Phosphodiesterase 10A (PDE10A) is a highly expressed enzyme in the basal ganglia, where cortical glutamatergic and midbrain dopaminergic inputs are integrated. Therapeutic PDE10A inhibition effects on schizophrenia have been reported previously, but the status of this molecule in the living patients with schizophrenia remains elusive. Therefore, this study aimed to investigate the central PDE10A status in patients with schizophrenia and examine its relationship with psychopathology, cognition, and corticostriatal glutamate levels. STUDY DESIGN: This study included 27 patients with schizophrenia, with 5 antipsychotic-free cases, and 27 healthy controls. Positron emission tomography with [18F]MNI-659, a specific PDE10A radioligand, was employed to quantify PDE10A availability by measuring non-displaceable binding potential (BPND) of the ligand in the limbic, executive, and sensorimotor striatal functional subregions, and in the pallidum. BPND estimates were compared between patients and controls while controlling for age and gender. BPND correlations were examined with behavioral and clinical measures, along with regional glutamate levels quantified by the magnetic resonance spectroscopy. STUDY RESULTS: Multivariate analysis of covariance demonstrated a significant main effect of diagnosis on BPND (p = .03). A posthoc test showed a trend-level higher sensorimotor striatal BPND in patients, although it did not survive multiple comparison corrections. BPND in controls in this subregion was significantly and negatively correlated with the Tower of London scores, a cognitive subtest. Striatal or dorsolateral prefrontal glutamate levels did not correlate significantly with BPND in either group. CONCLUSIONS: The results suggest altered striatal PDE10A availability and associated local neural dysfunctions in patients with schizophrenia.

An insight from computational approach to explore novel, high-affinity phosphodiesterase 10A inhibitors for neurological disorders.

The enzyme Phosphodiesterase 10A (PDE10A) plays a regulatory role in the cAMP/protein kinase A (PKA) signaling pathway by means of hydrolyzing cAMP and cGMP. PDE10A emerges as a relevant pharmacological drug target for neurological conditions such as psychosis, schizophrenia, Parkinson's, Huntington's disease, and other memory-related disorders. In the current study, we subjected a set of 1,2,3-triazoles to be explored as PDE10A inhibitors using diverse computational approaches, including molecular docking, classical molecular dynamics (MD) simulations, Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA) calculations, steered MD, and umbrella sampling simulations. Molecular docking of cocrystallized ligands papaverine and PFJ, along with a set of in-house synthesized molecules, suggested that molecule 3i haded the highest binding affinity, followed by 3h and 3j. Furthermore, the structural stability studies using MD and MM-PBSA indicated that the 3h and 3j formed stable complexes with PDE10A. The binding free energy of -240.642 kJ/mol and -201.406 kJ/mol was observed for 3h and 3j, respectively. However, the cocrystallized ligands papaverine and PFJ exhibited comparitively higher binding free energy values of -202.030 kJ/mol and -138.764 kJ/mol, respectively. Additionally, steered MD and umbrella sampling simulations provided conclusive evidence that the molecules 3h and 3j could be exploited as promising candidates to target PDE10A.Communicated by Ramaswamy H. Sarma.

Phosphodiesterase 10A (PDE10A) as a novel target to suppress ß-catenin and RAS signaling in epithelial ovarian cancer.

A leading theory for ovarian carcinogenesis proposes that inflammation associated with incessant ovulation is a driver of oncogenesis. Consistent with this theory, nonsteroidal anti-inflammatory drugs (NSAIDs) exert promising chemopreventive activity for ovarian cancer. Unfortunately, toxicity is associated with long-term use of NSAIDs due to their cyclooxygenase (COX) inhibitory activity. Previous studies suggest the antineoplastic activity of NSAIDs is COX independent, and rather may be exerted through phosphodiesterase (PDE) inhibition. PDEs represent a unique chemopreventive target for ovarian cancer given that ovulation is regulated by cyclic nucleotide signaling. Here we evaluate PDE10A as a novel therapeutic target for ovarian cancer. Analysis of The Cancer Genome Atlas (TCGA) ovarian tumors revealed PDE10A overexpression was associated with significantly worse overall survival for patients. PDE10A expression also positively correlated with the upregulation of oncogenic and inflammatory signaling pathways. Using small molecule inhibitors, Pf-2545920 and a novel NSAID-derived PDE10A inhibitor, MCI-030, we show that PDE10A inhibition leads to decreased ovarian cancer cell growth and induces cell cycle arrest and apoptosis. We demonstrate these pro-apoptotic properties occur through PKA and PKG signaling by using specific inhibitors to block their activity. PDE10A genetic knockout in ovarian cancer cells through CRISP/Cas9 editing lead to decreased cell proliferation, colony formation, migration and invasion, and in vivo tumor growth. We also demonstrate that PDE10A inhibition leads to decreased Wnt-induced ß-catenin nuclear translocation, as well as decreased EGF-mediated activation of RAS/MAPK and AKT pathways in ovarian cancer cells. These findings implicate PDE10A as novel target for ovarian cancer chemoprevention and treatment.

A PDE10A inhibitor CPL500036 is a novel agent modulating striatal function devoid of most neuroleptic side-effects.

Background: Phosphodiesterase 10A (PDE10A) is expressed almost exclusively in the striatum and its inhibition is suggested to offer potential treatment in disorders associated with basal ganglia. We evaluated the selectivity, cytotoxicity, genotoxicity, pharmacokinetics and potential adverse effects of a novel PDE10A inhibitor, CPL500036, in vivo. Methods: The potency of CPL500036 was demonstrated by microfluidic technology, and selectivity was investigated in a radioligand binding assay against 44 targets. Cardiotoxicity in vitro was evaluated in human ether-a-go-go related gene (hERG)-potassium channel-overexpressing cells by the patch-clamp method and by assessing key parameters in 3D cardiac spheroids. Cytotoxicity was determined in H1299, HepG2 and SH-SY5Y cell lines. The Ames test was used for genotoxicity analyses. During in vivo studies, CPL500036 was administered by oral gavage. CPL500036 exposure were determined by liquid chromatography-tandem mass spectrometry and plasma protein binding was assessed. The bar test was employed to assess catalepsy. Prolactin and glucose levels in rat blood were measured by ELISAs and glucometers, respectively. Cardiovascular safety in vivo was investigated in dogs using a telemetry method. Results: CPL500036 inhibited PDE10A at an IC50 of 1 nM, and interacted only with the muscarinic M2 receptor as a negative allosteric modulator with an IC50 of 9.2 µM. Despite inhibiting hERG tail current at an IC25 of 3.2 µM, cardiovascular adverse effects were not observed in human cardiac 3D spheroids or in vivo. Cytotoxicity in vitro was observed only at > 60 µM and genotoxicity was not recorded during the Ames test. CPL500036 presented good bioavailability and penetration into the brain. CPL500036 elicited catalepsy at 0.6 mg/kg, but hyperprolactinemia or hyperglycemic effects were not observed in doses up to 3 mg/kg. Conclusion: CPL500036 is a potent, selective and orally bioavailable PDE10A inhibitor with a good safety profile distinct from marketed antipsychotics. CPL500036 may be a compelling drug candidate.

Motor, epileptic, and developmental phenotypes in genetic disorders affecting G protein coupled receptors-cAMP signaling.

Over the last years, a constantly increasing number of genetic diseases associated with epilepsy and movement disorders have been recognized. An emerging group of conditions in this field is represented by genetic disorders affecting G-protein-coupled receptors (GPCRs)-cAMP signaling. This group of postsynaptic disorders includes genes encoding for proteins highly expressed in the central nervous system and involved in GPCR signal transduction and cAMP production (e.g., GNAO1, GNB1, ADCY5, GNAL, PDE2A, PDE10A, and HPCA genes). While the clinical phenotype associated with ADCY5 and GNAL is characterized by movement disorder in the absence of epilepsy, GNAO1, GNB1, PDE2A, PDE10A, and HPCA have a broader clinical phenotype, encompassing movement disorder, epilepsy, and neurodevelopmental disorders. We aimed to provide a comprehensive phenotypical characterization of genetic disorders affecting the cAMP signaling pathway, presenting with both movement disorders and epilepsy. Thus, we reviewed clinical features and genetic data of 203 patients from the literature with GNAO1, GNB1, PDE2A, PDE10A, and HPCA deficiencies. Furthermore, we delineated genotype-phenotype correlation in GNAO1 and GNB1 deficiency. This group of disorders presents with a highly recognizable clinical phenotype combining distinctive motor, epileptic, and neurodevelopmental features. A severe hyperkinetic movement disorder with potential life-threatening exacerbations and high susceptibility to a wide range of triggers is the clinical signature of the whole group of disorders. The existence of a distinctive clinical phenotype prompting diagnostic suspicion and early detection has relevant implications for clinical and therapeutic management. Studies are ongoing to clarify the pathophysiology of these rare postsynaptic disorders and start to design disease-specific treatments.

A double-blind, randomized, placebo-controlled proof of concept study of the efficacy and safety of Lu AF11167 for persistent negative symptoms in people with schizophrenia.

Lu AF11167 is a selective, high-affinity inhibitor of PDE10A that modulates dopamine D1 and D2 receptor-mediated intraneuronal signalling without binding to these receptors. This randomized, double-blind, parallel-group, placebo-controlled study (NCT03793712) with open-label extension (NCT03929497) evaluated the efficacy of two fixed-flexible doses (1-2mg/day and 3-4mg/day) of Lu AF11167 in stable, non-acute patients with schizophrenia and persistent prominent negative symptoms. The studies were discontinued following a futility analysis of the double-blind study, and we report data collected up to study termination. Of the 210 patients screened, 162 were randomized, 111 completed the double-blind study and 96 entered the open-label study before early termination. The withdrawal rate due to impending relapse was low and comparable across treatment groups (n = 2-4 per group in the double-blind study and n = 1 in the open-label extension). Double-blind treatment with Lu AF11167 3-4mg was not superior to placebo in the reduction of Brief Negative Symptom Scale (BNSS) total scores from Baseline to Week 12 (primary endpoint); adjusted mean changes were -6.8 with placebo, -5.7 with Lu AF11167 1-2 mg group and -6.0 with Lu AF11167 3-4mg. Treatment with Lu AF11167 1-2mg also failed to separate from placebo on the primary endpoint. Neither dose group showed significant improvements versus placebo on any of the secondary efficacy measures exploring effect of treatment on overall symptomology, negative symptoms, positive symptoms, or functioning. Administration of Lu AF11167 was safe and well tolerated and adverse events were not a major reason for withdrawal from the study.

A Glimpse of Molecular Biomarkers in Huntington's Disease.

Huntington's disease (HD) is a devastating neurodegenerative disorder that is caused by an abnormal expansion of CAG repeats in the Huntingtin (HTT) gene. Although the main symptomatology is explained by alterations at the level of the central nervous system, predominantly affecting the basal ganglia, a peripheral component of the disease is being increasingly acknowledged. Therefore, the manifestation of the disease is complex and variable among CAG expansion carriers, introducing uncertainty in the appearance of specific signs, age of onset and severity of disease. The monogenic nature of the disorder allows a precise diagnosis, but the use of biomarkers with prognostic value is still needed to achieve clinical management of the patients in an individual manner. In addition, we need tools to evaluate the patient's response to potential therapeutic approaches. In this review, we provide a succinct summary of the most interesting molecular biomarkers that have been assessed in patients, mostly obtained from body fluids such as cerebrospinal fluid, peripheral blood and saliva.

Underlying mechanisms of phosphodiesterase 10A and glutamate-ammonia ligase genes that regulate inosine monophosphate deposition and thereby affect muscle tenderness in Jingyuan chickens.

OBJECTIVE: Inosine monophosphate (IMP) is a key factor that imparts of meat flavor. Differences in the IMP content in the muscles were evaluated to improve chicken meat quality. METHODS: For this study, the IMP content was detected by high performance liquid chromatography. The gene expression profiles of Jingyuan chickens with different feeding patterns and different sexes were analyzed by RNA-sequencing (RNA-seq). RESULTS: Breast muscle IMP content in free-range chickens was extremely significantly higher than that of caged chickens (p<0.01). Breast muscle IMP content in hens was also higher than that of cocks, but the difference was not significant. Correlation analysis showed that the breast muscle IMP content in caged hens and cocks was negatively correlated with the shear force, and the breast muscle IMP content in free-range hens was significantly negatively correlated with the shear force (p<0.05). The two key genes associated with IMP synthesis in chickens with different feeding patterns were glutamate-ammonia ligase (GLUL) and phosphodiesterase 10A (PDE10A). Bioinformatics analysis revealed that the GLUL and PDE10A genes are involved in glutamine biosynthesis and purine salvage pathways respectively. In addition, GLUL expression was positively correlated with the IMP content in caged and free-range chickens, and PDE10A expression was significantly positively correlated with the IMP content in caged and free-range chickens (p<0.05). CONCLUSION: These findings will facilitate the comprehension of the deposition of IMP in the muscles and thereby aid the process of selection and breeding of good quality local chickens.

Phosphodiesterase 10A Is a Critical Target for Neuroprotection in a Mouse Model of Ischemic Stroke.

Phosphodiesterase 10A (PDE10A) hydrolyzes adenosine 3',5'-cyclic monophosphate (cAMP) and guanosine 3',5'-cyclic monophosphate (cGMP). It is highly expressed in the striatum. Recent evidence implied that PDE10A may be involved in the inflammatory processes following injury, such as ischemic stroke. Its role in ischemic injury was unknown. Herein, we exposed mice to 90 or 30-min middle cerebral artery occlusion, followed by the delivery of the highly selective PDE10A inhibitor TAK-063 (0.3 mg/kg or 3 mg/kg) immediately after reperfusion. Animals were sacrificed after 24 or 72 h, respectively. Both TAK-063 doses enhanced neurological function, reduced infarct volume, increased neuronal survival, reduced brain edema, and increased blood-brain barrier integrity, alongside cerebral microcirculation improvements. Post-ischemic neuroprotection was associated with increased phosphorylation (i.e., activation) of pro-survival Akt, Erk-1/2, GSK-3α/ß and anti-apoptotic Bcl-xL abundance, decreased phosphorylation of pro-survival mTOR, and HIF-1α, MMP-9 and pro-apoptotic Bax abundance. Interestingly, PDE10A inhibition reduced inflammatory cytokines/chemokines, including IFN-γ and TNF-α, analyzed by planar surface immunoassay. In addition, liquid chromatography-tandem mass spectrometry revealed 40 proteins were significantly altered by TAK-063. Our study established PDE10A as a target for ischemic stroke therapy.

Inhibition of PDE10A in a New Rat Model of Severe Dopamine Depletion Suggests New Approach to Non-Dopamine Parkinson's Disease Therapy.

Parkinson's disease is the second most common neurodegenerative pathology. Due to the limitations of existing therapeutic approaches, novel anti-parkinsonian medicines with non-dopamine mechanisms of action are clearly needed. One of the promising pharmacological targets for anti-Parkinson drug development is phosphodiesterase (PDE) 10A. The stimulating motor effects of PDE10A inhibition were detected only under the conditions of partial dopamine depletion. The results raise the question of whether PDE10A inhibitors are able to restore locomotor activity when dopamine levels are very low. To address this issue, we (1) developed and validated the rat model of acute severe dopamine deficiency and (2) tested the action of PDE10A inhibitor MP-10 in this model. All experiments were performed in dopamine transporter knockout (DAT-KO) rats. A tyrosine hydroxylase inhibitor, α-Methyl-DL-tyrosine (αMPT), was used as an agent to cause extreme dopamine deficiency. In vivo tests included estimation of locomotor activity and catalepsy levels in the bar test. Additionally, we evaluated the tissue content of dopamine in brain samples by HPLC analysis. The acute administration of αMPT to DAT-KO rats caused severe depletion of dopamine, immobility, and catalepsy (Dopamine-Deficient DAT-KO (DDD) rats). As expected, treatment with the L-DOPA and carbidopa combination restored the motor functions of DDD rats. Strikingly, administration of MP-10 also fully reversed immobility and catalepsy in DDD rats. According to neurochemical studies, the action of MP-10, in contrast to L-DOPA + carbidopa, seems to be dopamine-independent. These observations indicate that targeting PDE10A may represent a new promising approach in the development of non-dopamine therapies for Parkinson's disease.

Antiparkinsonian-like effects of CPL500036, a novel selective inhibitor of phosphodiesterase 10A, in the unilateral rat model of Parkinson's disease.

Phosphodiesterase 10A (PDE10A), the enzyme which catalyzes hydrolysis of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), is located almost exclusively in striatal γ-amino-butyric acid (GABA)ergic medium spiny neurons (MSNs). Since dopaminergic deficiency in Parkinson's disease (PD) leads to functional imbalance of striatal direct and indirect output pathways formed by MSNs, PDE10A seems to be of special interest as a potential therapeutic target in PD. The aim of the present study was to examine the influence of 7-{5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl}-2-phenylimidazo[1,2-a]pyrimidine (CPL500036), a novel selective inhibitor of PDE10A, on sensorimotor deficits and therapeutic effects of L-3,4-dihydroxyphenylalanine (L-DOPA) in hemiparkinsonian rats. Animals were unilaterally lesioned with 6-hydroxydopamine, and their sensorimotor deficits were examined in the stepping, cylinder, vibrissae and catalepsy tests. CPL500036 (0.1 and 0.3 mg/kg) was administered either acutely or chronically (2 weeks), alone or in combination with L-DOPA/benserazide (6 mg/kg/6 mg/kg). Acute treatment with CPL500036 reversed the lesion-induced impairments of contralateral forelimb use in the stepping and cylinder tests but did not influence deficits in the vibrissae test and the lesion-induced catalepsy. Moreover, CPL500036 did not diminish the therapeutic effects produced by acute and chronic treatment with L-DOPA in these tests. The present study suggests a potential use of CPL500036 as a co-treatment to L-DOPA in PD therapy.

Second Report of PDE10A-BRAF Fusion in Pediatric Spindle Cell Sarcoma With Infantile Fibrosarcoma-Like Morphology Suggesting PDE10A-BRAF Fusion Is a Recurrent Event.

Infantile/congenital fibrosarcoma (IFS) is the most common soft tissue tumor in children less than one year of age. The most common anatomic site of IFS is in the extremities or trunk, and rarely in the abdomen or retroperitoneum. Approximately 70-90% of cases are characterized by a distinct t(12;15)(p13;q25) translocation resulting in an ETV6-NTRK3 gene fusion. As such, TRK inhibitors are considered frontline therapy in TRK-fusion positive IFS. The ETV6-NTRK3 fusion is also detected in congenital mesoblastic nephroma (CMN) and less frequently in myeloid leukemias, secretory breast carcinoma, and mammary-type secretory carcinoma of the skin and salivary glands. Infrequently, cases of tumors with IFS-like morphology without the characteristic ETV6-NTRK3 gene fusion have been identified. Herein, an ETV6-NTRK3 fusion negative spindle cell sarcoma with IFS-like morphology subjected to genomic profiling revealed a PDE10A-BRAF fusion, a fusion event that has been detected previously in an isolated case of undifferentiated infantile sarcoma.

Structure-based identification of dual ligands at the A2AR and PDE10A with anti-proliferative effects in lung cancer cell-lines.

Enhanced/prolonged cAMP signalling has been suggested as a suppressor of cancer proliferation. Interestingly, two key modulators that elevate cAMP, the A2A receptor (A2AR) and phosphodiesterase 10A (PDE10A), are differentially co-expressed in various types of non-small lung cancer (NSCLC) cell-lines. Thus, finding dual-target compounds, which are simultaneously agonists at the A2AR whilst also inhibiting PDE10A, could be a novel anti-proliferative approach. Using ligand- and structure-based modelling combined with MD simulations (which identified Val84 displacement as a novel conformational descriptor of A2AR activation), a series of known PDE10A inhibitors were shown to dock to the orthosteric site of the A2AR. Subsequent in-vitro analysis confirmed that these compounds bind to the A2AR and exhibit dual-activity at both the A2AR and PDE10A. Furthermore, many of the compounds exhibited promising anti-proliferative effects upon NSCLC cell-lines, which directly correlated with the expression of both PDE10A and the A2AR. Thus, we propose a structure-based methodology, which has been validated in in-vitro binding and functional assays, and demonstrated a promising therapeutic value.

Medicinal chemistry strategies for the development of phosphodiesterase 10A (PDE10A) inhibitors - An update of recent progress.

Phosphodiesterase 10A is a member of Phosphodiesterase (PDE)-superfamily of the enzyme which is responsible for hydrolysis of cAMP and cGMP to their inactive forms 5'-AMP and 5'-GMP, respectively. PDE10A is highly expressed in the brain, particularly in the putamen and caudate nucleus. PDE10A plays an important role in the regulation of localization, duration, and amplitude of the cyclic nucleotide signalling within the subcellular domain of these regions, and thereby modulation of PDE10A enzyme can give rise to a new therapeutic approach in the treatment of schizophrenia and other neurodegenerative disorders. Limitation of the conventional therapy of schizophrenia forced the pharmaceutical industry to move their efforts to develop a novel treatment approach with reduced side effects. In the past decade, considerable developments have been made in pursuit of PDE10A centric antipsychotic agents by several pharmaceutical industries due to the distribution of PDE10A in the brain and the ability of PDE10A inhibitors to mimic the effect of D2 antagonists and D1 agonists. However, no selective PDE10A inhibitor is currently available in the market for the treatment of schizophrenia. The present compilation concisely describes the role of PDE10A inhibitors in the therapy of neurodegenerative disorders mainly in psychosis, the structure of PDE10A enzyme, key interaction of different PDE10A inhibitors with human PDE10A enzyme and recent medicinal chemistry developments in designing of safe and effective PDE10A inhibitors for the treatment of schizophrenia. The present compilation also provides useful information and future direction to bring further improvements in the discovery of PDE10A inhibitors.

The role of circadian rhythm in the regulation of cellular protein profiles in the brain.

BACKGROUND: Circadian rhythm plays a significant role in the regulation of almost all kinds of physiological processes. In addition, it may also have a direct or indirect effect on the neurodegenerative processes, including Alzheimer's disease, Parkinson's disease, and ischemic stroke. Therefore, the identification of circadian rhythm-related proteins is crucial to be able to understand the molecular mechanism of the circadian rhythm and to define new therapeutic target for the treatment of degenerative disorders. METHODS: To identify the light and dark regulated proteins, 8-12 weeks, male Balb/C mice were used at two different time points (morning (Zeitgeber time-0 (ZT0)) and midnight (ZT18)) under physiological conditions. Therefore, brain tissues were analyzed via liquid chromatography tandem mass spectrometry. RESULTS: A total of 1621 different proteins were identified between ZT0 and ZT18 mice. Among these proteins, 23 proteins were differentially expressed (p < 0.05 and fold change 1.4) in ZT18 mice, 11 upregulated (AKAP10, ALDOC, BLK, NCALD, NFL, PDE10A, PICAL, PSMB6, RL10, SH3L3, and SYNJ1), and 12 downregulated (AT2A2, AT2B1, CPNE5, KAP3, MAON, NPM, PI51C, PPR1B, SAM50, TOM70, TY3H, and VAPA) as compared with ZT0 mice. DISCUSSION: Taken together, here we identified circadian rhythm-related proteins, and our further analysis revealed that these proteins play significant roles in molecular function, membrane trafficking, biogenesis, cellular process, metabolic process, and neurodegenerative disorders such as Parkinson's disease.