Glutamate becomes neurotoxic via the N-methyl-d-aspartate receptor when intracellular energy levels are reduced

Novelli, Antonello; Reilly, J.; Lysko, Paul G.; Henneberry, Richard C.

doi:10.1016/0006-8993(88)90765-2

Cited by 954 publications

(410 citation statements)

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“…The reported decrease in glucose uptake mediated by stress or by high levels of GCs could place neurons in an energy-compromised environment, which could detrimentally affect neuronal responsiveness to pathophysiological events. In fact, glucose transport impairment precedes ATP depletion in brain, increasing neuronal vulnerability to excitotoxicity by compromising function of ion-motive ATPases (Mark et al, 1995), as it has been seen to occur in some neurodegenerative processes such Ab-induced toxicity, schizophrenia and others (Novelli et al, 1988;Kalaria and Harik, 1989;Sims, 1990;Mark et al, 1997;McDermott and De Silva, 2005) in which the reduction in glucose uptake occurs as an early step in the disease process prior to neuronal degeneration (Pettegrew et al, 1994;Reiman et al, 1996). On the other hand, GCs promote reduction in ATP levels (Tombaugh and Sapolsky, 1992;Lawrence and Sapolsky, 1994).…”

Section: Discussionmentioning

confidence: 99%

“…The consequence is an increased vulnerability to excitotoxicity (ie, calcium overload, reduction in the reuptake of glutamate capacity of neurons) (Novelli et al, 1988;Cheng and Mattson, 1992;Joëls and Vreugdenhil, 1998) and less ability to afford the costly task of managing the consequences of an excitotoxic or metabolic insult (Yusim et al, 2000). This impairment in the brain glucose uptake, ATP loss and excitotoxicity has been seen not only after stress or glucocorticoids, but also as an early step before neuronal degeneration takes place, such as in Alzheimer disease (Hoyer et al, 1988).…”

Section: Introductionmentioning

confidence: 99%

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Effects of Peroxisome Proliferator-Activated Receptor Gamma Agonists on Brain Glucose and Glutamate Transporters after Stress in Rats

García‐Bueno

Caso

Perez‐Nievas

et al. 2006

Neuropsychopharmacol

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Repeated stress causes an energy-compromised status in the brain, with a decrease in glucose utilization by the brain cells, which might account for excitotoxicity processes seen in this condition. In fact, brain glucose metabolism mechanisms are impaired in some neurodegenerative disorders, including stress-related neuropsychopathologies. More recently, it has been demonstrated that some synthetic peroxisome proliferator-activated receptor gamma (PPARg) agonists increase glucose utilization in rat cortical slices and astrocytes, as well as inhibit brain oxidative damage after repeated stress, which add support for considering these drugs as potential neuroprotective agents. To assess if stress causes glucose utilization impairment in the brain and to study the mechanisms by which this effect is achieved, young-adult male Wistar rats (control and immobilized for 6 h during 7 or 14 consecutive days, S7, S14) were i.p. injected with the natural ligand 15-deoxy-D-12,14-prostaglandin J 2 (PGJ 2 , 120 mg/kg) or the high-affinity ligand rosiglitazone (RG, 3 mg/kg) at the onset of stress. Repeated immobilization during 1 or 2 weeks produces a decrease in brain cortical synaptosomal glucose uptake, and this effect was prevented by treatment with both natural and synthetic PPARg ligands by restoring protein expression of the neuronal glucose transporter, GLUT-3 in membrane fractions. On the other hand, treatment with PPARg ligands prevents stress-induced ATP loss in rat brain. Finally, repeated immobilization stress also produces a decrease in brain cortical synaptosomal glutamate uptake, and this effect was prevented by treatment with PPARg ligands by restoring synaptosomal protein expression of the glial glutamate transporter, EAAT2. In summary, our results demonstrate that 15d-PGJ 2 and the thiazolidinedione rosiglitazone increase neuronal glucose metabolism, restore brain ATP levels and prevent the impairment in glutamate uptake mechanisms induced by exposure to stress, suggesting that this class of drugs may be therapeutically useful in conditions in which brain glucose levels or availability are limited after exposure to stress.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Effects of Peroxisome Proliferator-Activated Receptor Gamma Agonists on Brain Glucose and Glutamate Transporters after Stress in Rats

García‐Bueno

Caso

Perez‐Nievas

et al. 2006

Neuropsychopharmacol

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“…The compromised energy supply, induced by MPP + could result in a partial membrane depolarisation which in turn would remove the voltage-dependent Mg 2+ block from NMDA receptor ion channels (Nowak et al 1984). This would enable EAAs such as glutamate to become neurotoxic through persistent receptor stimulation (Novelli et al 1988). The compromised energy metabolism and Ca 2+ homeostasis are further factors in the increased vulnerability of these cells.…”

Section: Discussionmentioning

confidence: 99%

The competitive NMDA antagonist CPP protects substantia nigra neurons from MPTP-induced degeneration in primates

Lange

Löschmann²,

Sofić

et al. 1993

Naunyn-Schmiedeberg's Arch Pharmacol

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“…Gangliosides have been found to protect cultured cerebellar granule cells against glutamate-induced toxicity (Favaron et aI., 1988;Manev et aI., 1989Manev et aI., , 1990 by inhibiting translocation and activation of protein kinase C (Vaccarino et aI., 1987;Manev et aI., 1989Manev et aI., , 1990). In addition, Novelli et al (1988) used cultured cerebellar granule cells to show that activation of NMDA receptors becomes neurotoxic when intracellular energy levels are re duced. Cultured cerebellar granule cells degenerate spontaneously within 12-15 days.…”

Section: Discussionmentioning

confidence: 99%

Ubiquinone Protects Cultured Neurons against Spontaneous and Excitotoxin-Induced Degeneration

Favit

Nicoletti

Scapagnini

et al. 1992

J Cereb Blood Flow Metab

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Summary:Ubiquinone is an endogenous quinone with pharmacological actions mainly related to its antioxidant properties. Here we report that ubiquinone protects cul tured cerebellar granule cells against glutamate-induced neurotoxicity. In control cultures at 9 days of maturation in vitro (DIY), a 30-min exposure to 100 fLM glutamate induced neuronal degeneration, as reflected by the great percentage (>90%) of cells labeled with propidium iodide 24 h after the exposure. Glutamate-induced neuronal death was dramatically reduced in cultures treated daily with Ubiquinone since the second DIV. In these cultures, glutamate failed to induce a "delayed" increase in the An excessive activation of glutamate receptors has been implicated in the pathophysiology of neu ronal damage in acute and chronic degenerative dis eases of the central nervous system (CNS) (re viewed in Choi, 1988). The neurotoxic action of glu tamate is mostly mediated by an exaggerated activation of N-methyl-D-aspartate (NMDA) recep tors, which leads to a persistent perturbation of in tracellular Ca2+ homeostasis. The excessive rise in cytosolic free Ca2+ results in a sustained activation of a variety of Ca2 + -dependent enzymes, including neutral proteases, protein kinases, phospholipases, and endonucleases. These enzymes may trigger a cascade of intracellular reactions that are ultimately responsible for neuronal degeneration and death (Vaccarino et ai

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Glutamate becomes neurotoxic via the N-methyl-d-aspartate receptor when intracellular energy levels are reduced

Cited by 954 publications

References 38 publications

Effects of Peroxisome Proliferator-Activated Receptor Gamma Agonists on Brain Glucose and Glutamate Transporters after Stress in Rats

Effects of Peroxisome Proliferator-Activated Receptor Gamma Agonists on Brain Glucose and Glutamate Transporters after Stress in Rats

The competitive NMDA antagonist CPP protects substantia nigra neurons from MPTP-induced degeneration in primates

Ubiquinone Protects Cultured Neurons against Spontaneous and Excitotoxin-Induced Degeneration

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