Recovery of Postischemic Brain Metabolism and Function Following Treatment with a Free Radical Scavenger and Platelet‐Activating Factor Antagonists

Gilboe, David D.; Kintner, Douglas B.; Fitzpatrick, J.; Emoto, Sherrie E.; Esanu, André; Braquet, P.; Bazán, Nicolás G.

doi:10.1111/j.1471-4159.1991.tb02597.x

Cited by 83 publications

(30 citation statements)

References 26 publications

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“…Therefore, PAF is a neuronal injury mediator, and consequently, PAF antagonists elicit neuroprotection (23,24). Both PAF (25)(26)(27) and glutamate (28 -30) activate MAP kinases.…”

Section: Resultsmentioning

confidence: 99%

“…In brain ischemia and seizures, there is also PAF accumulation (19,20), which in turn, contributes to increased glutamate release (5) and COX-2 transcription (21,22), both enhancing brain injury. Therefore, PAF is a neuronal injury mediator, and consequently, PAF antagonists elicit neuroprotection (23,24). Both PAF (25)(26)(27) and glutamate (28 -30) activate MAP kinases.…”

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confidence: 99%

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Glutamate Receptor Signaling Interplay Modulates Stress-sensitive Mitogen-activated Protein Kinases and Neuronal Cell Death

Mukherjee

DeCoster

Campbell

et al. 1999

Journal of Biological Chemistry

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Glutamate receptors modulate multiple signaling pathways, several of which involve mitogen-activated protein (MAP) kinases, with subsequent physiological or pathological consequences. Here we report that stimulation of the N-methyl-D-aspartate (NMDA) receptor, using platelet-activating factor (PAF) as a messenger, activates MAP kinases, including c-Jun NH 2 -terminal kinase, p38, and extracellular signal-regulated kinase, in primary cultures of hippocampal neurons. Activation of the metabotropic glutamate receptor (mGluR) blocks this NMDA-signaling through PAF and MAP kinases, and the resultant cell death. Recombinant PAF-acetylhydrolase degrades PAF generated by NMDA-receptor activation; the hetrazepine BN50730 (an intracellular PAF receptor antagonist) also inhibits both NMDA-stimulated MAP kinases and neuronal cell death. The finding that the NMDA receptor-PAF-MAP kinase signaling pathway is attenuated by mGluR activation highlights the exquisite interplay between glutamate receptors in the decision making process between neuronal survival and death.Glutamate receptors participate in neural development, plasticity, learning, memory, and pathology, (e.g. excitotoxicity and neurodegenerative diseases.) Overactivation of the glutamate ionotropic receptors leads to excitotoxic cell death. NMDA 1 receptor antagonism results in prominent neuroprotection in vivo and in vitro. The signals generated by these receptors activate the stress-sensitive MAP kinases JNK and p38 that are implicated in neuronal apoptosis (1). A role for JNK in the excitotoxic death of hippocampal neurons in vivo has been recently illustrated using JNK3 Ϫ/Ϫ mice (2). However, the specific messengers and potential antagonist drugs involved in these signaling pathways are not understood. The bioactive phospholipid, platelet-activating factor (PAF), is a candidate mediator of excitatory amino acid signaling because it is a retrograde messenger of long-term potentiation (LTP) (3, 4) that enhances glutamate release (5), is generated by NMDA receptor activation (6), and participates in memory formation (7-9). PAF is synthetized through several pathways (10). The PAF precursor is enriched in arachidonate at the C 2 position. The Ca 2ϩ -dependent PAF remodeling pathway engages a phospholipase A 2 , followed by acetylation to give rise to PAF (11). Neuronal stimulation, such as at the onset of seizures or from ischemia, promotes the rapid release of arachidonic acid (12, 13), reflecting synaptic phospholipase A 2 activation (14, 15). The cytosolic form of phospholipase A 2 is important in postischemic neuronal cell death as is shown using knockout cPLA 2 mice (16). Also, a secretory PLA 2 may contribute to excitotoxicity (17, 18). Again, the signaling events are not clear. In brain ischemia and seizures, there is also PAF accumulation (19,20), which in turn, contributes to increased glutamate release (5) and COX-2 transcription (21, 22), both enhancing brain injury. Therefore, PAF is a neuronal injury mediator, and consequently, PAF antagonists elicit n...

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“…Therefore, PAF is a neuronal injury mediator, and consequently, PAF antagonists elicit neuroprotection (23,24). Both PAF (25)(26)(27) and glutamate (28 -30) activate MAP kinases.…”

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

Glutamate Receptor Signaling Interplay Modulates Stress-sensitive Mitogen-activated Protein Kinases and Neuronal Cell Death

Mukherjee

DeCoster

Campbell

et al. 1999

Journal of Biological Chemistry

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“…Following arterial occlusion in brain, production of reactive oxygen species (ROS) is increased in ischemic areas during early reperfusion (Chan 1996;Piantadosi and Zhang 1996;Kuroda and Siesjo 1997). Exposure to elevated ROS levels results in oxidation of mitochondrial lipids, sulfhydryl groups and iron sulfur complexes of mitochondrial respiratory enzymes (Wagner et al 1990;Gilboe et al 1991;Nakahara et al 1992;Liu et al 1993) leading to impairment of mitochondrial oxidative phosphorylation. Different isoforms of nitric oxide synthase are activated during cerebral ischemia (Endoh et al 1994;Nakashima et al 1995;Bolanos et al 1997;Wiencken and Casagrande 1999) leading to excessive production of nitric oxide (NO).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of mitochondrial function in astrocytes: implications for neuroprotection

Voloboueva¹,

Suh²,

Swanson³

et al. 2007

J Neurochem

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Much evidence suggests that astrocytes protect neurons against ischemic injury. Although astrocytes are more resistant to some insults than neurons, few studies offer insight into the real time changes of astrocytic protective functions with stress. Mitochondria are one of the primary targets of ischemic injury in astrocytes. We investigated the time course of changes in astrocytic ATP levels, plasma membrane potential, and glutamate uptake, a key protective function, induced by mitochondrial inhibition. Our results show that significant functional change precedes reduction in astrocytic viability with mitochondrial inhibition. Using the mitochondrial inhibitor fluorocitrate (FC, 0.25 mM) that is preferentially taken by astrocytes we found that inhibition of astrocyte mitochondria increased vulnerability of co-cultured neurons to glutamate toxicity. In our studies the rates of FC-induced astrocytic mitochondrial depolarization were accelerated in mixed astrocyte/neuron cultures. We hypothesized that the more rapid mitochondrial depolarization was promoted by an additional energetic demand imposed be the co-cultured neurons. To test this hypothesis we exposed pure astrocytic cultures to 0.01 -1 mM aspartate as a metabolic load. Aspartate application accelerated the rates of FC-induced mitochondrial depolarization, and, at 1 mM, induced astrocytic death, suggesting that strong energetic demands during ischemia can compromise astrocytic function and viability.

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“…Many of these actions have been studied in nonneural cells and are assumed to occur in the nervous system as well. Therefore, excessive PAF promotes neuronal damage, and PAFreceptor antagonists elicit neuroprotection in various models of neural injury (120,(133)(134)(135)(136)(137).…”

Section: Paf-mediated Cell Signal Transduction In the Nervous Systemmentioning

confidence: 99%

Synaptic lipid signaling

Bazán

2003

Journal of Lipid Research

230

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Neuronal cellular and intracellular membranes are rich in specialized phospholipids that are reservoirs of lipid messengers released by specific phospholipases and stimulated by neurotransmitters, neurotrophic factors, cytokines, membrane depolarization, ion channel activation, etc. Secretory phospholipases A 2 may be both intercellular messengers and generators of lipid messengers. The highly networked nervous system includes cells (e.g., astrocytes, oligodendrocytes, microglial cells, endothelial microvascular cells) that extensively interact with neurons; several lipid messengers participate in these interactions. This review highlights modulation of postsynaptic membrane excitability and long-term synaptic plasticity by cyclooxygenase-2-generated prostaglandin E2, arachidonoyldiacylcylglycerol, and arachidonic acid-containing endocannabinoids. The peroxidation of docosahexaenoic acid (DHA), a critical component of excitable membranes in brain and retina, is promoted by oxidative stress. DHA is also the precursor of enzyme-derived, neuroprotective docosanoids. The phospholipid platelet-activating factor is a retrograde messenger of long-term potentiation, a modulator of glutamate release, and an upregulator of memory formation. Lipid messengers modulate signaling cascades and contribute to cellular differentiation, function, protection, and repair in the nervous system. Lipidomic neurobiology will advance our knowledge of the brain, spinal cord, retina, and peripheral nerve function and diseases that affect them, and new discoveries on networks of signaling in health and disease will likely lead to novel therapeutic interventions. -Bazan, N. G. Synaptic lipid signaling: significance of polyunsaturated fatty acids and platelet-activating factor. J. Lipid Res.

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Recovery of Postischemic Brain Metabolism and Function Following Treatment with a Free Radical Scavenger and Platelet‐Activating Factor Antagonists

Cited by 83 publications

References 26 publications

Glutamate Receptor Signaling Interplay Modulates Stress-sensitive Mitogen-activated Protein Kinases and Neuronal Cell Death

Glutamate Receptor Signaling Interplay Modulates Stress-sensitive Mitogen-activated Protein Kinases and Neuronal Cell Death

Inhibition of mitochondrial function in astrocytes: implications for neuroprotection

Synaptic lipid signaling

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