Glutamate-based therapeutic approaches: clinical trials with NMDA antagonists

Muir, Keith W.

doi:10.1016/j.coph.2005.12.002

Cited by 284 publications

(202 citation statements)

References 55 publications

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“…Third, although the data presented here demonstrates that DLK is essential for neuronal degeneration downstream of NMDA receptor hyper-activation (Fig. 6, B and C), the normal viability of Tamoxifen-treated DLK lox ;Cre pos animals suggests that inhibition of DLK would not be expected to demonstrate the same type of toxicity that plagued NMDA receptor antagonists (Muir, 2006). However,…”

Section: Discussionmentioning

confidence: 58%

Dual leucine zipper kinase is required for excitotoxicity induced neuronal degeneration

Pozniak¹,

Ghosh²,

Gogineni³

et al. 2013

J Cell Biol

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Excessive glutamate signaling is thought to underlie neurodegeneration in multiple contexts, yet the pro-degenerative signaling pathways downstream of glutamate receptor activation are not well defined. We show that dual leucine zipper kinase (DLK) is essential for excitotoxicity-induced degeneration of neurons in vivo. In mature neurons, DLK is present in the synapse and interacts with multiple known postsynaptic density proteins including the scaffolding protein PSD-95. To examine DLK function in the adult, DLK-inducible knockout mice were generated through Tamoxifen-induced activation of Cre-ERT in mice containing a floxed DLK allele, which circumvents the neonatal lethality associated with germline deletion. DLK-inducible knockouts displayed a modest increase in basal synaptic transmission but had an attenuation of the JNK/c-Jun stress response pathway activation and significantly reduced neuronal degeneration after kainic acid-induced seizures. Together, these data demonstrate that DLK is a critical upstream regulator of JNK-mediated neurodegeneration downstream of glutamate receptor hyper-activation and represents an attractive target for the treatment of indications where excitotoxicity is a primary driver of neuronal loss.

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Section: Discussionmentioning

confidence: 58%

Dual leucine zipper kinase is required for excitotoxicity induced neuronal degeneration

Pozniak¹,

Ghosh²,

Gogineni³

et al. 2013

J Cell Biol

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“…14,17 However, all clinical trials investigating NMDAR antagonists in TBI and stroke have been unsuccessful. 14,30 It has been postulated that one of the main reasons why the NMDAR antagonists have failed are due to the tight time-window for neuroprotection after brain injury. 11,15,21,53 Patients with positive BAC on injury overcome this dilemma by already having the NMDAR antagonist present prior to injury.…”

mentioning

confidence: 99%

Alcohol and mortality after moderate to severe traumatic brain injury: a meta-analysis of observational studies

Raj¹,

Mikkonen

Siironen³

et al. 2016

JNS

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T raumaTic brain injury (TBI) is defined as an alteration of brain function, or other evidence of brain pathology, caused by an external force.28 Moderate to severe TBI is a major cause of mortality and morbidity in the world. 27 Every year approximately 1.5 million people die and 10 million people are hospitalized due to TBI. 18 This leads to great suffering for patients and their relatives, with huge direct and indirect costs to society. 10,32 It has been estimated that the annual costs of TBI in the US are more than $76.5 billion.9 Numerous clinical trials have failed to demonstrate the efficacy of promising experimental neuroprotective agents despite convincing preclinical data. Over the past 2 decades there have not been clear improvements in the prognosis of patients with TBI. 24,25 Description of the interventionUp to half of all patients with TBI are under the influence of alcohol at the time of injury. 44,49 Clinical studies investigating the role of alcohol (ethanol, CH 3 CH 2 OH, referred to as alcohol in the present study) on the outcome of TBI have been either retrospective or observational, as it probably would be unethical, unless strong evidence can be laid out, to administer alcohol to patients presenting with TBI. This meta-analysis investigates the impact of the presence of blood alcohol concentration (BAC) on outcome after TBI. How Might alcohol work as a Neuroprotective agent?The neuroprotective properties of alcohol have been abbreviatioNs AIS = Abbreviated Injury Scale; BAC = blood alcohol concentration; GCS = Glasgow Coma Scale; NMDAR = N-methyl-d-aspartate receptor; TBI = traumatic brain injury. but with good study homogeneity (I 2 = 36% and 14%). coNclusioNs Positive BAC was significantly associated with lower mortality rates in moderate to severe TBI. Whether this observation is due to selection bias or neuroprotective effects of alcohol remains unknown. Future prospective studies adjusting for TBI heterogeneity is advocated to establish the potential favorable effects of alcohol on outcome after TBI.

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“…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 . 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 .…”

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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

198

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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Glutamate-based therapeutic approaches: clinical trials with NMDA antagonists

Cited by 284 publications

References 55 publications

Dual leucine zipper kinase is required for excitotoxicity induced neuronal degeneration

Dual leucine zipper kinase is required for excitotoxicity induced neuronal degeneration

Alcohol and mortality after moderate to severe traumatic brain injury: a meta-analysis of observational studies

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

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