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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.

AbstractInhibition 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.

Topics: Neuropathic pain (54%), Chronic pain (53%), Spinal Cord Dorsal Horn (52%), Gabapentin (50%)

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Citations
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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.

33 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.

28 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.
Abstract: We have previously demonstrated that activation of the spinal sigma-1 receptor (Sig-1R) plays an important role in the development of mechanical allodynia (MA) via secondary activation of the N-methyl-d-aspartate (NMDA) receptor. Sig-1Rs have been shown to localize to astrocytes, and blockade of Sig-1Rs inhibits the pathologic activation of astrocytes in neuropathic mice. However, the mechanism by which Sig-1R activation in astrocytes modulates NMDA receptors in neurons is currently unknown. d-serine, synthesized from l-serine by serine racemase (Srr) in astrocytes, is an endogenous co-agonist for the NMDA receptor glycine site and can control NMDA receptor activity. Here, we investigated the role of d-serine in the development of MA induced by spinal Sig-1R activation in chronic constriction injury (CCI) mice. The production of d-serine and Srr expression were both significantly increased in the spinal cord dorsal horn post-CCI surgery. Srr and d-serine were only localized to astrocytes in the superficial dorsal horn, while d-serine was also localized to neurons in the deep dorsal horn. Moreover, we found that Srr exists in astrocytes that express Sig-1Rs. The CCI-induced increase in the levels of d-serine and Srr was attenuated by sustained intrathecal treatment with the Sig-1R antagonist, BD-1047 during the induction phase of neuropathic pain. In behavioral experiments, degradation of endogenous d-serine with DAAO, or selective blockade of Srr by LSOS, effectively reduced the development of MA, but not thermal hyperalgesia in CCI mice. Finally, BD-1047 administration inhibited the development of MA and this inhibition was reversed by intrathecal treatment with exogenous d-serine. These findings demonstrate for the first time that the activation of Sig-1Rs increases the expression of Srr and d-serine in astrocytes. The increased production of d-serine induced by CCI ultimately affects dorsal horn neurons that are involved in the development of MA in neuropathic mice.

28 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]....

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Journal ArticleDOI
TL;DR: For the first time, the authors identify a novel spinal astroglial DAAO–hydrogen peroxide pathway that is critically involved in the initiation and maintenance of morphine antinociceptive tolerance, and suggest that this pathway is of potential utility for the management of morphine tolerance and chronic pain.
Abstract: Background: D-Amino acid oxidase (DAAO) is a flavin adenine dinucleotide-dependent peroxisomal flavoenzyme which is almost exclusively expressed within astrocytes in the spinal cord. DAAO catalyzes oxidation of D-amino acids to hydrogen peroxide, which is a stable and less active reactive oxygen species, and may represent a final form of reactive oxygen species. This study tested the hypothesis that the spinal astroglial DAAO–hydrogen peroxide pathway plays an important role in the development of morphine antinociceptive tolerance. Methods: Rat and mouse formalin, hot-plate, and tail-flick tests were used, and spinal DAAO expression and hydrogen peroxide level were measured. Sample size of animals was six in each study group. Results: Subcutaneous and intrathecal DAAO inhibitors, including 5-chloro-benzo[d]isoxazol-3-ol, AS057278, and sodium benzoate, completely prevented and reversed morphine antinociceptive tolerance in the formalin, hot-plate, and tail-immersion tests, with a positive correlation to their DAAO inhibitory activities. Intrathecal gene silencers, small interfering RNA/DAAO and small hairpin RNA/DAAO, almost completely prevented morphine tolerance. Intrathecal 5-chloro-benzo[d]isoxazol-3-ol and small interfering RNA/DAAO completely prevented increased spinal hydrogen peroxide levels after chronic morphine treatment. Intrathecal nonselective hydrogen peroxide scavenger phenyl-tert-N-butyl nitrone and the specific hydrogen peroxide catalyst catalase also abolished established morphine tolerance. Spinal dorsal horn astrocytes specifically expressed DAAO was significantly up-regulated, accompanying astrocyte hypertrophy after chronic morphine treatment. Conclusions: For the first time, the authors’ result identify a novel spinal astroglial DAAO–hydrogen peroxide pathway that is critically involved in the initiation and maintenance of morphine antinociceptive tolerance, and suggest that this pathway is of potential utility for the management of morphine tolerance and chronic pain.

27 citations


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.

27 citations


References
More filters

Journal ArticleDOI
01 Apr 1988-Pain
TL;DR: A peripheral mononeuropathy was produced in adult rats by placing loosely constrictive ligatures around the common sciatic nerve and the postoperative behavior of these rats indicated that hyperalgesia, allodynia and, possibly, spontaneous pain were produced.
Abstract: A peripheral mononeuropathy was produced in adult rats by placing loosely constrictive ligatures around the common sciatic nerve. The postoperative behavior of these rats indicated that hyperalgesia, allodynia and, possibly, spontaneous pain (or dysesthesia) were produced. Hyperalgesic responses to noxious radiant heat were evident on the second postoperative day and lasted for over 2 months. Hyperalgesic responses to chemogenic pain were also present. The presence of allodynia was inferred from the nocifensive responses evoked by standing on an innocuous, chilled metal floor or by innocuous mechanical stimulation, and by the rats' persistence in holding the hind paw in a guarded position. The presence of spontaneous pain was suggested by a suppression of appetite and by the frequent occurrence of apparently spontaneous nocifensive responses. The affected hind paw was abnormally warm or cool in about one-third of the rats. About one-half of the rats developed grossly overgrown claws on the affected side. Experiments with this animal model may advance our understanding of the neural mechanisms of neuropathic pain disorders in humans.

4,835 citations


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

  • ...Increases in cerebellum D-serine concentrations have also been reported after cerebellar DAAO activity was inhibited by RNAi (Burnet et al., 2011)....

    [...]


Journal ArticleDOI
01 Sep 1992-Pain
TL;DR: Results suggested that the surgical procedure in all 3 groups produced a long-lasting hyperalgesia to noxious heat and mechanical allodynia of the affected foot and there were behavioral signs of the presence of spontaneous pain in the affectedFoot.
Abstract: SummaryWe attempted to develop an experimental animal model for peripheral neuropathic pain Under sodium pentobarbital anesthesia, both the L5 and L6 spinal nerves (group 1) or the L5 spinal nerve alone (group 2) of one side of the rat were tightly ligated For comparison, a parallel study was cond

3,191 citations


Journal ArticleDOI
TL;DR: D-serine is an endogenous modulator of the glycine site of NMDA receptors and fully occupies this site at some functional synapses and greatly attenuates NMDA receptor-mediated neurotransmission as assessed by using whole-cell patch-clamp recordings or indirectly by using biochemical assays of the sequelae of NMda receptor- mediated calcium flux.
Abstract: Functional activity of N-methyl-d-aspartate (NMDA) receptors requires both glutamate binding and the binding of an endogenous coagonist that has been presumed to be glycine, although d-serine is a more potent agonist. Localizations of d-serine and it biosynthetic enzyme serine racemase approximate the distribution of NMDA receptors more closely than glycine. We now show that selective degradation of d-serine with d-amino acid oxidase greatly attenuates NMDA receptor-mediated neurotransmission as assessed by using whole-cell patch–clamp recordings or indirectly by using biochemical assays of the sequelae of NMDA receptor-mediated calcium flux. The inhibitory effects of the enzyme are fully reversed by exogenously applied d-serine, which by itself did not potentiate NMDA receptor-mediated synaptic responses. Thus, d-serine is an endogenous modulator of the glycine site of NMDA receptors and fully occupies this site at some functional synapses.

1,010 citations


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

  • ...…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
19 May 2006-Cell
TL;DR: The degree of astrocytic coverage of neurons governs the level of glycine site occupancy on the NMDA receptor, thereby affecting their availability for activation and thus the activity dependence of long-term synaptic changes.
Abstract: Summary The NMDA receptor is a key player in excitatory transmission and synaptic plasticity in the central nervous system. Its activation requires the binding of both glutamate and a coagonist like d-serine to its glycine site. As d-serine is released exclusively by astrocytes, we studied the physiological impact of the glial environment on NMDA receptor-dependent activity and plasticity. To this end, we took advantage of the changing astrocytic ensheathing of neurons occurring in the supraoptic nucleus during lactation. We provide direct evidence that in this hypothalamic structure the endogenous coagonist of NMDA receptors is d-serine and not glycine. Consequently, the degree of astrocytic coverage of neurons governs the level of glycine site occupancy on the NMDA receptor, thereby affecting their availability for activation and thus the activity dependence of long-term synaptic changes. Such a contribution of astrocytes to synaptic metaplasticity fuels the emerging concept that astrocytes are dynamic partners of brain signaling.

782 citations


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

  • ...…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
03 Aug 2012-Cell
TL;DR: It is demonstrated that long-term potentiation and NMDA-induced neurotoxicity rely on synaptic NMDARs only, and long- term depression requires both synaptic and extrasynaptic receptors.
Abstract: N-methyl-d-aspartate receptors (NMDARs) are located in neuronal cell membranes at synaptic and extrasynaptic locations, where they are believed to mediate distinct physiological and pathological processes. Activation of NMDARs requires glutamate and a coagonist whose nature and impact on NMDAR physiology remain elusive. We report that synaptic and extrasynaptic NMDARs are gated by different endogenous coagonists, d-serine and glycine, respectively. The regionalized availability of the coagonists matches the preferential affinity of synaptic NMDARs for d-serine and extrasynaptic NMDARs for glycine. Furthermore, glycine and d-serine inhibit NMDAR surface trafficking in a subunit-dependent manner, which is likely to influence NMDARs subcellular location. Taking advantage of this coagonist segregation, we demonstrate that long-term potentiation and NMDA-induced neurotoxicity rely on synaptic NMDARs only. Conversely, long-term depression requires both synaptic and extrasynaptic receptors. Our observations provide key insights into the operating mode of NMDARs, emphasizing functional distinctions between synaptic and extrasynaptic NMDARs in brain physiology.

529 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)....

    [...]


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