D-amino Acid Oxidase Inhibitors Research Articles

Directly and Indirectly Targeting the Glycine Modulatory Site to Modulate NMDA Receptor Function to Address Unmet Medical Needs of Patients With Schizophrenia.

Schizophrenia is a severe mental illness that affects ~1% of the world's population. It is clinically characterized by positive, negative, and cognitive symptoms. Currently available antipsychotic medications are relatively ineffective in improving negative and cognitive deficits, which are related to a patient's functional outcomes and quality of life. Negative symptoms and cognitive deficits are unmet by the antipsychotic medications developed to date. In recent decades, compelling animal and clinical studies have supported the NMDA receptor (NMDAR) hypofunction hypothesis of schizophrenia and have suggested some promising therapeutic agents. Notably, several NMDAR-enhancing agents, especially those that function through the glycine modulatory site (GMS) of NMDAR, cause significant reduction in psychotic and cognitive symptoms in patients with schizophrenia. Given that the NMDAR-mediated signaling pathway has been implicated in cognitive/social functions and that GMS is a potential therapeutic target for enhancing the activation of NMDARs, there is great interest in investigating the effects of direct and indirect GMS modulators and their therapeutic potential. In this review, we focus on describing preclinical and clinical studies of direct and indirect GMS modulators in the treatment of schizophrenia, including glycine, D-cycloserine, D-serine, glycine transporter 1 (GlyT1) inhibitors, and D-amino acid oxidase (DAO or DAAO) inhibitors. We highlight some of the most promising recently developed pharmacological compounds designed to either directly or indirectly target GMS and thus augment NMDAR function to treat the cognitive and negative symptoms of schizophrenia. Overall, the current findings suggest that indirectly targeting of GMS appears to be more beneficial and leads to less adverse effects than direct targeting of GMS to modulate NMDAR functions. Indirect GMS modulators, especially GlyT1 inhibitors and DAO inhibitors, open new avenues for the treatment of unmet medical needs for patients with schizophrenia.

Colorimetric quantification of sodium benzoate in food by using d-amino acid oxidase and 2D metal organic framework nanosheets mediated cascade enzyme reactions

A rapid colorimetric method for detecting sodium benzoate in food products was established based on the d-amino acid oxidase (DAAO) and 2D metal organic framework (2D MOF) nanosheets mediated cascade enzyme reactions. Firstly, the synthesized 2D MOF nanosheets served as high efficient nanozyme with outstanding peroxidase-like catalytic activity and catalyzed the color reaction between H2O2 and 3, 3’, 5, 5′- tetramethylbenzidine. Secondly, sodium benzoate as a competitive inhibitor of DAAO, could influence the production of H2O2 in DAAO mediated oxidation reaction. After a combination of those two reactions, this colorimetric quantitative method was constructed and validated for sodium benzoate determination with wide linear range (2.0–200.0 μM), low limit of detection (2.0 μM), high accuracy (recovery rate in 95.80–108.00%) and satisfied selectivity. Lastly, this method was utilized to analyze sodium benzoate concentration in juice, wine and vinegar by naked eyes.

Novel Biomarkers of Alzheimer's Disease: Based Upon N-methyl-D-aspartate Receptor Hypoactivation and Oxidative Stress.

Early detection and prevention of Alzheimer’s disease (AD) is important. The current treatment for early AD is acetylcholine esterase inhibitors (AChEIs); however, the efficacy is poor. Besides, AChEI did not show efficacy in mild cognitive impairment (MCI). Beta-amyloid (Aβ) deposits have been regarded to be highly related to the pathogenesis of AD. However, many clinical trials aiming at the clearance of Aβ deposits failed to improve the cognitive decline of AD, even at its early phase. There should be other important mechanisms unproven in the course of AD and MCI. Feasible biomarkers for the diagnosis and treatment response of AD are lacking to date. The N-methyl-D-aspartate receptor (NMDAR) activation plays an important role in learning and memory. On the other hand, oxidative stress has been regarded to contribute to aging with the assumption that free radicals damage cell constituents and connective tissues. Our recent study found that an NMDAR enhancer, sodium benzoate (the pivotal inhibitor of D-amino acid oxidase [DAAO]), improved the cognitive and global function of patients with early-phase AD. Further, we found that peripheral DAAO levels were higher in patients with MCI and AD than healthy controls. We also found that sodium benzoate was able to change the activity of antioxidant. These pieces of evidence suggest that the NMDAR function is associated with anti-oxidation, and have potential to be biomarkers for the diagnosis and treatment response of AD.

D-Serine: A Cross Species Review of Safety.

Background:D-Serine, a direct, full agonist at the D-serine/glycine modulatory site of the N-methyl-D-aspartate-type glutamate receptors (NMDAR), has been assessed as a treatment for multiple psychiatric and neurological conditions. Based on studies in rats, concerns of nephrotoxicity have limited D-serine research in humans, particularly using high doses. A review of D-serine's safety is timely and pertinent, as D-serine remains under active study for schizophrenia, both directly (R61 MH116093) and indirectly through D-amino acid oxidase (DAAO) inhibitors. The principal focus is on nephrotoxicity, but safety in other physiologic and pathophysiologic systems are also reviewed.Methods: Using the search terms “D-serine,” “D-serine and schizophrenia,” “D-serine and safety,” “D-serine and nephrotoxicity” in PubMed, we conducted a systematic review on D-serine safety. D-serine physiology, dose-response and efficacy in clinical studies and dAAO inhibitor safety is also discussed.Results: When D-serine doses >500 mg/kg are used in rats, nephrotoxicity, manifesting as an acute tubular necrosis syndrome, seen within hours of administration is highly common, if not universal. In other species, however, D-serine induced nephrotoxicity has not been reported, even in other rodent species such as mice and rabbits. Even in rats, D--serine related toxicity is dose dependent and reversible; and does not appear to be present in rats at doses producing an acute Cmax of <2,000 nmol/mL. For comparison, the Cmax of D-serine 120 mg/kg, the highest dose tested in humans, is ~500 nmol/mL in acute dosing. Across all published human studies, only one subject has been reported to have abnormal renal values related to D-serine treatment. This abnormality did not clearly map on to the acute tubular necrosis syndrome seen in rats, and fully resolved within a few days of stopping treatment. DAAO inhibitors may be nephroprotective. D-Serine may have a physiologic role in metabolic, extra-pyramidal, cardiac and other systems, but no other clinically significant safety concerns are revealed in the literature.Conclusions: Even before considering human to rat differences in renal physiology, using current FDA guided monitoring paradigms, D-serine appears safe at currently studied maximal doses, with potential safety in combination with DAAO inhibitors.

Novel approaches in schizophrenia-from risk factors and hypotheses to novel drug targets.

Schizophrenia is a severe psychiatric disorder characterized by emotional, behavioral and cognitive disturbances, and the treatment of schizophrenia is often complicated by noncompliance and pharmacoresistance. The search for the pathophysiological mechanisms underlying schizophrenia has resulted in the proposal of several hypotheses to explain the impacts of environmental, genetic, neurodevelopmental, immune and inflammatory factors on disease onset and progression. This review discusses the newest insights into the pathophysiology of and risk factors for schizophrenia and notes novel approaches in antipsychotic treatment and potential diagnostic and theranostic biomarkers. The current hypotheses focusing on neuromediators (dopamine, glutamate, and serotonin), neuroinflammation, the cannabinoid hypothesis, the gut-brain axis model, and oxidative stress are summarized. Key genetic features, including small nucleotide polymorphisms, copy number variations, microdeletions, mutations and epigenetic changes, are highlighted. Current pharmacotherapy of schizophrenia relies mostly on dopaminergic and serotonergic antagonists/partial agonists, but new findings in the pathophysiology of schizophrenia have allowed the expansion of novel approaches in pharmacotherapy and the establishment of more reliable biomarkers. Substances with promising results in preclinical and clinical studies include lumateperone, pimavanserin, xanomeline, roluperidone, agonists of trace amine-associated receptor 1, inhibitors of glycine transporters, AMPA allosteric modulators, mGLUR2-3 agonists, D-amino acid oxidase inhibitors and cannabidiol. The use of anti-inflammatory agents as an add-on therapy is mentioned.

Effect of Sodium Benzoate on Cognitive Function Among Patients With Behavioral and Psychological Symptoms of Dementia

Female gender is a major risk factor for dementia; however, gender has not yet been adequately addressed by clinical trials. A recent study demonstrated that sodium benzoate, a D-amino acid oxidase inhibitor, improved cognitive function in early-phase Alzheimer disease. To examine the potential gender difference in the effects of benzoate treatment on the behavioral and psychological symptoms of dementia (BPSD). This post hoc secondary analysis used data from a randomized, double-masked, placebo-controlled trial conducted in 3 major medical centers in Taiwan and enrolled 97 patients with BPSD. Data were analyzed between February 2014 and November 2017. Six weeks of treatment of 250 to 1500 mg/d of sodium benzoate or placebo. The primary outcome measures were Alzheimer disease assessment scale-cognitive subscale (ADAS-cog) and Behavioral Pathology in Alzheimer Disease Rating Scale (BEHAVE-AD) scores. Among 97 total participants (62 [64%] women; mean [SD] age, 75.4 [7.7] years), 49 patients (30 women and 19 men) were randomized to sodium benzoate, and 48 (32 women and 16 men) were randomized to placebo. Among 62 women, 6-week benzoate treatment significantly surpassed placebo in the effects on ADAS-cog performance (mean [SD] difference in score between baseline and end point, -3.1 [6.4] points vs 0 [4.5] points; Cohen d = 0.56; P = .04) but not BEHAVE-AD performance. In contrast, among 35 men, the 2 treatment groups did not differ significantly in both ADAS-cog and BEHAVE-AD scores. Compared with placebo, benzoate treatment also increased estradiol to follicle-stimulating hormone ratios among women (mean [SD] difference between baseline and end point, 0 [0.2] vs -0.1 [0.3]; P = .03). These findings suggest that benzoate treatment may improve cognitive function in women with later-phase dementia. In the future, longer dose-finding trials are warranted to further clarify the efficacy of benzoate for later-phase dementia and investigate the role of sex hormones and other factors in the pathogenesis of dementia. ClinicalTrials.gov Identifier: NCT02103673.

Mouse strain specificity of DAAO inhibitors-mediated antinociception.

D‐Amino acid oxidase (DAAO) specifically catalyzes the oxidative deamination of neutral and polar D‐amino acids and finally yields byproducts of hydrogen peroxide. Our previous work demonstrated that the spinal astroglial DAAO/hydrogen peroxide (H2O2) pathway was involved in the process of pain and morphine antinociceptive tolerance. This study aimed to report mouse strain specificity of DAAO inhibitors on antinociception and explore its possible mechanism. DAAO inhibitors benzoic acid, CBIO, and SUN significantly inhibited formalin‐induced tonic pain in Balb/c and Swiss mice, but had no antinociceptive effect in C57 mice. In contrast, morphine and gabapentin inhibited formalin‐induced tonic pain by the same degrees among Swiss, Balb/c and C57 mice. Therefore, mouse strain difference in antinociceptive effects was DAAO inhibitors specific. In addition, intrathecal injection of D‐serine greatly increased spinal H2O2 levels by 80.0% and 56.9% in Swiss and Balb/c mice respectively, but reduced spinal H2O2 levels by 29.0% in C57 mice. However, there was no remarkable difference in spinal DAAO activities among Swiss, Balb/c and C57 mice. The spinal expression of glutathione (GSH) and glutathione peroxidase (GPx) activity in C57 mice were significantly higher than Swiss and Balb/c mice. Furthermore, the specific GPx inhibitor D‐penicillamine distinctly restored SUN antinociception in C57 mice. Our results reported that DAAO inhibitors produced antinociception in a strain‐dependent manner in mice and the strain specificity might be associated with the difference in spinal GSH and GPx activity.

Brain Activity of Benzoate, a D-Amino Acid Oxidase Inhibitor, in Patients With Mild Cognitive Impairment in a Randomized, Double-Blind, Placebo Controlled Clinical Trial.

BackgroundCurrent anti-dementia drugs cannot benefit mild cognitive impairment (MCI). Sodium benzoate (a D-amino acid oxidase [DAO] inhibitor) has been found to improve the cognitive function of patients with early-phase Alzheimer’s disease (mild Alzheimer’s disease or MCI). However, its effect on brain function remains unknown. This study aimed to evaluate the influence of benzoate on functional magnetic resonance imaging in patients with amnestic MCI.MethodsThis was a 24-week, randomized, double-blind, placebo-controlled trial that enrolled 21 patients with amnestic MCI and allocated them randomly to either of 2 treatment groups: (1) benzoate group (250–1500 mg/d), or (2) placebo group. We assessed the patients’ working memory, verbal learning and memory, and resting-state functional magnetic resonance imaging and regional homogeneity (ReHo) maps at baseline and endpoint.ResultsResting-state ReHo decreased in right orbitofrontal cortex after benzoate treatment but did not change after placebo. Moreover, after benzoate treatment, the change in working memory was positively correlated with the change in ReHo in right precentral gyrus and right middle occipital gyrus; and the change in verbal learning and memory was positively correlated with the change in ReHo in left precuneus. In contrast, after placebo treatment, the change in working memory or in verbal learning and memory was not correlated with the change in ReHo in any brain region.ConclusionThe current study is the first to our knowledge to demonstrate that a DAO inhibitor, sodium benzoate herein, can alter brain activity as well as cognitive functions in individuals with MCI. The preliminary finding lends supports for DAO inhibition as a novel approach for early dementing processes.

Local injection of D-amino acid oxidase inhibitor into the prefrontal cortex improves AD/HD-like behaviors of SHRSP/Ezo.

Local injection of D-amino acid oxidase inhibitor into the prefrontal cortex improves AD/HD-like behaviors of SHRSP/Ezo.

Converging Evidence on D-Amino Acid Oxidase-Dependent Enhancement of Hippocampal Firing Activity and Passive Avoidance Learning in Rats.

BackgroundN-methyl-D-aspartate (NMDA) receptor activation requires the binding of a co-agonist on the glycine-binding site. D-serine is the main endogenous co-agonist of NMDA receptors, and its availability significantly depends on the activity of the metabolic enzyme D-amino acid oxidase (DAAO). Inhibition of DAAO increases the brain levels of D-serine and modulates a variety of physiological functions, including cognitive behavior.MethodsHere, we examined the effects of a novel 4-hydroxypyridazin-3(2H)-one derivative DAAO inhibitor, Compound 30 (CPD30), on passive avoidance learning and on neuronal firing activity in rats.ResultsD-serine administration was applied as reference, which increased cognitive performance and enhanced hippocampal firing activity and responsiveness to NMDA after both local and systemic application. Similarly to D-serine, CPD30 (0.1 mg/kg) effectively reversed MK-801–induced memory impairment in the passive avoidance test. Furthermore, local iontophoretic application of CPD30 in the vicinity of hippocampal pyramidal neurons significantly increased firing rate and enhanced their responses to locally applied NMDA. CPD30 also enhanced hippocampal firing activity after systemic administration. In 0.1- to 1.0-mg/kg doses, CPD30 increased spontaneous and NMDA-evoked firing activity of the neurons. Effects of CPD30 on NMDA responsiveness emerged faster (at 10 minutes post-injection) when a 1.0-mg/kg dose was applied compared with the onset of the effects of 0.1 mg/kg CPD30 (at 30 minutes post-injection).ConclusionsThe present results confirm that the inhibition of DAAO enzyme is an effective strategy for cognitive enhancement. Our findings further facilitate the understanding of the cellular mechanisms underlying the behavioral effects of DAAO inhibition in the mammalian brain.

Mechanistic Multilayer Quantitative Model for Nonlinear Pharmacokinetics, Target Occupancy and Pharmacodynamics (PK/TO/PD) Relationship of D-Amino Acid Oxidase Inhibitor, TAK-831 in Mice

PurposeTAK-831 is a highly selective and potent inhibitor of D-amino acid oxidase (DAAO) currently under clinical development for schizophrenia. In this study, a mechanistic multilayer quantitative model that parsimoniously connects pharmacokinetics (PK), target occupancy (TO) and D-serine concentrations as a pharmacodynamic (PD) readout was established in mice.MethodsPK, TO and PD time-profiles were obtained in mice and analyzed by mechanistic binding kinetics model connected with an indirect response model in a step wise fashion. Brain distribution was investigated to elucidate a possible mechanism driving the hysteresis between PK and TO.ResultsThe observed nonlinear PK/TO/PD relationship was well captured by mechanistic modeling framework within a wide dose range of TAK-831 in mice. Remarkably different brain distribution was observed between target and reference regions, suggesting that the target-mediated slow binding kinetics rather than slow penetration through the blood brain barrier caused the observed distinct kinetics between PK and TO.ConclusionA quantitative mechanistic model for concentration- and time-dependent nonlinear PK/TO/PD relationship was established for TAK-831 in mice with accounting for possible rate-determining process. The established mechanistic modeling framework will provide a quantitative means for multilayer biomarker-assisted clinical development in multiple central nervous system indications.

Synthesis and preliminary evaluation of 4-hydroxy-6-(3-[11C]methoxyphenethyl)pyridazin-3(2H)-one, a 11C-labeled d-amino acid oxidase (DAAO) inhibitor for PET imaging

Selective DAAO inhibitors have demonstrated promising therapeutic effects in clinical studies, including clinically alleviating symptoms of schizophrenic patients and ameliorating cognitive function in Alzheimer’s patients with early phase. Herein we report the synthesis and preliminary evaluation of a 11C-labeled positron emission tomography ligand based on a DAAO inhibitor, DAO-1903 (8). 11C-Isotopologue of 8 was prepared in high radiochemical yield with high radiochemical purity (>99%) and high molar activity (>37 GBq/µmol). In vitro autoradiography studies indicated that the ligand possessed high in vitro specific binding to DAAO, while in vivo dynamic PET studies demonstrated that [11C]8 failed to cross the blood–brain barrier possibly due to moderate brain efflux mechanism. Further chemical scaffold optimization is necessary to overcome limited brain permeability and improve specific binding.

Novel Treatment for the Most Resistant Schizophrenia: Dual Activation of NMDA Receptor and Antioxidant.

Clozapine has been regarded as the last-line antipsychotic agent for patients with refractory schizophrenia. However, many patients remain unresponsive to clozapine, referred to as "clozapineresistant", "ultra-treatment-resistant", or remain in incurable state. There has been no convincing evidence for augmentation on clozapine so far. Novel treatments including numerous N-methyl-Daspartate (NMDA) receptor (NMDAR) enhancers, such as glycine, D-serine, D-cycloserine, and Nmethylglycine (sarcosine) failed in clinical trials. Earlier, the inhibition of D-amino acid oxidase (DAAO) that may metabolize D-amino acids and activate NMDAR has been reported to be beneficial for patients with schizophrenia receiving antipsychotics except for clozapine. A recent randomized, double-blind, placebo-controlled clinical trial found that add-on sodium benzoate, a DAAO inhibitor, improved the clinical symptoms in patients with clozapine- resistant schizophrenia, possibly through DAAO inhibition (and thereby NMDAR activation) and antioxidation as well; additionally, sodium benzoate showed no obvious side effects, indicating that the treatment is safe at doses up to 2 g per day for 6 weeks. More studies are warranted to elucidate the mechanisms of sodium benzoate for the treatment of schizophrenia and the etiology of this severe brain disease. If the finding can be reconfirmed, this approach may bring new hope for the treatment of the most refractory schizophrenia. This review summarizes the current status of clinical trials and related mechanisms for treatmentresistant, especially, clozapine-resistant schizophrenia. The importance of understanding the molecular circuit switches is also highlighted which can restore brain function in patients with schizophrenia. Future directions in developing better treatments for the most difficult to cure schizophrenia are also discussed.

&lt;p&gt;Precision Medicine of Sodium Benzoate for the Treatment of Behavioral and Psychological Symptoms of Dementia (BPSD)&lt;/p&gt;

ObjectiveBehavioral and psychological symptoms of dementia (BPSD) are associated with poorer prognosis of dementia. A 24-week study demonstrated that sodium benzoate, a D-amino acid oxidase (DAAO) inhibitor, surpassed placebo in improving cognitive function in early-phase Alzheimer’s disease; however, benzoate did not excel placebo in another 6-week study on BPSD. The current study examined whether the precision medicine approach was able to identify specific individuals with BPSD who could benefit from benzoate treatment.MethodsIn the randomized, double-blind, placebo-controlled, 6-week trial, 97 patients with BPSD were allocated to receive 250–1500 mg/day of sodium benzoate or placebo. Cognitive function was measured by the Alzheimer’s disease assessment scale-cognitive subscale (ADAS-cog) and behavioral and psychological symptoms were mainly measured by Behavioral Pathology in Alzheimer’s Disease Rating Scale (BEHAVE-AD). DAAO level, amino acids (L-serine, D-serine, L-alanine, and D-alanine, glycine), and two antioxidants (catalase, superoxide dismutase) were assayed in peripheral blood.ResultsAfter benzoate treatment, DAAO inhibition was correlated with ADAS-cog decrease (p = 0.034), while baseline DAAO level was correlated with baseline BEHAVE-AD score. Multiple linear regression analyses showed that cognitive improvement after benzoate treatment was correlated with DAAO decrease, female gender, younger age, BMI, baseline BPSD severity, and antipsychotic use.ConclusionThe finding suggests that sodium benzoate may have potential to benefit cognitive function in a fraction of BPSD patients after 6 weeks of treatment. Of note, the precision medicine approach may be helpful for identifying individuals who could respond to benzoate. More studies are warranted to confirm the preliminary findings.Trial RegistrationThe trial was registered online (https://clinicaltrials.gov/ct2/show/NCT02103673).

P.166 Safety, pharmacokinetics, and pharmacodynamics of TAK-831, a selective d-amino acid oxidase inhibitor, in healthy volunteers

P.166 Safety, pharmacokinetics, and pharmacodynamics of TAK-831, a selective d-amino acid oxidase inhibitor, in healthy volunteers

Keeping up with the therapeutic advances in schizophrenia: a review of novel and emerging pharmacological entities.

Schizophrenia remains one of the most severe medical diseases. Current dopamine modulating first-generation and second-generation antipsychotics target mainly positive symptoms, but not/inadequately negative and cognitive symptoms. Additional challenges include non-adherence and adverse effects, especially cardiometabolic dysregulation. This review evaluates new/emerging pharmacological treatments for schizophrenia. Therapies targeting total symptoms include cannabidiol, D3 antagonist/5-HT1A partial agonist F17464, lumateperone (ITI-007), phosphodiesterase 10A (PDE10A) inhibitors MK-8189 and TAK-063, sodium nitroprusside, and trace amine-associated receptor-1 (TAAR1) agonist RO5263397 and SEP-363856. Treatments targeting negative symptoms include the PDE10A inhibitor LuAF-11167, 5-HT2A inverse agonist pimavanserin, sigma-2/5-HT2A antagonist roluperidone (MIN-101), and d-amino acid oxidase (DAAO) inhibitor TAK-831. Agents targeting primarily cognitive dysfunction are the glycine transporter-1 inhibitor BI-425809 and cannabidiol. Therapies targeting residual positive symptoms/treatment-resistant schizophrenia include pimavanserin, dopamine D1/D2 antagonist LuAF-35700, and DAAO inhibitor sodium benzoate. Two new long-acting injectable antipsychotic formulations, Aripiprazole Lauroxil NanoCrystal® and the first subcutaneous injectable LAI Perseris (RBP-7000), were recently approved by U.S. Food and Drug Administration, and positive results were announced for Risperidone ISM®, each achieving therapeutic levels within 24 hours, without need for initial oral cotreatment/loading injection-strategies. Paliperidone palmitate 6-monthly intramuscularly injectable and Risperidone subcutaneously injectable TV46000 are currently under investigation. Finally, the samidorphan+olanzapine combination targets reduced weight gain liability, while maintaining olanzapine's efficacy. Most of these trial programs are still ongoing or have yielded mixed or even negative results. Thus, additional mechanisms of action and agents require study to improve schizophrenia outcomes for total/positive symptoms with reduced adverse effects, but also cognitive symptoms, negative symptoms, and treatment resistance, the areas of greatest need in schizophrenia currently.

Involvement of d-amino acid oxidase in cerebral ischaemia induced by transient occlusion of the middle cerebral artery in mice.

d-Amino acid oxidase (DAAO) is a flavine adenine dinucleotide-containing flavoenzyme and specifically catalyses oxidative deamination of d-amino acids. This study aimed to explore the association between increased cerebral DAAO expression or enzymic activity and the development of cerebral ischaemia. A mouse model of transient (90 min) middle cerebral artery occlusion (MCAO) was established, and western blotting, enzymic activity assay, and fluorescent immunostaining techniques were used. The expression and enzymic activity of DAAO increased over time in the cortical peri-infarct area of the mice subjected to transient MCAO. The DAAO was specifically expressed in astrocytes, and its double immunostaining with the astrocytic intracellular marker, glial fibrillary acidic protein, in the cortical peri-infarct area was up-regulated following ischaemic insult, with peak increase on Day 5 after MCAO. Single intravenous injection of the specific and potent DAAO inhibitor Compound SUN reduced the cerebral DAAO enzymic activity and attenuated neuronal infarction and neurobehavioural deficits with optimal improvement apparent immediately after the MCAO procedure. The neuroprotective effect was dose dependent, with ED50 values of 3.9-4.5mg·kg-1 . Intracerebroventricular injection of the DAAO gene silencer siRNA/DAAO significantly reduced cerebral DAAO expression and attenuated MCAO-induced neuronal infarction and behavioural deficits. Our results, for the first time, demonstrated that increased cerebral astrocytic DAAO expression and enzymic activity were causally associated with the development of neuronal destruction following ischaemic insults, suggesting that targeting cerebral DAAO could be a potential approach for treatment of neurological conditions following cerebral ischaemia.

The Role of N-Methyl-D-Aspartate Receptor Neurotransmission and Precision Medicine in Behavioral and Psychological Symptoms of Dementia.

While the world’s population is aging, the prevalence of dementia and the associated behavioral and psychological symptoms of dementia (BPSD) rises rapidly. BPSD are associated with worsening of cognitive function and poorer prognosis. No pharmacological treatment has been approved to be beneficial for BPSD to date. Dysfunction of the N-methyl-D-aspartate receptor (NMDAR)-related neurotransmission leads to cognitive impairment and behavioral changes, both of which are core symptoms of BPSD. Memantine, an NMDAR partial antagonist, is used to treat moderate to severe Alzheimer’s disease (AD). On the other hand, a D-amino acid oxidase inhibitor improved early-phase AD. Whether to enhance or to attenuate the NMDAR may depend on the phases of dementia. It will be valuable to develop biomarkers indicating the activity of NMDAR, particularly in BPSD. In addition, recent reports suggest that gender difference exists in the treatment of dementia. Selecting subpopulations of patients with BPSD who are prone to improvement with treatment would be important. We reviewed literatures regarding the treatment of BPSD, focusing on the NMDAR-related modulation and precision medicine. Future studies examining the NMDAR modulators with the aid of potential biomarkers to tailor the treatment for individualized patients with BPSD are warranted.

Safety, Pharmacokinetics (PK), and Pharmacodynamics (PD) of TAK-831, a Selective D-amino Acid Oxidase Inhibitor, in Healthy Volunteers (P2.1-015)

Safety, Pharmacokinetics (PK), and Pharmacodynamics (PD) of TAK-831, a Selective D-amino Acid Oxidase Inhibitor, in Healthy Volunteers (P2.1-015)

D-Serine Contributes to Seizure Development via ERK Signaling.

A seizure is one of the leading neurological disorders. NMDA receptor-mediated neuronal excitation has been thought to be essential for epileptogenesis. As an endogenous co-agonist of the NMDA receptor, D-serine has been suggested to play a role in epileptogenesis. However, the underlying mechanisms remain unclear. In the current study, we investigated the effects of antagonizing two key enzymes in D-serine metabolism on the development of seizures and the downstream signaling. Our results showed that serine racemase (SR), a key enzyme in regulating the L-to-D-serine conversion, was significantly up-regulated in hippocampal astrocytes in rats and patients who experienced seizure, in comparison with control rats and patients. L-aspartic acid β-hydroxamate (LaaβH), an inhibitor of SR, significantly prolonged the latencies of seizures, shortened the durations of seizures, and decreased the total EEG power in rats. In contrast, D-amino acid oxidase inhibitor 5-chlorobenzo[d]isoxazol-3-ol (CBIO), which can increase D-serine levels, showed the opposite effects. Furthermore, our data showed that LaaβH and CBIO significantly affected the phosphorylation of Extracellular Signal-regulated Kinase (ERK). Antagonizing or activating ERK could significantly block the effects of LaaβH/CBIO on the occurrence of seizures. In summary, our study revealed that D-serine is involved in the development of epileptic seizures, partially through ERK signaling, indicating that the metabolism of D-serine may be targeted for the treatment of epilepsy.