PDE2A Inhibition Enhances Axonal Sprouting, Functional Connectivity, and Recovery after Stroke.

Phosphodiesterase (PDE) inhibitors have been safely and effectively used in the clinic and increase the concentration of intracellular cyclic nucleotides (cAMP/cGMP). These molecules activate downstream mediators, including the cAMP response element-binding protein (CREB), which controls neuronal excitability and growth responses. CREB gain of function enhances learning and allocates neurons into memory engrams. CREB also controls recovery after stroke. PDE inhibitors are linked to recovery from neural damage and to stroke recovery in specific sites within the brain. PDE2A is enriched in cortex. In the present study, we use a mouse cortical stroke model in young adult and aged male mice to test the effect of PDE2A inhibition on functional recovery, and on downstream mechanisms of axonal sprouting, tissue repair, and the functional connectivity of neurons in recovering cortex. Stroke causes deficits in use of the contralateral forelimb, loss of axonal projections in cortex adjacent to the infarct, and functional disconnection of neuronal networks. PDE2A inhibition enhances functional recovery, increases axonal projections in peri-infarct cortex, and, through two-photon in vivo imaging, enhances the functional connectivity of motor system excitatory neurons. PDE2A inhibition after stroke does not have an effect on other aspects of tissue repair, such as angiogenesis, gliogenesis, neurogenesis, and inflammatory responses. These data suggest that PDE2A inhibition is an effective therapeutic approach for stroke recovery in the rodent and that it simultaneously enhances connectivity in peri-infarct neuronal populations.SIGNIFICANCE STATEMENT Inhibition of PDE2A enhances motor recovery, axonal projections, and functional connectivity of neurons in peri-infarct tissue. This represents an avenue for a pharmacological therapy for stroke recovery.

Translational Development Strategies for TAK-063, a Phosphodiesterase 10A Inhibitor.

BACKGROUND: TAK-063 is an inhibitor of phosphodiesterase 10A (PDE10A), an enzyme highly expressed in medium spiny neurons of the striatum. PDE10A hydrolyzes both cyclic adenosine monophosphate and cyclic guanosine monophosphate and modulates dopamine signaling downstream of receptor activation in both direct and indirect pathways of the striatum. TAK-063 exhibited antipsychotic-like effects in animal models; however, the translatability of these models to the clinical manifestations of schizophrenia and the meaningfulness for new targets such as PDE10A has not been established. METHODS: The TAK-063 phase 1 program included a comprehensive translational development strategy with the main objective of determining whether the antipsychotic-like pharmacodynamic effects seen in nonclinical models would translate to human subjects. To evaluate this objective, we conducted a single-rising dose study (84 healthy subjects), a positron emission tomography (PET) study (12 healthy subjects), a functional magnetic resonance imaging blood oxygen level-dependent (BOLD) study (27 healthy subjects), and a multiple-rising dose study that included people with schizophrenia (30 healthy Japanese subjects and 47 subjects with stable schizophrenia). In addition, assessments of cognition and electroencephalography (27 healthy subjects and 47 subjects with stable schizophrenia) were included. RESULTS: PDE10A engagement by TAK-063 was verified with a novel PET radiotracer for use in primates and humans. TAK-063 showed favorable pharmacokinetic and safety profiles in humans, and TAK-063 reduced ketamine-induced changes in electroencephalography and BOLD signaling in animal models and healthy human subjects. In addition, analogous effects on cognition were observed in animal models and human subjects. CONCLUSIONS: Overall, the phase 1 results showed some consistent evidence of antipsychotic activity. This translational strategy may be valuable for the future development of novel therapeutic approaches, even when relevant nonclinical models are not available.

Balanced Activation of Striatal Output Pathways by Faster Off-Rate PDE10A Inhibitors Elicits Not Only Antipsychotic-Like Effects But Also Procognitive Effects in Rodents.

BACKGROUND: Faster off-rate competitive enzyme inhibitors are generally more sensitive than slower off-rate ones to binding inhibition by enzyme substrates. We previously reported that the cyclic adenosine monophosphate concentration in dopamine D1 receptor-expressing medium spiny neurons (D1-MSNs) may be higher than that in D2-MSNs. Consequently, compared with slower off-rate phosphodiesterase 10A inhibitors, faster off-rate ones comparably activated D2-MSNs but partially activated D1-MSNs. We further investigated the pharmacological profiles of phosphodiesterase 10A inhibitors with different off-rates. METHODS: Phosphodiesterase 10A inhibitors with slower (T-609) and faster (T-773) off-rates were used. D1- and D2-MSN activation was assessed by substance P and enkephalin mRNA induction, respectively, in rodents. Antipsychotic-like effects were evaluated by MK-801- and methamphetamine-induced hyperactivity and prepulse inhibition in rodents. Cognition was assessed by novel object recognition task and radial arm maze in rats. Prefrontal cortex activation was evaluated by c-Fos immunohistochemistry in rats. Gene translations in D1- and D2-MSNs were evaluated by translating ribosome affinity purification and RNA sequencing in mice. RESULTS: Compared with T-609, T-773 comparably activated D2-MSNs but partially activated D1-MSNs. Haloperidol (a D2 antagonist) and T-773, but not T-609, produced antipsychotic-like effects in all paradigms. T-773, but not T-609 or haloperidol, activated the prefrontal cortex and improved cognition. Overall gene translation patterns in D2-MSNs by all drugs and those in D1-MSNs by T-773 and T-609 were qualitatively similar. CONCLUSIONS: Differential pharmacological profiles among those drugs could be attributable to activation balance of D1- and D2-MSNs. The "balanced activation" of MSNs by faster off-rate phosphodiesterase 10A inhibitors may be favorable to treat schizophrenia.

De Novo Mutations in PDE10A Cause Childhood-Onset Chorea with Bilateral Striatal Lesions.

Chorea is a hyperkinetic movement disorder resulting from dysfunction of striatal medium spiny neurons (MSNs), which form the main output projections from the basal ganglia. Here, we used whole-exome sequencing to unravel the underlying genetic cause in three unrelated individuals with a very similar and unique clinical presentation of childhood-onset chorea and characteristic brain MRI showing symmetrical bilateral striatal lesions. All individuals were identified to carry a de novo heterozygous mutation in PDE10A (c.898T>C [p.Phe300Leu] in two individuals and c.1000T>C [p.Phe334Leu] in one individual), encoding a phosphodiesterase highly and selectively present in MSNs. PDE10A contributes to the regulation of the intracellular levels of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). Both substitutions affect highly conserved amino acids located in the regulatory GAF-B domain, which, by binding to cAMP, stimulates the activity of the PDE10A catalytic domain. In silico modeling showed that the altered residues are located deep in the binding pocket, where they are likely to alter cAMP binding properties. In vitro functional studies showed that neither substitution affects the basal PDE10A activity, but they severely disrupt the stimulatory effect mediated by cAMP binding to the GAF-B domain. The identification of PDE10A mutations as a cause of chorea further motivates the study of cAMP signaling in MSNs and highlights the crucial role of striatal cAMP signaling in the regulation of basal ganglia circuitry. Pharmacological modulation of this pathway could offer promising etiologically targeted treatments for chorea and other hyperkinetic movement disorders.

Dietary intake of the citrus flavonoid hesperidin affects stress-resilience and brain kynurenine levels in a subchronic and mild social defeat stress model in mice.

Depressive disorders are partly caused by chronic inflammation through the kynurenine (KYN) pathway. Preventive intervention using anti-inflammatory reagents may be beneficial for alleviating the risk of depression. In this study, we focused on the Japanese local citrus plant, Citrus tumida hort. ex Tanaka (C. tumida; CT), which contains flavonoids such as hesperidin that have anti-inflammatory actions. The dietary intake of 5% immature peels of CT fruits slightly increased stress resilience in a subchronic and mild social defeat (sCSDS) model in mice. Moreover, the dietary intake of 0.1% hesperidin significantly increased stress resilience and suppressed KYN levels in the hippocampus and prefrontal cortex in these mice. In addition, KYN levels in the hippocampus and prefrontal cortex were significantly correlated with the susceptibility to stress. In conclusion, these results suggest that dietary hesperidin increases stress resilience by suppressing the augmentation of KYN signaling under sCSDS.

TAK-063, a Novel Phosphodiesterase 10A Inhibitor, Protects from Striatal Neurodegeneration and Ameliorates Behavioral Deficits in the R6/2 Mouse Model of Huntington's Disease.

Huntington's disease (HD) is characterized by progressive loss of striatal medium spiny neurons (MSNs) that constitute direct and indirect pathways: the indirect pathway MSNs is more vulnerable than the direct pathway MSNs. Impairment of cAMP/cGMP signaling by mutant huntingtin is hypothesized as the molecular mechanism underlying degeneration of MSNs. Phosphodiesterase 10A (PDE10A) is selectively expressed in MSNs and degrades both cAMP and cGMP; thus, PDE10A inhibition can restore impaired cAMP/cGMP signaling. Compared with other PDE10A inhibitors, a novel PDE10A inhibitor 1-[2-fluoro-4-(1H-pyrazol-1-yl)phenyl]-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (TAK-063) showed comparable activation of the indirect pathway MSNs, whereas it produced partial activation of the direct pathway MSNs by its faster off-rate property. In this study, we report the effects of TAK-063 on striatal neurodegeneration and behavioral deficits in the R6/2 mouse model of HD. TAK-063 at 0.5 or 5 mg/kg/day was orally administrated from 4.5-5 to 12 weeks of age, and the effects of TAK-063 were characterized over this period. Repeated treatment with TAK-063 suppressed the reduction of brain-derived neurotrophic factor levels, prevented striatal neurodegeneration, and suppressed increase in seizure frequency, but did not prevent the suppression of body weight gain. As for motor deficits, TAK-063 suppressed the development of clasping behavior and motor dysfunctions, including decreased motor activity in the open field, but did not improve the impairment in motor coordination on the rotarod. Regarding cognitive functions, TAK-063 improved deficits in procedural learning, but was ineffective for deficits in contextual memory. These results suggest that TAK-063 reduces striatal neurodegeneration and ameliorates behavioral deficits in R6/2 mice.

The Phosphodiesterase 10A Selective Inhibitor TAK-063 Improves Cognitive Functions Associated with Schizophrenia in Rodent Models.

Cognitive deficits in various domains, including recognition memory, attention, impulsivity, working memory, and executive function, substantially affect functional outcomes in patients with schizophrenia. TAK-063 [1-[2-fluoro-4-(1H-pyrazol-1-yl)phenyl]-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one] is a potent and selective phosphodiesterase 10A inhibitor that produces antipsychotic-like effects in rodent models of schizophrenia. We evaluated the effects of TAK-063 on multiple cognitive functions associated with schizophrenia using naïve and drug-perturbed rodents. TAK-063 at 0.1 and 0.3 mg/kg p.o. improved time-dependent memory decay in object recognition in naïve rats. TAK-063 at 0.1 and 0.3 mg/kg p.o. increased accuracy rate, and TAK-063 at 0.3 mg/kg p.o. reduced impulsivity in a five-choice serial reaction time task in naïve rats. N-methyl-d-aspartate receptor antagonists, such as phencyclidine and MK-801 [(5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine], were used to induce working memory deficits relevant to schizophrenia in animals. TAK-063 at 0.3 mg/kg p.o. attenuated both phencyclidine-induced working memory deficits in a Y-maze test in mice and MK-801-induced working memory deficits in an eight-arm radial maze task in rats. An attentional set-shifting task using subchronic phencyclidine-treated rats was used to assess the executive function. TAK-063 at 0.3 mg/kg p.o. reversed cognitive deficits in extradimensional shifts. These findings suggest that TAK-063 has a potential to ameliorate deficits in multiple cognitive domains impaired in schizophrenia.

Comparison of single-stapling and hemi-double-stapling methods for intracorporeal esophagojejunostomy using a circular stapler after totally laparoscopic total gastrectomy.

BACKGROUND: Laparoscopic total gastrectomy is not widely performed because of the difficulty of esophagojejunal reconstruction. This study analyzed complication rates of two different methods for reconstruction by a circular stapler after totally laparoscopic total gastrectomy (TLTG). METHODS: Between 2010 and 2014, clinical data of 19 patients who underwent TLTG for gastric adenocarcinoma were collected retrospectively. There were two methods to fix the anvil of a circular stapler into the distal esophagus: In the single-stapling technique (SST) group, Endo-PSI(II) was used for purse-suturing on the distal esophagus for reconstruction, and in the hemi-double-stapling technique (hemi-DST) group, the esophagus was cut by linear stapler with the entry hole of the anvil shaft opened after inserting the anvil tail. In both groups, surgical procedures were the same, except for the reconstruction. RESULTS: All TLTGs were performed securely without mortality. Intracorporeal laparoscopic esophagojejunal anastomosis was performed successfully for all the patients. In the hemi-DST group, four patients experienced anastomotic stenosis, three of whom required endoscopic balloon dilation. In contrast, no stenosis was seen in the SST group (p = 0.033). CONCLUSIONS: Anastomosis with SST is preferred to that with hemi-DST to minimize postoperative complications.

In vivo pharmacological characterization of TAK-063, a potent and selective phosphodiesterase 10A inhibitor with antipsychotic-like activity in rodents.

Phosphodiesterase 10A (PDE10A) is a cAMP/cGMP phosphodiesterase highly expressed in medium spiny neurons (MSNs) in the striatum. We evaluated the in vivo pharmacological profile of a potent and selective PDE10A inhibitor, TAK-063 (1-[2-fluoro-4-(1H-pyrazol-1-yl)phenyl]-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)-pyridazin-4(1H)-one). TAK-063 at 0.3 and 1 mg/kg p.o., increased cAMP and cGMP levels in the rodent striatum and upregulated phosphorylation levels of key substrates of cAMP- and cGMP-dependent protein kinases. TAK-063 at 0.3 and 1 mg/kg p.o., strongly suppressed MK-801 [(5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine]-induced hyperlocomotion, which is often used as a predictive model for antipsychotic-like activity in rodents. Upregulation of striatal cAMP/cGMP levels and the antipsychotic-like effect of TAK-063 were not attenuated after 15 days of pretreatment with TAK-063 in mice. The potential side effect profile of TAK-063 was assessed in rats using the clinical antipsychotics haloperidol, olanzapine, and aripiprazole as controls. TAK-063 did not affect plasma prolactin or glucose levels at doses up to 3 mg/kg p.o. At 3 mg/kg p.o., TAK-063 elicited a weak cataleptic response compared with haloperidol and olanzapine. Evaluation of pathway-specific markers (substance P mRNA for the direct pathway and enkephalin mRNA for the indirect pathway) revealed that TAK-063 activated both the direct and indirect pathways of MSNs. These findings suggest that TAK-063 represents a promising drug for the treatment of schizophrenia with potential for superior safety and tolerability profiles.

Primary CNS lymphoma treated with radiotherapy in Japan: a survey of patients treated in 2005-2009 and a comparison with those treated in 1985-2004.

BACKGROUND: The aim of our study was to analyze changes over time in the characteristics, treatment, and outcome of patients with primary central nervous system lymphoma (PCNSL). METHODS: Data on 315 patients with histologically proven PCNSL undergoing radiotherapy between 2005 and 2009 were collected from 20 Japanese institutions using a questionnaire. These data were then compared with data on 273 patients treated during the period 1995-2004 and those on 466 patients treated during the period 1985-1994. RESULTS: In terms of patient and tumor characteristics, we found a significant increase in mean patient age in the 2005-2009 period compared to the 1985-2004 period (63 vs. 58-59 years, respectively) and in the percentage of patients with better performance status (PS) during the 2005-2009 period compared with the 1995-2004 period (World Health Organization PS 0-2: 73 vs. 65 %, respectively). Regarding treatment, relative to the 1995-2004 period, significant changes in the 2005-2009 period were (1) decreased rate of attempting tumor resection (23 vs. 44 %); (2) increased use of chemotherapy (78 vs. 68 %), and (3) increased use of methotrexate (MTX)-containing regimens (84 vs. 53 %). The 5-year overall survival rates were 15.3, 30.1, and 36.5 % for patients seen during the 1985-1994, 1995-2004, and 2005-2009 periods, respectively, but relapse-free survival did not improve between the 1995-2004 and 2005-2009 periods (26.7 vs. 25.7 % at 5 years, respectively). Patients receiving MTX-containing chemotherapy had 5-year survival rates of 19, 50, and 44 % during these three periods, respectively. CONCLUSIONS: Although patient backgrounds differed among the study periods, recent trends were a high patient age, better PS, avoidance of extensive tumor resection, more frequent use of chemotherapy, and improved survival. The recent improvement in survival may be due to improvements in second-line treatment and supportive care.

A Case of Isolated Superior Mesenteric Artery Dissection Resulting in Recurrent Necrosis of the Small Intestine.

Isolated superior mesenteric artery dissection (ISMAD) is a rare cause of acute abdominal conditions. Most cases of ISMAD have a favorable prognosis, and only a few cases of ISMAD-associated intestinal necrosis have been reported. A 75-year-old male was referred to our department because of abdominal pain and portal venous gas detected on imaging. Computed tomography suggested ileal necrosis, necessitating emergency surgery. Indocyanine green was used for blood flow assessment; however, no fluorescence was observed in the ileum proximal to the Bauhin valve, leading to the decision for ileocecal resection. On postoperative day 6, abdominal pain recurred when meals were resumed. As a surgical intervention for ISMAD, a bypass was created using the left great saphenous vein as a graft between the superior mesenteric artery and the right external iliac artery. This case highlights a rare occurrence where intestinal necrosis recurred due to ISMAD. We propose that in cases of ISMAD with concomitant intestinal necrosis, a more aggressive revascularization strategy for the dissected segment of the superior mesenteric artery may be required.

Electrical impedance myography detects dystrophin-related muscle changes in mdx mice.

BACKGROUND: The lack of functional dystrophin protein in Duchenne muscular dystrophy (DMD) causes chronic skeletal muscle inflammation and degeneration. Therefore, the restoration of functional dystrophin levels is a fundamental approach for DMD therapy. Electrical impedance myography (EIM) is an emerging tool that provides noninvasive monitoring of muscle conditions and has been suggested as a treatment response biomarker in diverse indications. Although magnetic resonance imaging (MRI) of skeletal muscles has become a standard measurement in clinical trials for DMD, EIM offers distinct advantages, such as portability, user-friendliness, and reduced cost, allowing for remote monitoring of disease progression or response to therapy. To investigate the potential of EIM as a biomarker for DMD, we compared longitudinal EIM data with MRI/histopathological data from an X-linked muscular dystrophy (mdx) mouse model of DMD. In addition, we investigated whether EIM could detect dystrophin-related changes in muscles using antisense-mediated exon skipping in mdx mice. METHODS: The MRI data for muscle T2, the magnetic resonance spectroscopy (MRS) data for fat fraction, and three EIM parameters with histopathology were longitudinally obtained from the hindlimb muscles of wild-type (WT) and mdx mice. In the EIM study, a cell-penetrating peptide (Pip9b2) conjugated antisense phosphorodiamidate morpholino oligomer (PPMO), designed to induce exon-skipping and restore functional dystrophin production, was administered intravenously to mdx mice. RESULTS: MRI imaging in mdx mice showed higher T2 intensity at 6 weeks of age in hindlimb muscles compared to WT mice, which decreased at ≥ 9 weeks of age. In contrast, EIM reactance began to decline at 12 weeks of age, with peak reduction at 18 weeks of age in mdx mice. This decline was associated with myofiber atrophy and connective tissue infiltration in the skeletal muscles. Repeated dosing of PPMO (10 mg/kg, 4 times every 2 weeks) in mdx mice led to an increase in muscular dystrophin protein and reversed the decrease in EIM reactance. CONCLUSIONS: These findings suggest that muscle T2 MRI is sensitive to the early inflammatory response associated with dystrophin deficiency, whereas EIM provides a valuable biomarker for the noninvasive monitoring of subsequent changes in skeletal muscle composition. Furthermore, EIM reactance has the potential to monitor dystrophin-deficient muscle abnormalities and their recovery in response to antisense-mediated exon skipping.

Urine titin as a novel biomarker for Duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD) is the most severe form of muscular dystrophy that is caused by lack of dystrophin, a critical structural protein in skeletal muscle. DMD treatments, and quantitative biomarkers to assess the efficacy of potential treatments, are urgently needed. Previous evidence has shown that titin, a muscle cell protein, is increased in the urine of patients with DMD, suggesting its usefulness as a DMD biomarker. Here, we demonstrated that the elevated titin in urine is directly associated with the lack of dystrophin and urine titin responses to drug treatment. We performed a drug intervention study using mdx mice, a DMD mouse model. We showed that mdx mice, which lack dystrophin due to a mutation in exon 23 of the Dmd gene, have elevated urine titin. Treatment with an exon skipper that targets exon 23 rescued muscle dystrophin level and dramatically decreased urine titin in mdx mice and correlates with dystrophin expression. We also demonstrated that titin levels were significantly increased in the urine of patients with DMD. This suggests that elevated urine titin level might be a hallmark of DMD and a useful pharmacodynamic marker for therapies designed to restore dystrophin levels.

Lamotrigine and retigabine increase motor threshold in transcranial magnetic stimulation at the dose required to produce an antiepileptic effect against maximal electroshock-induced seizure in rats.

Transcranial magnetic stimulation (TMS) is a neurophysiological technique that enables noninvasive evaluation of neuronal excitability in the brain. In the past, a large number of antiepileptic drugs were shown to increase the motor threshold (MT) in clinical TMS studies, suggesting the inhibition of excessive neuronal excitability. To facilitate drug development, the confirmation of similar changes in neurophysiological biomarkers in both preclinical and clinical studies is crucial; however, until now, there have been no data showing the drug efficacies on neuronal excitabilities as measured using TMS in rodents. In this study, we found that the antiepileptic drugs, lamotrigine (10 mg/kg) and retigabine (5 mg/kg), significantly increased the MT in rats using TMS, which is similar to clinical study findings. In addition, we demonstrated that these drugs could inhibit maximal electroshock (MES)-induced seizures in rats when given at the same dose required to be effective in the TMS experiment. These findings suggest that the effects of antiepileptic drugs in our rat TMS system have a similar sensitivity to that of the antiepileptic effects in rats with MES-induced seizures. The measurement of MT in a TMS study may be a noninvasive translational approach for predicting antiepileptic efficacy in drug development.

A case of juvenile idiopathic polyarticular arthritis complicated by IgA deficiency in 22q11 deletion syndrome.

Chronic arthritis may occur in association with antibody deficiency and chromosomal aberrations. This report presents the case of a 6-year-old girl with chromosome 22q11 deletion syndrome and chronic arthritis. The onset of arthritis occurred at 4 years of age. The chronic arthritis course has been the polyarticular type. Neither antinuclear antibody nor rheumatoid factor was detected. Serum IgA was extremely low. She was diagnosed with juvenile idiopathic polyarticular arthritis (JIA) complicated by IgA deficiency in the 22q11 deletion syndrome. There is an increased prevalence of chronic arthritis in association with 22q11 deletion syndrome with IgA deficiency, but the reasons for this association are unknown. This study evaluated the possible correlation between cytokines and the susceptibility to chronic arthritis in the 22q11 deletion syndrome with IgA deficiency. The expression of pro-inflammatory cytokines such as IL-8, IL-6, MIP-1ß, and MCP-1 suggests that T and B cells, macrophages and neutrophils modulate joint inflammation by an immune response. And the presence of IL-10 and IL-5 might suggest that the synovitis is associated with JIA and IgA deficiency.

Phosphodiesterase 10A Inhibition Leads to Brain Region-Specific Recovery Based on Stroke Type.

Stroke is the leading cause of adult disability. Recovery of function after stroke involves signaling events that are mediated by cAMP and cGMP pathways, such as axonal sprouting, neurogenesis, and synaptic plasticity. cAMP and cGMP are degraded by phosphodiesterases (PDEs), which are differentially expressed in brain regions. PDE10A is highly expressed in the basal ganglia/striatum. We tested a novel PDE10A inhibitor (TAK-063) for its effects on functional recovery. Stroke was produced in mice in the cortex or the striatum. Behavioral recovery was measured to 9 weeks. Tissue outcome measures included analysis of growth factor levels, angiogenesis, neurogenesis, gliogenesis, and inflammation. TAK-063 improved motor recovery after striatal stroke in a dose-related manner, but not in cortical stroke. Recovery of motor function correlated with increases in striatal brain-derived neurotrophic factor. TAK-063 treatment also increased motor system axonal connections. Stroke affects distinct brain regions, with each comprising different cellular and molecular elements. Inhibition of PDE10A improved recovery of function after striatal but not cortical stroke, consistent with its brain localization. This experiment is the first demonstration of brain region-specific enhanced functional recovery after stroke, and indicates that differential molecular signaling between brain regions can be exploited to improve recovery based on stroke subtype.

Anti-glutamate receptor antibodies in pediatric enteroviral encephalitis.

In order to better understand enteroviral encephalitis we investigated the clinical symptoms and several disease markers. Between 2000 and 2005 eight patients aged between 9 months and 5 years were admitted to our hospital with one case having sequela. Glutamic oxaloacetic transaminase (GOT), serum IL-6, and ferritin were elevated in most of the cases. Their IL-6 and diacron-reactive oxygen metabolites (d-ROM) in cerebral spinal fluid (CSF) were also high (86%). However, pleocytosis and high protein levels in CSF were rarely found. In viral loads of the first CSF, there were no differences between the patient with sequela and the ones without sequela. However, anti-glutamate receptor IgMdelta2 was only detected in the CSF of the patient with sequela. These findings suggest that the immunological phenomenon is more closely related to the development of sequela related to enteroviral encephalitis than other disease markers, such as inflammatory cytokine, free radicals, and viral loads. Therefore, a specific therapy against immunological status might decrease the sequela; however, further research is necessary to confirm this.

Effects of basic fibroblast growth factor on the development of the stem cell properties of human dental pulp cells.

We isolated adherent fibroblastic cells after collagenase and dispase treatment of human dental pulp. When human dental pulp cells (hDPCs) were cultured in the presence of basic fibroblast growth factor (bFGF), the ratio of hDPCs in the S-phase was significantly higher in comparison with incubation without bFGF. The ratio of hDPCs expressing STRO-1 as a marker of stem cell populations increased approximately eightfold in the presence of bFGF as opposed to that in the absence of bFGF. We demonstrated the characterization and distinctiveness of the hDPCs and showed that, when cultured with the medium containing serum and bFGF, they were highly proliferative and capable of differentiating in vitro into osteoblasts, chondrocytes, and adipocytes. Furthermore, the in vitro differentiation was confirmed at both the protein and gene expression levels. Transplantation of hDPCs -- expanded ex vivo in the presence of bFGF into immunocompromised mice -- revealed the formation of bone, cartilage, and adipose tissue. The donor hDPC-derived cells were labeled in the bone tissues located near the PLGA in the subcutaneous tissues of recipient mice using a human-specific Alu probe. When cultured with a serum-free medium containing bFGF, the hDPCs strongly expressed STRO-1 immunoreactive products and sustained self-renewal, and thus were almost identical in differentiation potential and proliferation activity to hDPCs cultured with the medium containing serum and bFGF. The present results suggest that the hDPCs cultured in the presence of bFGF irrespective of the presence or absence of the bovine serum are rich in mesenchymal stem cells or progenitor cells and useful for cell-based therapies to treat dental diseases.

Primary central nervous system lymphoma in Japan: changes in clinical features, treatment, and prognosis during 1985-2004.

We have conducted nationwide surveys of primary central nervous system lymphoma (PCNSL) treated since 1985. In the present study, we newly collected data between 2000 and 2004 and investigated changes in clinical features and outcome over time. A total of 739 patients with histologically proven PCNSL under going radiotherapy were analyzed. Seventeen institutions were surveyed, and data on 131 patients were collected. These data were compared with updated data that were previously obtained for 466 patients treated during 1985-1994 and 142 patients treated during 1995-1999. Recent trends toward decrease in male/female ratio, increase in aged patients, and increase in patients with multiple lesions were seen. Regarding treatment, decrease in attempts at surgical tumor removal and increases in use of systemic chemotherapy and methotrexate (MTX)-containing regimens were observed. The median survival time was 18, 29, and 24 months for patients seen during 1985-1994, 1995-1999, and 2000-2004, respectively, and the respective 5-year survival rates were 15%, 30%, and 30%. In groups seen during 1995-1999 and during 2000-2004, patients who received systemic or MTX-containing chemotherapy had better prognosis than those who did not. Multivariate analysis of all patients seen during 1985-2004 suggested the usefulness of MTX-containing chemotherapy as well as the importance of age, lactate dehydrogenase level, and tumor multiplicity as prognostic factors. Thus, this study revealed several notable changes in clinical features of PCNSL patients. The prognosis improved during the last 10 years. Advantage of radiation plus chemotherapy, especially MTX-containing chemotherapy, over radiation alone was suggested.

TAK-063, a novel PDE10A inhibitor with balanced activation of direct and indirect pathways, provides a unique opportunity for the treatment of schizophrenia.

The basal ganglia regulates motor, cognitive, and emotional behaviors. Dysfunction of dopamine system in this area is implicated in the pathophysiology of schizophrenia characterized by positive symptoms, negative symptoms, and cognitive deficits. Medium spiny neurons (MSNs) are principal output neurons of striatum in the basal ganglia. Similar to current antipsychotics with dopamine D2 receptor antagonism or partial agonism, phosphodiesterase 10A (PDE10A) inhibitors activate indirect pathway MSNs, leading to the expectation of therapeutic potential for the treatment of psychosis. PDE10A inhibitors also activate direct pathway MSNs which may be associated with cognitive functions. These pathways have competing effects on antipsychotic-like activities and extrapyramidal symptoms in rodents. Therefore, careful consideration of activation pattern of these pathways by a PDE10A inhibitor is critical to produce potent efficacy and superior safety profiles. In this review, we outline the pharmacological profile of TAK-063, a novel PDE10A selective inhibitor. Our study revealed that off-rates of PDE10A inhibitors may characterize their pharmacological profiles via regulation of each MSN pathway. TAK-063, with a faster off-rate property, could provide a unique opportunity as a novel therapeutic approach to treatment of psychosis and cognitive deficits in schizophrenia. TAK-063 also has a therapeutic potential in other basal ganglia disorders.