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
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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
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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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Patent
Pyrrole and pyrazole DAAO inhibitors
TL;DR: In this article, the authors proposed a general formula for increasing the concentration of D-serine and decreasing the concentrations of Dserine oxidative toxic products, a method for enhancing learning, memory and / or cognition, or schizophrenia, Alzheimer's disease, ataxia or neuropathic pain.
Patent
Fused heterocyclic inhibitors of D- amino acid oxidase
オグブ,シプリアン,オー.,ジョーンズ,スティーブン,ダブリュー.,ジョーンズ,マイケル,エル.,スペア,ケリー,エル.,ソウクリ,ムスタファ,ドーシー,ジェームス,エム.,バーニー,マーク,エー.,ファン,クン,ケビン,フォグレソング,ロバート,ジェイ.,ヘファーナン,ミシェル,エル.アール.,ペラレス,ジョー,ビー.,ホプキンス,セス,シー. +11 more
TL;DR: This invention provides novel inhibitors of the enzyme D-amino acid oxidase as well as pharmaceutical compositions including the compounds of the invention for the treatment and prevention of neurological disorders, such as neuropsychiatric and neurodegenerative diseases, and pain, ataxia and convulsion.
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