Journal ArticleDOI
Pharmacodynamic Effects of a d-Amino Acid Oxidase Inhibitor Indicate a Spinal Site of Action in Rat Models of Neuropathic Pain
Seth C. Hopkins,Fei-Yue Zhao,Bowen Carrie A,Xin Fang,Haifeng Wei,Michelle L. R. Heffernan,Kerry L. Spear,David Spanswick,Mark A. Varney,Thomas H. Large +9 more
TLDR
Results indicate that inhibition of DAAO in peripheral afferent spinal circuits reduced spontaneous neuronal activity to attenuate pain-related behaviors in rat models of neuropathic and inflammatory pain.Abstract:
Inhibition of d-amino acid oxidase (DAAO) activity is a potential target for the treatment of chronic pain. Here we characterized the effects of systemic administration of the DAAO inhibitor 4H-furo[3,2-b]pyrrole-5-carboxylic acid (SUN) in rat models of neuropathic and inflammatory pain. Oral administration of SUN dose dependently attenuated tactile allodynia induced by ligation of the L5 spinal nerve (SNL) and similarly reversed thermal hyperalgesia produced by chronic constriction injury. In addition, SUN was efficacious against complete Freund's adjuvant-induced thermal hyperalgesia. In these models, maximal reversal of pain-related behaviors corresponded with maximum rates of increase in brain and plasma d-serine concentrations, indicative of full inhibition of DAAO activity. To investigate the possible site(s) of action, we recorded spontaneous nerve activity and mechanically evoked responses of central spinal cord dorsal horn neurons and compared these with spontaneous activity of peripheral dorsal root filaments in anesthetized SNL model animals. Oral SUN reduced spontaneous activity in both central and peripheral recordings at doses and pretreatment times that corresponded to reduced mechanical allodynia in behavioral experiments. After intravenous administration of SUN, the onset of action for this central effect was rapid (maximal effects within 30 minutes), but was abolished by severing afferent inputs to the dorsal horn. Overall, these results indicate that inhibition of DAAO in peripheral afferent spinal circuits reduced spontaneous neuronal activity to attenuate pain-related behaviors in rat models of neuropathic and inflammatory pain.read more
Citations
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Journal ArticleDOI
Human D-Amino Acid Oxidase: Structure, Function, and Regulation
TL;DR: The known properties of human DAAO suggest that its activity must be finely tuned to fulfill a main physiological function such as the control of D-serine levels in the brain as well as the role of post-translational modifications on its main biochemical properties at the cellular level.
Journal ArticleDOI
Effects of quercetin on chronic constriction nerve injury in an experimental rat model.
TL;DR: Comparison of QUE with morphine and gabapentine has revealed significant effects of this agent in the current chronic constriction injury model, and QUE was significantly superior to Gabapentin and morphine in terms of alleviating mechanical and thermal hypersensitivity.
Journal ArticleDOI
Neuropathic pain depends upon D-serine co-activation of spinal NMDA receptors in rats.
Yan Lefèvre,Aurélie Amadio,Peggy Vincent,Amélie Descheemaeker,Stéphane H. R. Oliet,Radhouane Dallel,Daniel L. Voisin +6 more
TL;DR: Results show that neuropathic pain depends upon glial d-serine that co-activates spinal NMDA receptors and that upregulated serine racemase expression was upregulated in astrocyte processes in neuropathic rats compared to sham rats.
Journal ArticleDOI
Spinal sigma-1 receptor activation increases the production of d-serine in astrocytes which contributes to the development of mechanical allodynia in a mouse model of neuropathic pain.
Jiyoung Moon,Sheu Ran Choi,Dae Hyun Roh,Seo Yeon Yoon,Soon Gu Kwon,Hoon Seong Choi,Suk Yun Kang,Ho Jae Han,Hyun-Woo Kim,Alvin J. Beitz,Seog Bae Oh,Jang Hern Lee +11 more
TL;DR: These findings demonstrate for the first time that the activation of Sig-1Rs increases the expression of Srr and d-serine in astrocytes and ultimately affects dorsal horn neurons that are involved in the development of MA in neuropathic mice.
Journal ArticleDOI
Novel human D-amino acid oxidase inhibitors stabilize an active-site lid-open conformation.
Ryan T. Terry-Lorenzo,Lawrence Chun,Scott P. Brown,Michelle L. R. Heffernan,Q. K. Fang,M. A. Orsini,Loredano Pollegioni,Larry W. Hardy,Kerry L. Spear,Thomas H. Large +9 more
TL;DR: The results confirm previous hypotheses regarding active-site lid flexibility of mammalian D-amino acid oxidases and could assist in the design of the next generation of hDAAO inhibitors.
References
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Journal ArticleDOI
The N-methyl D-aspartate receptor glycine site and D-serine metabolism: an evolutionary perspective.
TL;DR: In this article, an evolutionary framework for the appearance of a glycine site in animals and the metabolic events leading to high levels of D-serine in brain is outlined, along with the sequence alignments of the glycine-binding regions, which suggest that the properties of invertebrate NMDA receptor glycine sites are probably different from those in vertebrates.
Journal ArticleDOI
Discovery, SAR, and pharmacokinetics of a novel 3-hydroxyquinolin-2(1H)-one series of potent D-amino acid oxidase (DAAO) inhibitors.
Allen J. Duplantier,Stacey L. Becker,Michael John Bohanon,Kris A. Borzilleri,Boris A. Chrunyk,James T. Downs,Lain-Yen Hu,Ayman El-Kattan,Larry C. James,Shenping Liu,Jiemin Lu,Noha Maklad,Mahmoud N. Mansour,Scot Richard Mente,Mary Piotrowski,Subas M. Sakya,Sheehan Susan M,Stefanus J. Steyn,Christine A. Strick,Victoria A. Williams,Lei Zhang +20 more
TL;DR: Subsequent evaluation against the rat DAAO enzyme revealed a divergent SAR versus the human enzyme and may explain the high exposures of drug necessary to achieve significant changes in rat or mouse cerebellum D-serine.
Journal ArticleDOI
The discovery of fused pyrrole carboxylic acids as novel, potent D-amino acid oxidase (DAO) inhibitors.
Tim Sparey,Pravien Abeywickrema,Sarah Almond,Nicholas J. Brandon,Noel Byrne,Alister Campbell,Pete H. Hutson,Marlene A. Jacobson,Brian A. Jones,Sanjeev Munshi,Danette Pascarella,Andrew Pike,G. Sridhar Prasad,Nancy A. Sachs,Melanie Zea Sakatis,V V Sardana,Shankar Venkatraman,Mary Beth Young +17 more
TL;DR: Novel DAO inhibitors are identified, in particular, acid 1, which demonstrated moderate potency for DAO in vitro and ex vivo, and raised plasma d-serine levels after dosing ip to rats.
Journal ArticleDOI
Exaggerated responses to chronic nociceptive stimuli and enhancement of N-methyl-D-aspartate receptor-mediated synaptic transmission in mutant mice lacking D-amino-acid oxidase.
Kohji Wake,Hajime Yamazaki,Shinji Hanzawa,Ryuichi Konno,Hideaki Sakio,Akira Niwa,Yuuichi Hori +6 more
TL;DR: The present observations provide another line of evidence that D-serine functions as an endogenous coagonist at the glycine site of NMDA receptors, and raise the possibility that D -amino-acid oxidase exerts a neuromodulatory function by controlling the concentration of D- Serine in the central nervous system.
Journal Article
Spatiotemporal relationships among D-serine, serine racemase, and D-amino acid oxidase during mouse postnatal development.
Li-zhen Wang,Xing-Zu Zhu +1 more
TL;DR: Novel mechanisms might be involved in D-Serine deposition in mouse tissues with high level of D-serine and no detectable DAO activity such as cortex and striatum, but DAO in cerebellum and kidney might have other physiological functions in addition to degrading D-amino acid.
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Discovery, SAR, and pharmacokinetics of a novel 3-hydroxyquinolin-2(1H)-one series of potent D-amino acid oxidase (DAAO) inhibitors.
Allen J. Duplantier,Stacey L. Becker,Michael John Bohanon,Kris A. Borzilleri,Boris A. Chrunyk,James T. Downs,Lain-Yen Hu,Ayman El-Kattan,Larry C. James,Shenping Liu,Jiemin Lu,Noha Maklad,Mahmoud N. Mansour,Scot Richard Mente,Mary Piotrowski,Subas M. Sakya,Sheehan Susan M,Stefanus J. Steyn,Christine A. Strick,Victoria A. Williams,Lei Zhang +20 more