scispace - formally typeset
Search or ask a question
Journal ArticleDOI

Pharmacodynamic Effects of a d-Amino Acid Oxidase Inhibitor Indicate a Spinal Site of Action in Rat Models of Neuropathic Pain

01 Jun 2013-Journal of Pharmacology and Experimental Therapeutics (American Society for Pharmacology and Experimental Therapeutics)-Vol. 345, Iss: 3, pp 502-511
TL;DR: 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.

Content maybe subject to copyright    Report

Citations
More filters
Journal ArticleDOI
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.
Abstract: D-Amino acid oxidase (DAAO) is an FAD-containing flavoenzyme that catalyzes with absolute stereoselectivity the oxidative deamination of all natural D-amino acids, the only exception being the acidic ones. This flavoenzyme plays different roles during evolution and in different tissues in humans. Its three-dimensional structure is well conserved during evolution: minute changes are responsible for the functional differences between enzymes from microorganism sources and those from humans. In recent years several investigations focused on human DAAO, mainly because of its role in degrading the neuromodulator D-serine in the central nervous system. D-Serine is the main coagonist of N-methyl D-aspartate receptors, i.e., excitatory amino acid receptors critically involved in main brain functions and pathologic conditions. Human DAAO possesses a weak interaction with the FAD cofactor; thus, in vivo it should be largely present in the inactive, apoprotein form. Binding of active-site ligands and the substrate stabilizes flavin binding, thus pushing the acquisition of catalytic competence. Interestingly, the kinetic efficiency of the enzyme on D-serine is very low. Human DAAO interacts with various proteins, in this way modulating its activity, targeting, and cell stability. 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. At present, studies are focusing on the epigenetic modulation of human DAAO expression and the role of post-translational modifications on its main biochemical properties at the cellular level.

59 citations

Journal ArticleDOI
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.
Abstract: Flavonoids are popular substances in the literature, with proven effects on cardiovascular, neoplastic and neurodegenerative diseases. Antioxidant effect is the most pronounced and studied one. Among thousands of flavonoids, quercetin (QUE) is a prototype with significant antioxidant effects. This study aims to demonstrate the effects of QUE in an experimental rat model of chronic constriction injury (CCI). A two-level study was designed with 42 adult Wistar rats that were randomly assigned to different groups. In the first part, animals in sham, control, quercetin, morphine and gabapentine groups received chronic constriction injury to their sciatic nerves and received a single dose of QUE, morphine and gabapentine. In the second part, different dose regimens of QUE were administered to different groups of animals. Pre-injury and post-injury assessments for mechanical hypersensitivity, thermal sensitivity, locomotor activity and anxiety were recorded and statistical comparisons were performed between different groups. Comparison of QUE with morphine and gabapentine has revealed significant effects of this agent in the current chronic constriction injury model. QUE was significantly superior to Gabapentine and morphine in terms of alleviating mechanical and thermal hypersensitivity. Additionally, pre-injury administration of QUE for 4 days demonstrated long-term effectiveness on mechanical hypersensitivity. This preliminary report the on effects of QUE in a chronic constriction injury model proved significant effects of the agent, which should be supplemented with different studies using different dose regimens.

33 citations

Journal ArticleDOI
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.

33 citations

Journal ArticleDOI
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.

32 citations


Cites background from "Pharmacodynamic Effects of a d-Amin..."

  • ...inhibitor, which increased D-serine concentrations in brain and plasma,reduced spontaneous neuronal activity in both central and peripheral recordings and alsoattenuated pain behaviors in rat models of neuropathic and inflammatory pain[34]....

    [...]

Journal ArticleDOI
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.
Abstract: The NMDAR (N-methyl-D-aspartate receptor) is a central regulator of synaptic plasticity and learning and memory. hDAAO (human D-amino acid oxidase) indirectly reduces NMDAR activity by degrading the NMDAR co-agonist D-serine. Since NMDAR hypofunction is thought to be a foundational defect in schizophrenia, hDAAO inhibitors have potential as treatments for schizophrenia and other nervous system disorders. Here, we sought to identify novel chemicals that inhibit hDAAO activity. We used computational tools to design a focused, purchasable library of compounds. After screening this library for hDAAO inhibition, we identified the structurally novel compound, ‘compound 2’ [3-(7-hydroxy-2-oxo-4-phenyl-2H-chromen-6-yl)propanoic acid], which displayed low nM hDAAO inhibitory potency (Ki=7 nM). Although the library was expected to enrich for compounds that were competitive for both D-serine and FAD, compound 2 actually was FAD uncompetitive, much like canonical hDAAO inhibitors such as benzoic acid. Compound 2 and an analog were independently co-crystalized with hDAAO. These compounds stabilized a novel conformation of hDAAO in which the active-site lid was in an open position. These 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.

30 citations

References
More filters
Journal ArticleDOI
TL;DR: In this article, a co-administration of NMDA-receptor antagonists with an opioid may prevent tolerance to opioid analgesia, which can suppress central sensitization in experimental animals.

251 citations

Journal ArticleDOI
TL;DR: A 1967-1999 MEDLINE search of published reports evaluating the role of the glutamate N-methyl-D-aspartate (NMDA) receptor in pain identified 378 animal studies and 132 human studies and there is convincing evidence in these studies that the NMDA receptor mediates prolonged nociceptive behaviors in animal models and various chronic pain symptoms in the clinical population as mentioned in this paper.

239 citations

Journal ArticleDOI
TL;DR: It is found that the content of D-serine in the serum and cerebellum of mutant mice is much higher than that of normal mice, whereas a slight but significant difference in the cerebral D-Serine level is observed between the two strains.

197 citations


"Pharmacodynamic Effects of a d-Amin..." refers background in this paper

  • ...Since DAAO has been reported to be expressed highly in the cerebellum (Wang and Zhu, 2003), this brain region exhibits lower baseline levels of D-serine (Hashimoto et al., 1993; Wang and Zhu, 2003)....

    [...]

Journal ArticleDOI
TL;DR: There is a growing body of evidence indicating that D-serine, rather than glycine as originally thought, is the endogenous ligand for NMDARs in many brain structures.

129 citations


"Pharmacodynamic Effects of a d-Amin..." refers background in this paper

  • ...Although D-serine occupancy of the glycine site on NR1 subunits serves to increase NMDA receptor activation, this increase would occur only in neuronal regions where this site is not already saturated by glycine or D-serine (Mothet et al., 2000; Panatier et al., 2006; Heffernan et al., 2009; Oliet and Mothet, 2009; Papouin et al., 2012)....

    [...]

  • ...…site on NR1 subunits serves to increase NMDA receptor activation, this increase would occur only in neuronal regions where this site is not already saturated by glycine or D-serine (Mothet et al., 2000; Panatier et al., 2006; Heffernan et al., 2009; Oliet and Mothet, 2009; Papouin et al., 2012)....

    [...]

Journal ArticleDOI
TL;DR: Data demonstrate that the GluRδ2 ligand-binding core is capable of binding ligands and that cleft closure of the ligand -binding core can induce conformational changes that alter ion permeation.
Abstract: The orphan glutamate-like receptor GluRδ2 is predominantly expressed in Purkinje cells of the central nervous system. The classification of GluRδ2 to the ionotropic glutamate receptor family is based on sequence similarities, because GluRδ2 does not form functional homomeric glutamate-gated ion channels in transfected cells. Studies in GluRδ2−/− knockout mice as well as in mice with naturally occurring mutations in the GluRδ2 gene have demonstrated an essential role of GluRδ2 in cerebellar long-term depression, motor learning, motor coordination, and synaptogenesis. However, the lack of a known agonist has hampered investigations on the function of GluRδ2. In this study, the ligand-binding core of GluRδ2 (GluRδ2–S1S2) was found to bind neutral amino acids such as d-serine and glycine, as demonstrated by isothermal titration calorimetry. Direct evidence for binding of d-serine and structural rearrangements in the binding cleft of GluRδ2–S1S2 is provided by x-ray structures of GluRδ2–S1S2 in its apo form and in complex with d-serine. Functionally, d-serine and glycine were shown to inactivate spontaneous ion-channel conductance in GluRδ2 containing the lurcher mutation (EC50 values, 182 and 507 μM, respectively). These data demonstrate that the GluRδ2 ligand-binding core is capable of binding ligands and that cleft closure of the ligand-binding core can induce conformational changes that alter ion permeation.

121 citations


"Pharmacodynamic Effects of a d-Amin..." refers background in this paper

  • ...Consistent with this idea, D-serine was recognized to have effects on another glutamate receptor, iGluRdelta (Naur et al., 2007)....

    [...]

Related Papers (5)