Cerebral Protein Synthesis and Ischemia

Bodsch, W.; Takahashi, Kumiko; Barbier, A; Ophoff, B. Grosse; Hossmann, K.‐A.

doi:10.1016/s0079-6123(08)61984-6

Cited by 154 publications

(63 citation statements)

References 29 publications

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“…As an analogy to hippocampal neurons [10], we speculate that an ischemia-induced alteration of GluR2 expression in Deiter's neurons induced cell death. Although further investigations are required to clarify the mechanisms underlying this selective vulnerability and delayed neuronal damage, they may also be related to several other factors such as the degree of cerebral hypoperfusion after reperfusion [11], inhibition of protein synthesis [12], neutrophil infiltration following reperfusion [13], free radical production [14], dysfunction of the mitochondrial shuttle system [15] or apoptosis [16]. …”

Section: Discussionmentioning

confidence: 99%

Delayed neuronal cell death in brainstem after transient brainstem ischemia in gerbils

et al. 2010

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Background Because of the lack of reproducible brainstem ischemia models in rodents, the temporal profile of ischemic lesions in the brainstem after transient brainstem ischemia has not been evaluated intensively. Previously, we produced a reproducible brainstem ischemia model of Mongolian gerbils. Here, we showed the temporal profile of ischemic lesions after transient brainstem ischemia. Results Brainstem ischemia was produced by occlusion of the bilateral vertebral arteries just before their entry into the transverse foramina of the cervical vertebrae of Mongolian gerbils. Animals were subjected to brainstem ischemia for 15 min, and then reperfused for 0 d (just after ischemia), 1 d, 3 d and 7 d (n = 4 in each group). Sham-operated animals (n = 4) were used as control. After deep anesthesia, the gerbils were perfused with fixative for immunohistochemical investigation. Ischemic lesions were detected by immunostaining for microtubule-associated protein 2 (MAP2). Just after 15-min brainstem ischemia, ischemic lesions were detected in the lateral vestibular nucleus and the ventral part of the spinal trigeminal nucleus, and these ischemic lesions disappeared one day after reperfusion in all animals examined. However, 3 days and 7 days after reperfusion, ischemic lesions appeared again and clusters of ionized calcium-binding adapter molecule-1(IBA-1)-positive cells were detected in the same areas in all animals. Conclusion These results suggest that delayed neuronal cell death took place in the brainstem after transient brainstem ischemia in gerbils.

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Section: Discussionmentioning

confidence: 99%

Delayed neuronal cell death in brainstem after transient brainstem ischemia in gerbils

et al. 2010

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“…The consequent reduction in levels of active eIF2-GTP results in impairment of the initiation process of protein synthesis (Hinnebusch, 2000). This stress response has been investigated in detail in various models of transient cerebral ischemia (Kleihues et al, 1975;Cooper et al, 1977;Bodsch et al, 1985;Thilmann et al, 1986;Burda et al, 1994;DeGracia et al, 1996;Althausen et al, 2001;Mengesdorf et al, 2002a). In the following, transient cerebral ischemia will be considered as a pathologic state of considerable clinical relevance to elucidate the possible significance of shutdown of translation for the final outcome of cells exposed to a severe form of stress.…”

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confidence: 99%

“…After transient cerebral ischemia, protein synthesis is severely suppressed in all cells within brain regions where the blood supply has been critically reduced below the threshold necessary to cover the energy demand of cells (Bodsch et al, 1985;Thilmann et al, 1986). This is a common response of cells to the severe form of stress triggered by a breakdown of energy-producing metabolism after interruption of blood supply.…”

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confidence: 99%

Shutdown of Translation: Lethal or Protective? Unfolded Protein Response versus Apoptosis

Paschen

2003

J Cereb Blood Flow Metab

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Summary:Shutdown of translation is a highly conserved response of cells to a severe form of metabolic, thermal, or physical stress. After the metabolic stress induced by transient cerebral ischemia, translational recovery is observed only in cells that withstand the transient interruption of blood supply, implying that restoration of translation critically determines the final outcome. On the other hand, apoptosis is believed to play a role in ischemia-induced cell death. Apoptosis is an active process that is blocked by agents known to suppress protein synthesis. Thus, the question arises whether stress-induced suppression of protein synthesis is protective or toxic for the affected cells. Accepting the notion that endoplasmic reticulum (ER) dysfunction is the mechanism underlying shutdown of translation after transient cerebral ischemia, an attempt may be made to try to solve the protein synthesis paradox by understanding the role of protein synthesis suppression in conditions associated with ER dysfunction. Endoplasmic reticulum dysfunction-induced accumulation of unfolded proteins in the ER lumen is the trigger of two signal transduction pathways: PKRlike ER kinase-induced shutdown of translation to suppress new synthesis of proteins that cannot be correctly folded, and IRE1-induced expression of ER stress genes, a protein synthesis-dependent pathway needed to restore ER functions. Together these comprise the unfolded protein response. They are also induced after transient ischemia, implying a dual effect of protein synthesis suppression, a protective and a pathologic effect during early and prolonged reperfusion.

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“…This finding suggests that transient ischemia induces ER dysfunction (6,7). Ischemia-induced suppression of protein synthesis is reversible in resistant neurons, but is irreversible in vulnerable cells (8,9). The inability of affected neurons to synthesize new proteins has far-reaching consequences, because such neurons cannot react to the severe form of stress elicited by transient ischemia with an up-regulation of the expression of stress genes coding for neuroprotective proteins like HSP70 or Bcl-2.…”

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confidence: 99%

“…ER stress-induced up-regulation of parkin expression is a defensive response as this protein confers protection on cells from toxicity elicited by ER dysfunction (14). To elucidate the mechanisms underlying neuronal cell injury triggered by transient cerebral ischemia, we sought to investigate parkin protein levels in transient focal cerebral ischemia, a pathological process associated with severe suppression of protein synthesis (8,9), ER dysfunction (4), and disturbance of the ubiquitin-proteasomal pathway (15).…”

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confidence: 99%

Down-regulation of parkin protein in transient focal cerebral ischemia: A link between stroke and degenerative disease?

Mengesdorf

Jensen

Mies

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

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Ubiquitylated protein aggregates are characteristic features of neurodegenerative disorders that are also found in acute pathological states of the brain such as stroke. Many of the proteins connected to neurodegenerative diseases play a role in the ubiquitin-proteasomal pathway. Mutation of one of these proteins, the E3 ubiquitin ligase parkin, is the cause of autosomal recessive juvenile Parkinson's disease. Here we show that transient focal cerebral ischemia of 1-h duration induces marked depletion of parkin protein levels, to 60%, 36%, 33%, and 25% of controls after 1, 3, 6, and 24 h of reperfusion, but that ischemia does not cause lower protein levels of E2 ubiquitin-conjugating enzymes Ubc6, Ubc7, or Ubc9. After 3 h of reperfusion, when parkin protein levels were already reduced to <40% of control, ATP levels were almost completely recovered from ischemia and we did not observe DNA fragmentation, suggesting that parkin depletion preceded development of neuronal cell death. Up-regulation of the expression of parkin has been shown to protect cells from injury induced by endoplasmic reticulum (ER) dysfunction, and this form of cellular stress is also triggered by transient cerebral ischemia. However, in contrast to observations in neuroblastoma cells, we saw no upregulation of parkin expression in primary neuronal cell cultures after induction of ER dysfunction. Our data thus suggest that ischemia-induced depletion of parkin protein may contribute to the pathological process resulting in cell injury by increasing the sensitivity of neurons to ER dysfunction and the aggregation of ubiquitylated proteins during the reperfusion period.

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Cerebral Protein Synthesis and Ischemia

Cited by 154 publications

References 29 publications

Delayed neuronal cell death in brainstem after transient brainstem ischemia in gerbils

Delayed neuronal cell death in brainstem after transient brainstem ischemia in gerbils

Shutdown of Translation: Lethal or Protective? Unfolded Protein Response versus Apoptosis

Down-regulation of parkin protein in transient focal cerebral ischemia: A link between stroke and degenerative disease?

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