Studies of the protein synthesis system in the brain cortex during global ischemia and reperfusion

DeGracia, Donald J.; O’Neil, Brian J.; Frisch, C.; Krause, Gary S.; Skjaerlund, John M.; White, Blaine C.; Grossman, Lawrence I.

doi:10.1016/0300-9572(93)90092-5

Cited by 18 publications

(5 citation statements)

References 31 publications

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“…Polysome profiles, which use sucrose gradient centrifugation to isolate intact polysomes from the post-mitochondrial supernatant, were generated based on the methods of MacManus, et al [30] and DeGracia, et al [31]. All procedures were performed on ice or in a 4°C walk-in cold room.…”

Section: Methodsmentioning

confidence: 99%

HuR Function and Translational State Analysis Following Global Brain Ischemia and Reperfusion

Szymanski

Wang

Jamison

et al. 2013

Transl. Stroke Res.

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Prolonged translation arrest in post-ischemic hippocampal CA1 pyramidal neurons precludes translation of induced stress genes and directly correlates with cell death. We evaluated regulation of mRNAs containing adenine and uridine rich elements (ARE) by assessing HuR protein and hsp70 mRNA nuclear translocation, HuR polysome binding, and translation state analysis of CA1 and CA3 at 8 hr reperfusion after 10 min global cerebral ischemia. There was no difference between CA1 and CA3 at 8 hr of reperfusion in nuclear or cytoplasmic HuR protein or hsp70 mRNA, or HuR polysome association, suggesting neither mechanism contributed to post-ischemic outcome. Translation state analysis revealed that 28% and 58% of unique mRNAs significantly different between 8hR and NIC, in CA3 and CA1, respectively, were not polysome-bound. There was significantly greater diversity of polysome-bound mRNAs in reperfused CA3 compared to CA1, and in both regions ARE-containing mRNAs accounted for 4% – 5% of the total. These data indicate that post-transcriptional ARE-containing mRNA regulation occurs in reperfused neurons and contributes to post-ischemic outcome. Understanding the differential responses of vulnerable and resistant neurons to ischemia will contribute to the development of effective neuroprotective therapies.

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Section: Methodsmentioning

confidence: 99%

HuR Function and Translational State Analysis Following Global Brain Ischemia and Reperfusion

Szymanski

Wang

Jamison

et al. 2013

Transl. Stroke Res.

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“…However, the persistent postischemic inhibition of synthesis occurs despite return of energy charge to normal values in slices (936) and of ATP to normal levels in vivo (12). Ribosomes from ischemic tissue seem competent (243) so are unlikely to be the site of damage.…”

Section: Basis For Prolonged Inhibition Of Protein Synthesismentioning

confidence: 99%

Ischemic Cell Death in Brain Neurons

Lipton

1999

Physiological Reviews

2,730

2,085

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This review is directed at understanding how neuronal death occurs in two distinct insults, global ischemia and focal ischemia. These are the two principal rodent models for human disease. Cell death occurs by a necrotic pathway characterized by either ischemic/homogenizing cell change or edematous cell change. Death also occurs via an apoptotic-like pathway that is characterized, minimally, by DNA laddering and a dependence on caspase activity and, optimally, by those properties, additional characteristic protein and phospholipid changes, and morphological attributes of apoptosis. Death may also occur by autophagocytosis. The cell death process has four major stages. The first, the induction stage, includes several changes initiated by ischemia and reperfusion that are very likely to play major roles in cell death. These include inhibition (and subsequent reactivation) of electron transport, decreased ATP, decreased pH, increased cell Ca(2+), release of glutamate, increased arachidonic acid, and also gene activation leading to cytokine synthesis, synthesis of enzymes involved in free radical production, and accumulation of leukocytes. These changes lead to the activation of five damaging events, termed perpetrators. These are the damaging actions of free radicals and their product peroxynitrite, the actions of the Ca(2+)-dependent protease calpain, the activity of phospholipases, the activity of poly-ADPribose polymerase (PARP), and the activation of the apoptotic pathway. The second stage of cell death involves the long-term changes in macromolecules or key metabolites that are caused by the perpetrators. The third stage of cell death involves long-term damaging effects of these macromolecular and metabolite changes, and of some of the induction processes, on critical cell functions and structures that lead to the defined end stages of cell damage. These targeted functions and structures include the plasmalemma, the mitochondria, the cytoskeleton, protein synthesis, and kinase activities. The fourth stage is the progression to the morphological and biochemical end stages of cell death. Of these four stages, the last two are the least well understood. Quite little is known of how the perpetrators affect the structures and functions and whether and how each of these changes contribute to cell death. According to this description, the key step in ischemic cell death is adequate activation of the perpetrators, and thus a major unifying thread of the review is a consideration of how the changes occurring during and after ischemia, including gene activation and synthesis of new proteins, conspire to produce damaging levels of free radicals and peroxynitrite, to activate calpain and other Ca(2+)-driven processes that are damaging, and to initiate the apoptotic process. Although it is not fully established for all cases, the major driving force for the necrotic cell death process, and very possibly the other processes, appears to be the generation of free radicals and peroxynitrite. Effects of a large number of damagin...

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“…However, it is not at all apparent that there is a requirement for an increased amount of ribosomes at later reperfusion. For example, we have shown that there is no evidence of oxidative damage to ribosomes at 8 hr of reperfusion (Krause et al, 1992) and that ribosomes isolated from 8‐hr‐reperfused cortex, when given cofactors from controls, are competent at in vitro protein synthesis (DeGracia et al, 1993). In fact, to our knowledge, no measurement of the phosphorylation level of ribosomal protein S6 itself has been made in reperfused brain, making the functional significance of changes in S6 kinase activity unclear.…”

Section: Other Regulators Of Protein Synthesis Following Cerebral I/rmentioning

confidence: 99%

Acute and persistent protein synthesis inhibition following cerebral reperfusion

DeGracia

2004

J of Neuroscience Research

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Lack of recovery from protein synthesis inhibition (PSI) closely correlates with neuronal death following brain ischemia and reperfusion. It has therefore been suggested that understanding the mechanisms of PSI will shed light on the mechanisms of selective neuronal death following ischemia and reperfusion. It is now known that the PKR-like ER kinase (PERK)-mediated phosphorylation of eukaryotic initiation factor 2alpha (eIF2alpha) causes translation inhibition at initial reperfusion. Activation of PERK, in turn, indicates endoplasmic reticulum stress and activation of the unfolded protein response. However, phosphorylation of eIF2alpha is a transient event and can account for PSI only in the initial hours of reperfusion. Although a number of other regulators of protein synthesis, such as eIF4F, 4EBP-1, eEF-2, and S6 kinase, have been assessed following cerebral ischemia and reperfusion, the causes of prolonged PSI have yet to be fully elucidated. The purpose of the present article is to bring together the evidence indicating that, at minimum, postischemic PSI should be conceptualized as consisting of two components: an acute, transient component mediated by unfolded protein response-induced eIF2alpha phosphorylation and a longer term component that correlates with neuronal death. Ischemic tolerance appears to separate the acute and persistent components of reperfusion-induced translation inhibition. Specific models of the relationship among acute PSI, persistent PSI, and neuronal death are presented to clarify issues that have emerged from ongoing work in this area.

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Studies of the protein synthesis system in the brain cortex during global ischemia and reperfusion

Cited by 18 publications

References 31 publications

HuR Function and Translational State Analysis Following Global Brain Ischemia and Reperfusion

HuR Function and Translational State Analysis Following Global Brain Ischemia and Reperfusion

Ischemic Cell Death in Brain Neurons

Acute and persistent protein synthesis inhibition following cerebral reperfusion

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