Changes in Brain Energy Metabolism and Protein Synthesis Following Transient Bilateral Ischemia in the Gerbil

Nowak, Thaddeus S.; Fried, Richard L.; Lust, W. David; Passonneau, Janet V.

doi:10.1111/j.1471-4159.1985.tb05440.x

Cited by 178 publications

(78 citation statements)

References 49 publications

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“…In vivo cerebral TAN or ATP levels recover after brief periods of ischemia (1-5 min) to pre-ischemic values after 60 -90 min reperfusion (Ljunggren et al, 1974;Kobayashi et al, 1977;Nowak et al, 1985). However, there was no significant increase in TAN levels in slices over a 5 h incubation period (Fig.…”

Section: Supplementation Of Acsf With Adenine Nucleotide Precursors Imentioning

confidence: 88%

Intracellular ATP Influences Synaptic Plasticity in Area CA1 of Rat Hippocampus via Metabolism to Adenosine and Activity-Dependent Activation of Adenosine A₁Receptors

Nedden¹,

Hawley²,

Pentland³

et al. 2011

J. Neurosci.

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The extent to which brain slices reflect the energetic status of the in vivo brain has been a subject of debate. We addressed this issue to investigate the recovery of energetic parameters and adenine nucleotides in rat hippocampal slices and the influence this has on synaptic transmission and plasticity. We show that, although adenine nucleotide levels recover appreciably within 10 min of incubation, it takes 3 h for a full recovery of the energy charge (to Ն0.93) and that incubation of brain slices at 34°C results in a significantly higher ATP/AMP ratio and a threefold lower activity of AMP-activated protein kinase compared with slices incubated at room temperature. Supplementation of artificial CSF with D-ribose and adenine (Rib/Ade) increased the total adenine nucleotide pool of brain slices, which, when corrected for the influence of the dead cut edges, closely approached in vivo values. Rib/Ade did not affect basal synaptic transmission or paired-pulse facilitation but did inhibit long-term potentiation (LTP) induced by tetanic or weak theta-burst stimulation. This decrease in LTP was reversed by strong theta-burst stimulation or antagonizing the inhibitory adenosine A 1 receptor suggesting that the elevated tissue ATP levels had resulted in greater activity-dependent adenosine release during LTP induction. This was confirmed by direct measurement of adenosine release with adenosine biosensors. These observations provide new insight into the recovery of adenine nucleotides after slice preparation, the sources of loss of such compounds in brain slices, the means by which to restore them, and the functional consequences of doing so.

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Section: Supplementation Of Acsf With Adenine Nucleotide Precursors Imentioning

confidence: 88%

Intracellular ATP Influences Synaptic Plasticity in Area CA1 of Rat Hippocampus via Metabolism to Adenosine and Activity-Dependent Activation of Adenosine A₁Receptors

Nedden¹,

Hawley²,

Pentland³

et al. 2011

J. Neurosci.

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“…Thus, it is possible that phenytoin exerts its effects on protein synthesis. On the other hand, Nowak et al 30 concluded that the regulation of protein synthesis during recirculation was independent of the GTP/GDP ratio. Further investigations are needed to clarify the relation between the GTP/ GDP ratio and protein synthesis during recirculation.…”

Section: Discussionmentioning

confidence: 99%

Phenytoin affects metabolism of free fatty acids and nucleotides in rat cerebral ischemia.

Kinouchi

Imaizumi

Yoshimoto

et al. 1990

Stroke

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We investigated the effects of phenytoin on the rate of enzymatic release of free fatty acids and on the levels of energy metabolites and nucleoside phosphates in ischemic brain. Phenytoin (10 mg/kg i.v.) was administered 30 minutes before the onset of ischemia induced in 30 male Wistar rats by occluding the basilar and both common carotid arteries. The rats' brains were frozen in situ after 0, 5, or 30 minutes of ischemia or 10, 30, or 60 minutes of recirculation following 30 minutes of ischemia (n=5 at each time). Nucleoside triphosphate levels were higher in the phenytoin-treated rats than in corresponding untreated rats at each time during and after ischemia. Phenytoin significantly attenuated the accumulation of lactate and free fatty acids (arachidonic acid and stearic acid) during ischemia and accelerated their recovery during recirculation. These results suggest that phenytoin has favorable protective effects on ischemic brain and that phenytoin may inhibit calciummediated phenomena, especially the inositol cycle, in cerebral ischemia. (Stroke 1990;21:1326-1332)

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“…Transient Exposure to NMDA Causes Persistent Inhibition of Protein Synthesis and eIF4E Dephosphorylation-We then addressed suppression of translation, another important aspect involved in neuronal death (6,8,10). We found a persistent inhibition of amino acid incorporation into proteins following transient exposure to NMDA, which was prevented by TGF-␣.…”

Section: Tgf-␣ Increases Neuronal Survival After An Excitotoxicmentioning

confidence: 99%

Transforming Growth Factor-α Attenuates N-Methyl-D-aspartic Acid Toxicity in Cortical Cultures by Preventing Protein Synthesis Inhibition through an Erk1/2-dependent Mechanism

Petegnief

Friguls

Sanfeliu

et al. 2003

Journal of Biological Chemistry

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Transforming growth factor-␣ (TGF-␣), a ligand of the epidermal growth factor receptor, reduces the infarct size after focal cerebral ischemia in rat, but the molecular basis underlying the protection is unknown. Excitotoxicity and global inhibition of translation are acknowledged to contribute significantly to the ischemic damage. Here we studied whether TGF-␣ can rescue neurons from excitotoxicity in vitro and how it affects calcium homeostasis, protein synthesis, and the associated Akt and extracellular signal-regulated kinase 1/2 (Erk1/2) intracellular signaling pathways in mixed neuron-glia cortical cultures. We found that 100 ng/ml TGF-␣ attenuated neuronal cell death induced by a 30-min exposure to 35 M N-methyl-D-aspartic acid (NMDA) (as it reduced lactate dehydrogenase release, propidium iodide staining, and caspase-3 activation) and decreased the elevation of intracellular Ca 2؉ elicited by NMDA. TGF-␣ induced a prompt and sustained phosphorylation of Erk1/2 and prevented the loss of Akt-P induced by NMDA 3 h after exposure. The protective effect of TGF-␣ was completely prevented by PD 98059, an inhibitor of the Erk1/2 pathway. Studies of incorporation of [ 3 H]leucine into proteins showed that NMDA decreased the rate of protein synthesis, and TGF-␣ attenuated this effect. TGF-␣ stimulated the phosphorylation of the eukaryotic initiation factor 4E (eIF4E) but did not affect eIF2␣, two proteins involved in translation regulation. PD 98059 abrogated the TGF-␣ effect on eIF4E. Our data demonstrate that TGF-␣ exerts a neuroprotective action against NMDA toxicity, in which Erk1/2 activation plays a key role, and suggest that the underlying mechanisms involve recovery of translation inhibition, mediated at least in part by eIF4E phosphorylation.TGF-␣ 1 is protective in models of permanent and transient focal ischemia induced by occlusion of the middle cerebral artery in the rat (1, 2). Although TGF-␣ is known to promote neuronal survival (3) and to induce proliferation and differentiation of astrocytes in vitro (4), little is known about its effects on neural cells. TGF-␣ binds to the epidermal growth factor receptor (EGFR), which stimulation induces its dimerization, autophosphorylation on tyrosine residues, and triggers a cascade of reactions that requires the contribution of adapter proteins and kinases. EGFR activates several signal transduction pathways, among others are phosphatidylinositol 3-kinase/protein kinase B (PI 3-kinase/Akt) and the p44/p42 mitogen-activated protein kinase, also referred to as extracellular signal-regulated kinases 1/2 (Erk1/2) (5).Among the very early consequences of energy depletion after an ischemic insult to the brain are membrane depolarization that induces excitatory amino acid release and inhibition of global protein synthesis, and both significantly contribute to the development of brain infarct (6 -8). Indeed, glutamate receptor overactivation results in an increase in intracellular calcium and extensive neuronal death by excitotoxicity (9). Likewise, persistent block...

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Changes in Brain Energy Metabolism and Protein Synthesis Following Transient Bilateral Ischemia in the Gerbil

Cited by 178 publications

References 49 publications

Intracellular ATP Influences Synaptic Plasticity in Area CA1 of Rat Hippocampus via Metabolism to Adenosine and Activity-Dependent Activation of Adenosine A₁Receptors

Intracellular ATP Influences Synaptic Plasticity in Area CA1 of Rat Hippocampus via Metabolism to Adenosine and Activity-Dependent Activation of Adenosine A₁Receptors

Phenytoin affects metabolism of free fatty acids and nucleotides in rat cerebral ischemia.

Transforming Growth Factor-α Attenuates N-Methyl-D-aspartic Acid Toxicity in Cortical Cultures by Preventing Protein Synthesis Inhibition through an Erk1/2-dependent Mechanism

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Changes in Brain Energy Metabolism and Protein Synthesis Following Transient Bilateral Ischemia in the Gerbil

Cited by 178 publications

References 49 publications

Intracellular ATP Influences Synaptic Plasticity in Area CA1 of Rat Hippocampus via Metabolism to Adenosine and Activity-Dependent Activation of Adenosine A1Receptors

Intracellular ATP Influences Synaptic Plasticity in Area CA1 of Rat Hippocampus via Metabolism to Adenosine and Activity-Dependent Activation of Adenosine A1Receptors

Phenytoin affects metabolism of free fatty acids and nucleotides in rat cerebral ischemia.

Transforming Growth Factor-α Attenuates N-Methyl-D-aspartic Acid Toxicity in Cortical Cultures by Preventing Protein Synthesis Inhibition through an Erk1/2-dependent Mechanism

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Intracellular ATP Influences Synaptic Plasticity in Area CA1 of Rat Hippocampus via Metabolism to Adenosine and Activity-Dependent Activation of Adenosine A₁Receptors

Intracellular ATP Influences Synaptic Plasticity in Area CA1 of Rat Hippocampus via Metabolism to Adenosine and Activity-Dependent Activation of Adenosine A₁Receptors