Protection against glutamate toxicity through inhibition of the p44/42 mitogen-activated protein kinase pathway in neuronally differentiated P19 cells22Abbreviations: AMPA, (±)-α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid; NMDA, N-methyl-d-aspartate; MAP, mitogen-activated protein; ERK1/2, extracellular signal regulated kinase 1/2; MEK, mitogen-activated protein kinase kinase; JNK, Jun N-terminal kinase; NO, nitric oxide; CDK1, cyclin-dependent kinase I; PKA, protein kinase A; PKC, protein kinase C

Grant, Elfrida R.; Errico, Monica; Emanuel, Stuart L.; Benjamin, Daniel; McMillian, Michael; Wadsworth, Scott; Zivin, Robert A.; Zhong, Zhong

doi:10.1016/s0006-2952(01)00665-7

Cited by 23 publications

(5 citation statements)

References 54 publications

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“…1B). Since neuronally differentiated P19 cells have characteristics of CNS neurons [3] and NgR1 is also expressed mainly in the CNS [12], the possibility that P19 cells differentiated by all trans-retinoic acid could express NgR1 was examined. The expression of mRNA and protein of NgR1 was measured by semiquantitative RT-PCR and western immunoblotting analysis, respectively.…”

Section: Resultsmentioning

confidence: 99%

“…Since neuronally differentiated P19 cells express many kinds of neuron-related molecules including functionally active N-methyl-D-aspartate (NMDA) receptors [2,3], which play roles in the processes of neuronal development and in the formation of synaptic plasticity, P19 cells have been used as a model system to study the function of NMDA receptors present in the central nervous system (CNS).…”

Section: Introductionmentioning

confidence: 99%

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NgR1 Expressed in P19 Embryonal Carcinoma Cells Differentiated by Retinoic Acid Can Activate STAT3

Lee

Yun

Baek

et al. 2015

Korean J Physiol Pharmacol

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NgR1, a Nogo receptor, is involved in inhibition of neurite outgrowth and axonal regeneration and regulation of synaptic plasticity. P19 embryonal carcinoma cells were induced to differentiate into neuron-like cells using all trans-retinoic acid and the presence and/or function of cellular molecules, such as NgR1, NMDA receptors and STAT3, were examined. Neuronally differentiated P19 cells expressed the mRNA and protein of NgR1, which could stimulate the phosphorylation of STAT3 when activated by Nogo-P4 peptide, an active segment of Nogo-66. During the whole period of differentiation, mRNAs of all of the NMDA receptor subtypes tested (NR1, NR2A-2D) were consistently expressed, which meant that neuronally differentiated P19 cells maintained some characteristics of neurons, especially central nervous system neurons. Our results suggests that neuronally differentiated P19 cells expressing NgR1 may be an efficient and convenient in vitro model for studying the molecular mechanism of cellular events that involve NgR1 and its binding partners, and for screening compounds that activate or inhibit NgR1.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

NgR1 Expressed in P19 Embryonal Carcinoma Cells Differentiated by Retinoic Acid Can Activate STAT3

Lee

Yun

Baek

et al. 2015

Korean J Physiol Pharmacol

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“…A similar mechanism involving mitochondrial degeneration has been proposed for the selective neurotoxic actions of Mn in neurons in the globus pallidus (Gunter et al, 2009; Spadoni et al, 2000). In addition, glutamate toxicity also involves activation of several kinases including ERK1/2, JNK and p38 (Grant et al, 2001; Wise et al, 2004). The involvement of these kinases in the toxic actions of glutamate is evidenced by the fact that inhibitors of ERK phosphorylation and p38 kinase activity prevent glutamate-induced cell death (Baldwin et al, 1999; Stanciu and DeFranco, 2002).…”

Section: Discussionmentioning

confidence: 99%

“…Related to this is the fact that cytotoxic events provoking Mn toxicity, to a large extent, parallel similar pathways for that of glutamate, as both involve loss of mitochondrial function initiated by excess sequestration of calcium. Additionally, both Mn and glutamate stimulate several MAP kinases which have been shown to be involved in their cytotoxic actions (Baldwin et al, 1999; Grant et al, 2001; Roth, 2006; Roth et al, 2002; Stanciu and DeFranco, 2002). Because these agents share common cytotoxic mechanisms, coupled with the fact that glutamate can stimulate Mn uptake via its Ca +2 ionotropic receptor (Kannurpatti et al, 2000), it is reasonable to hypothesize that these complimentary processes may provoke an increase in the cytotoxic responses which account for pallidal neurons being more sensitive to Mn.…”

Section: Introductionmentioning

confidence: 99%

Effect of glutamate and riluzole on manganese-induced apoptotic cell signaling in neuronally differentiated mouse P19 Cells

Roth

Sridhar

Singleton

2012

Neurochemistry International

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Excess exposure to Mn causes a neurological disorder known as manganism which is similar to dystonic movements associated with Parkinson’s disease. Manganism is largely restricted to occupations in which high atmospheric levels are prevalent which include Mn miners, welders and those employed in the ferroalloy processing or related industrial settings. T1 weighted MRI images reveal that Mn is deposited to the greatest extent in the globus pallidus, an area of the brain that is presumed to be responsible for the major CNS associated symptoms. Neurons within the globus pallidus receive glutamatergic input from the subthalamic nuclei which has been suggested to be involved in the toxic actions of Mn. The neurotoxic actions of Mn and glutamate are similar in that they both affect calcium accumulation in the mitochondria leading to apoptotic cell death. In this paper we demonstrate that the combination of Mn and glutamate potentiates toxicity of neuronally differentiated P19 cells over that observed with either agent alone. Apoptotic signals ROS, caspase 3 and JNK were increased in an additive fashion when the two neurotoxins were combined. The anti-glutamatergic drug, riluzole, was shown to attenuate these apoptotic signals and prevent P19 cell death. Results of this study confirm, for the first time, that Mn toxicity is potentiated in the presence of glutamate and that riluzole is an effective antioxidant which protects against both Mn and glutamate toxicity.

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“…Rare in Nature [1,2,3,4], azaindoles are interesting in terms of drug optimization strategies. Modification of Lipinski’s rule of five, solubility, pK A and lipophilicity, target binding and ADME-tox properties can be modulated and finely tuned using the azaindole core instead of other bicyclic fused heterocycles [5,6,7,8,9,10,11,12,13,14]. Azaindoles have been recognized as privileged structures in biological process modulation, in medicinal chemistry and drug discovery programs [15,16,17,18,19,20].…”

Section: Introductionmentioning

confidence: 99%

The Azaindole Framework in the Design of Kinase Inhibitors

et al. 2014

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This review article illustrates the growing use of azaindole derivatives as kinase inhibitors and their contribution to drug discovery and innovation. The different protein kinases which have served as targets and the known molecules which have emerged from medicinal chemistry and Fragment-Based Drug Discovery (FBDD) programs are presented. The various synthetic routes used to access these compounds and the chemical pathways leading to their synthesis are also discussed. An analysis of their mode of binding based on X-ray crystallography data gives structural insights for the design of more potent and selective inhibitors.

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Cited by 23 publications

References 54 publications

NgR1 Expressed in P19 Embryonal Carcinoma Cells Differentiated by Retinoic Acid Can Activate STAT3

NgR1 Expressed in P19 Embryonal Carcinoma Cells Differentiated by Retinoic Acid Can Activate STAT3

Effect of glutamate and riluzole on manganese-induced apoptotic cell signaling in neuronally differentiated mouse P19 Cells

The Azaindole Framework in the Design of Kinase Inhibitors

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