A novel glycine transporter-1 (GlyT1) inhibitor, ASP2535 (4-[3-isopropyl-5-(6-phenyl-3-pyridyl)-4H-1,2,4-triazol-4-yl]-2,1,3-benzoxadiazole), improves cognition in animal models of cognitive impairment in schizophrenia and Alzheimer's disease

Harada, Kensuke; Nakato, Kazuhiro; Yarimizu, Junko; Yamazaki, Mayako; Murakami, Masahiko; Takahashi, Shinji; Aota, Masaki; Saita, Kyoko; Doihara, Hitoshi; Sato, Yuichiro; Yamaji, Takayuki; Ni, Keni; Matsuoka, Naoki

doi:10.1016/j.ejphar.2012.04.013

Cited by 55 publications

(25 citation statements)

References 44 publications

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“…Importantly, our data presented here suggest that GlyT1 inhibitors represent a class of drugs with the potential to reduce the seizure burden in chronic epilepsy. Since GlyT1 antagonists have proven pro-cognitive activities in models of schizophrenia, autism, and Alzheimer’s disease (Burket et al, 2015; Chaki et al, 2015; Harada et al, 2012), GlyT1 inhibitors would differ from conventional antiepileptic drugs, which generally impede cognitive function (Arif et al, 2009; Ortinski and Meador, 2004; Vajda, 2007). While we currently do not propose to use GlyT1 inhibitors in lieu of conventional epilepsy therapy, the new agents, in particular at lower doses, might yield highly desirable outcome as add-on to existing treatments.…”

Section: Discussionmentioning

confidence: 99%

Glycine transporter 1 is a target for the treatment of epilepsy

et al. 2015

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Glycine is the major inhibitory neurotransmitter in brainstem and spinal cord, whereas in hippocampus glycine exerts dual modulatory roles on strychnine-sensitive glycine receptors and on the strychnine-insensitive glycineB site of the N-methyl-D-aspartate receptor (NMDAR). In hippocampus, the synaptic availability of glycine is largely under control of glycine transporter 1 (GlyT1). Since epilepsy is a disorder of disrupted network homeostasis affecting the equilibrium of various neurotransmitters and neuromodulators, we hypothesized that changes in hippocampal GlyT1 expression and resulting disruption of glycine homeostasis might be implicated in the pathophysiology of epilepsy. Using two different rodent models of temporal lobe epilepsy (TLE) – the intrahippocampal kainic acid model of TLE in mice, and the rat model of tetanic stimulation-induced TLE – we first demonstrated robust overexpression of GlyT1 in the hippocampal formation, suggesting dysfunctional glycine signaling in epilepsy. Overexpression of GlyT1 in the hippocampal formation was corroborated in human TLE samples by quantitative real time PCR. In support of a role of dysfunctional glycine signaling in the pathophysiology of epilepsy, both the genetic deletion of GlyT1 in hippocampus and the GlyT1 inhibitor LY2365109 increased seizure thresholds in mice. Importantly, chronic seizures in the mouse model of TLE were robustly suppressed by systemic administration of the GlyT1 inhibitor LY2365109. We conclude that GlyT1 overexpression in the epileptic brain constitutes a new target for therapeutic intervention, and that GlyT1 inhibitors constitute a new class of antiictogenic drugs. These findings are of translational value since GlyT1 inhibitors are already in clinical development to treat cognitive symptoms in schizophrenia.

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Section: Discussionmentioning

confidence: 99%

Glycine transporter 1 is a target for the treatment of epilepsy

et al. 2015

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“…Deficits in glutamatergic system were also observed in animal models, such as senescence-accelerated mouse/prone 8 (SAMP8) [74, 75]. Glycine is a coagonist of NMDA receptors, and increasing glycine concentration in the synaptic cleft can improve cognitive impairment in animal models of AD [76] indicating that increasing glycine is beneficial for AD. A previous study showed that DSS could elevate glycine in female SAMP8 [77], and we got the same results in this study.…”

Section: Discussionmentioning

confidence: 99%

Danggui-Shaoyao-San Improves Learning and Memory in Female SAMP8 via Modulation of Estradiol

Yan¹,

Hu²,

Yuan³

et al. 2014

Evidence-Based Complementary and Alternative Medicine

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Previous studies showed that Danggui-Shaoyao-San (DSS), a traditional Chinese medicinal prescription, could alleviate cognitive dysfunction of Alzheimer's disease (AD) patients. However, the mechanisms remain unclear; we have now examined the effect of DSS on SAMP8 and elucidated the possible mechanism. Animals were treated with DSS for 2 months, and step-down test and Morris water maze (MWM) test were used to evaluated cognitive abilities. The estradiol (E2), NO, and glycine in blood plasma or in hippocampus were detected to explore the possible mechanisms. The latency of SAMP8 in step-down test was shorter than that of age-matched SAMR1, and DSS increased the latency especially in female animals. In MWM test, we got similar results; SAMP8 spent more time to find the platform, and DSS decreased the time before finding the platform, with little effect on swim velocity, during the training sessions. During test session, DSS increased the time spent in target quadrant especially in female SAMP8. In female SAMP8, plasma E2, NO, and glycine were elevated in plasma or hippocampus tissue. In conclusion, DSS could ameliorate deterioration of cognition in SAMP8, especially in female animals. Increasing E2, NO, and glycine might contribute to the cognitive improvement effect of DSS in female SAMP8.

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“…Moreover, in an RCT to investigate adjunctive treatment with Org25935, a selective inhibitor of GlyT‐1, Org25935 did not differ significantly from placebo in reducing negative symptoms or improving cognitive functioning when administered as adjunctive treatment to SGA . Other types of GlyT‐1 inhibitors, such as PF‐03463275 and ASP2535, have shown promise in preclinical studies of cognitive remediation for schizophrenia.…”

Section: Treatment Based On Glutamate Hypothesismentioning

confidence: 99%

Glutamate hypothesis in schizophrenia

Uno

Coyle

2019

Psychiatry Clin Neurosci

248

172

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Schizophrenia is a chronic and severe psychiatric disorder that has profound impact on an individual’s life and on society. Thus, developing more effective therapeutic interventions is essential. Over the past quarter‐century, an abundance of evidence from pharmacologic challenges, post‐mortem studies, brain imaging, and genetic studies supports the role of glutamatergic dysregulation in the pathophysiology of schizophrenia, and the results of recent randomized clinical trials based on this evidence have yielded promising results. In this article, we review the evidence that alterations in glutamatergic neurotransmission, especially focusing on the N‐methyl‐d‐aspartate receptor (NMDAR) function, may be a critical causative feature of schizophrenia, how this contributes to pathologic circuit function in the brain, and how these insights are revealing whole new avenues for treatment development that could reduce treatment‐resistant symptoms, which account for persistent disability.

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A novel glycine transporter-1 (GlyT1) inhibitor, ASP2535 (4-[3-isopropyl-5-(6-phenyl-3-pyridyl)-4H-1,2,4-triazol-4-yl]-2,1,3-benzoxadiazole), improves cognition in animal models of cognitive impairment in schizophrenia and Alzheimer's disease

Cited by 55 publications

References 44 publications

Glycine transporter 1 is a target for the treatment of epilepsy

Glycine transporter 1 is a target for the treatment of epilepsy

Danggui-Shaoyao-San Improves Learning and Memory in Female SAMP8 via Modulation of Estradiol

Glutamate hypothesis in schizophrenia

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