N-Methyl-D-Aspartate Receptor (NMDA) Antagonists as Potential Pain Therapeutics

Brown, Dean G.; Krupp, Johannes

doi:10.2174/156802606777057571

Cited by 36 publications

(16 citation statements)

References 138 publications

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“…Abnormal expression and mutations in the NMDA-R have been implicated in neurological and psychiatric disorders (Kemp and McKernan, 2002;Jansen and Dannhardt, 2003;Missale et al, 2006;Brown and Krupp, 2006). Drugs targeting the NMDA-R are used in anesthesia and pain management (Ji et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

The NMDA receptor functions independently and as an LRP1 co-receptor to promote Schwann cell survival and migration

Mantuano

Lam

Shibayama

et al. 2015

Journal of Cell Science

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NMDA receptors (NMDA-Rs) are ionotropic glutamate receptors, which associate with LDL-receptor-related protein-1 (LRP1) to trigger cell signaling in response to protein ligands in neurons. Here, we demonstrate for the first time that the NMDA-R is expressed by rat Schwann cells and functions independently and with LRP1 to regulate Schwann cell physiology. The NR1 (encoded by GRIN1) and NR2b (encoded by GRIN2B) NMDA-R subunits were expressed by cultured Schwann cells and upregulated in sciatic nerves following crush injury. The ability of LRP1 ligands to activate ERK1/2 (also known as MAPK3 and MAPK1, respectively) and promote Schwann cell migration required the NMDA-R. NR1 gene silencing compromised Schwann cell survival. Injection of the LRP1 ligands tissue-type plasminogen activator (tPA, also known as PLAT) or MMP9-PEX into crush-injured sciatic nerves activated ERK1/2 in Schwann cells in vivo, and the response was blocked by systemic treatment with the NMDA-R inhibitor MK801. tPA was unique among the LRP1 ligands examined because tPA activated cell signaling and promoted Schwann cell migration by interacting with the NMDA-R independently of LRP1, albeit with delayed kinetics. These results define the NMDA-R as a Schwann cell signaling receptor for protein ligands and a major regulator of Schwann cell physiology, which may be particularly important in peripheral nervous system (PNS) injury.

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Section: Introductionmentioning

confidence: 99%

The NMDA receptor functions independently and as an LRP1 co-receptor to promote Schwann cell survival and migration

Mantuano

Lam

Shibayama

et al. 2015

Journal of Cell Science

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“…Multiple mechanisms including increased primary afferent excitability 3 , enhanced transmission in the dorsal horn 1 , changes in gene expression 4 , aberrant neuron-glia interactions 5,6 and neuronal apoptosis 7 are implicated in hypersensitivity in chronic pain models. Abundant pre-clinical evidence indicates that N-methyl-D-aspartate receptor (NMDARs) 8 are critically involved in pain hypersensitivity [9][10][11] . However, pharmacological blockade of these receptors in humans is deleterious because the activity of NMDARs is essential for many important physiological functions including breathing and locomotion 9,12,13 .…”

mentioning

confidence: 99%

Treatment of inflammatory and neuropathic pain by uncoupling Src from the NMDA receptor complex

Liu

Gingrich

Vargas‐Caballero

et al. 2008

Nat Med

197

205

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Chronic pain hypersensitivity depends upon N-methyl-D-aspartate receptors (NMDARs). However, clinical use of NMDAR blockers is limited by side effects from suppressing physiological functions of these receptors. Here we report a means to suppress pain hypersensitivity without blocking NMDARs but rather by inhibiting the binding of a key enhancer of NMDAR function, the protein tyrosine kinase Src. We show that a peptide consisting of amino acids 40-49 of Src fused to the protein transduction domain of the HIV Tat protein (Src40-49Tat) prevented pain behaviors induced by intraplantar formalin and reversed pain hypersensitivity produced by intraplantar injection of complete Freund's adjuvant or by peripheral nerve injury. Src40-49Tat had no effect on basal sensory thresholds, acute nociceptive responses, or cardiovascular, respiratory, locomotor or cognitive functions. Thus, by targeting Src-mediated enhancement of NMDARs, inflammatory and neuropathic pain are suppressed without deleterious consequences of directly blocking NMDARs, an approach that may be of broad relevance to managing chronic pain.Chronic pain is categorized as inflammatory or neuropathic, each involving neuroplastic changes leading to hypersensitivity in peripheral and central nociceptive systems 1,2 . Multiple mechanisms including increased primary afferent excitability 3 , enhanced transmission in the dorsal horn 1 , changes in gene expression 4 , aberrant neuron-glia interactions 5,6 and neuronal apoptosis 7 are implicated in hypersensitivity in chronic pain models. Abundant pre-clinical evidence indicates that N-methyl-D-aspartate receptor (NMDARs) 8 are critically involved in pain hypersensitivity 9-11 . However, pharmacological blockade of these receptors in humans is deleterious because the activity of NMDARs is essential for many important physiological functions including breathing and locomotion 9,12,13 . A crucial signaling event for NMDAR-dependent neuroplasticity, including pain hypersensitivity 1,14 , is upregulation of NMDAR currents by mechanisms including relieving Mg 2+ blockade and receptor phosphorylation 15,16 . Thus, preferentially inhibiting mechanisms which upregulate NMDARs without affecting basal channel activity represents a strategy that may suppress pain hypersensitivity without impairing key physiological functions.

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“…In addition, considerable evidence was found for enhanced NMDAR-mediated transmission and plasticity as a potential cause for pain conditions, e.g. neuropathic pain (13).…”

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confidence: 99%

The Structure of Mammalian Serine Racemase

Smith

Mack

Ebneth

et al. 2010

Journal of Biological Chemistry

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Serine racemase is responsible for the synthesis of D-serine, an endogenous co-agonist for N-methyl-D-aspartate receptor-type glutamate receptors (NMDARs). This pyridoxal 5-phosphatedependent enzyme is involved both in the reversible conversion of L-to D-serine and serine catabolism by ␣,␤-elimination of water, thereby regulating D-serine levels. Because D-serine affects NMDAR signaling throughout the brain, serine racemase is a promising target for the treatment of disorders related to NMDAR dysfunction. To provide a molecular basis for rational drug design the x-ray crystal structures of human and rat serine racemase were determined at 1.5-and 2.1-Å resolution, respectively, and in the presence and absence of the orthosteric inhibitor malonate. The structures revealed a fold typical of ␤-family pyridoxal 5-phosphate enzymes, with both a large domain and a flexible small domain associated into a symmetric dimer, and indicated a ligand-induced rearrangement of the small domain that organizes the active site for specific turnover of the substrate.N-Methyl-D-aspartate receptor-type glutamate receptors (NMDARs) 2 are a key component in glutamatergic transmission implicated in the development, function, and plasticity of the nervous system. In addition to the neurotransmitter glutamate, the activation of NMDARs requires the binding of either of the two endogenous co-agonists, glycine or D-serine, to the NMDAR "glycine modulatory site" (1, 2). Although both amino acids have similar potency as co-agonists, they display regional differences in modulating NMDAR function (3, 4). According to its distribution within the CNS, D-serine exerts its function predominantly in corticolimbic brain structures (5). This pivotal role of D-serine is supported by several experimental findings, including depletion studies in neuronal tissue preparations, indicating a strong reduction in NMDAR-mediated transmission and impaired synaptic plasticity in the absence of D-serine (6, 7).D-serine is produced by enzymatic conversion of L-to D-serine mediated by the pyridoxal 5Ј-phosphate (PLP)-containing enzyme serine racemase (SR). Mammalian SR was first purified from rat brain and functionally characterized in 1999 by Wolosker and colleagues (8). The enzyme is expressed in glial cells and neurons and constitutes the sole endogenous source for D-serine in mammals (9). Both human and rodent SR have been purified and extensively studied to generate comprehensive knowledge of the enzymatic characteristics and allosteric modulation by a number of agents such as ATP and Mg 2ϩ ions. In addition to serine isomerization, the enzyme catalyzes the ␣,␤-elimination of water from L-and D-serine to produce pyruvate and ammonia, thus, offering the possibility for SR not only to elevate but also to reduce the level of D-serine (5), a role that previously has mainly been attributed to D-amino acid oxidase (10).Recent data from SR-deficient mice strongly implicate this enzyme in the process of NMDAR-dependent plasticity and neurotoxicity. Knock-out mice were ...

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N-Methyl-D-Aspartate Receptor (NMDA) Antagonists as Potential Pain Therapeutics

Cited by 36 publications

References 138 publications

The NMDA receptor functions independently and as an LRP1 co-receptor to promote Schwann cell survival and migration

The NMDA receptor functions independently and as an LRP1 co-receptor to promote Schwann cell survival and migration

Treatment of inflammatory and neuropathic pain by uncoupling Src from the NMDA receptor complex

The Structure of Mammalian Serine Racemase

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