Differences in DNA Fragmentation following Transient Cerebral or Decapitation Ischemia in Rats

MacManus, J. P.; Hill, Irene E.; Preston, Edward; Rasquinha, Ingrid; Walker, Teena; Buchan, Alastair

doi:10.1038/jcbfm.1995.93

Cited by 113 publications

(52 citation statements)

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“…These have been in both global (Fer rer et al, 1994;Heron et al, 1993;Iwai et al, 1995;Nitatori et al, 1995;Okamoto et al, 1993;Tortosa et al, 1994) and focal (Li et al, 1995a-c; Linnik et al, 1993 andTominaga et al, 1993;Sei et al, 1994) models of transient brain hemostasis. Some of this evidence came from this laboratory, where we concluded that a component of the apoptotic degra dative machinery is at work in the ischemic neurons (Hill et al, 1995;MacManus 1993MacManus , 1994MacManus , 1995a. In general, an absence of the morphological hallmark in ischemic brain has precluded wide acceptance of an apoptotic mode of cell death being operative fol lowing ischemia (Deshpande et al, 1992).…”

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confidence: 99%

“…Since our own studies showed that apoptotic laddered DNA appeared in brain following transient ischemia (Hill et al, 1995;MacManus et al, 1993MacManus et al, , 1994MacManus et al, , 1995a, we undertook to detect higher-order chromatin fragments. While these studies were in progress [described in abstract form in MacManus et al (1995b)], a report appeared describing the appearance of 300-kbp fragments of DNA following ischemia produced by middle cerebral artery occlu sion, with evidence of subsequent breakdown to smaller pieces (Charriaut-Marlangue et al, 1995).…”

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confidence: 99%

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Detection of Higher-Order 50- and 10-kbp DNA Fragments before Apoptotic Internucleosomal Cleavage after Transient Cerebral Ischemia

MacManus

Rasquinha

Tuor

et al. 1997

J Cereb Blood Flow Metab

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Summary: DNA fragments of SO and 10 kbp were found in ischemic brain in adult rats following two-vessel occlu sion or in neonates following hypoxia-ischemia. These higher-order fragments were detected before any laddered oligonucleosomal DNA fragmentation characteristic of apoptosis. Both the SO-and 10-kbp fragments were also detected during necrosis produced by decapitation, but these led to smeared smaller fragments, not laddered pat terns. End-group analysis showed the presence of both 3' OH and S;-OH ends in both the SO-and lO-kbp fragments

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confidence: 99%

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confidence: 99%

Detection of Higher-Order 50- and 10-kbp DNA Fragments before Apoptotic Internucleosomal Cleavage after Transient Cerebral Ischemia

MacManus

Rasquinha

Tuor

et al. 1997

J Cereb Blood Flow Metab

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“…T he mechanism by which stroke-induced neuronal death occurs is complex and is likely dependent upon the severity and duration of ischemic insult and an elaborate interplay between ischemic death initiators such as excitotoxicity, oxidative stress, DNA damage, and inflammatory responses (1)(2)(3). Neurons that survive the acute ischemic injury undergo a delayed cell death that exhibits some characteristics of apoptosis (1)(2)(3).…”

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“…Neurons that survive the acute ischemic injury undergo a delayed cell death that exhibits some characteristics of apoptosis (1)(2)(3). This delayed cell death is dependent upon selected death-signaling elements such as caspases, poly(ADP-ribose) polymerase, and p53 (4).…”

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Cyclin-dependent kinases as a therapeutic target for stroke

Osuga

Wang

et al. 2000

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

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Cyclin-dependent kinases (CDKs) are commonly known to regulate cell proliferation. However, previous reports suggest that in cultured postmitotic neurons, activation of CDKs is a signal for death rather than cell division. We determined whether CDK activation occurs in mature adult neurons during focal stroke in vivo and whether this signal was required for neuronal death after reperfusion injury. Cdk4͞cyclin D1 levels and phosphorylation of its substrate retinoblastoma protein (pRb) increase after stroke. Deregulated levels of E2F1, a transcription factor regulated by pRb, are also observed. Administration of a CDK inhibitor blocks pRb phosphorylation and the increase in E2F1 levels and dramatically reduces neuronal death by 80%. These results indicate that CDKs are an important therapeutic target for the treatment of reperfusion injury after ischemia.T he mechanism by which stroke-induced neuronal death occurs is complex and is likely dependent upon the severity and duration of ischemic insult and an elaborate interplay between ischemic death initiators such as excitotoxicity, oxidative stress, DNA damage, and inflammatory responses (1-3). Neurons that survive the acute ischemic injury undergo a delayed cell death that exhibits some characteristics of apoptosis (1-3). This delayed cell death is dependent upon selected death-signaling elements such as caspases, poly(ADP-ribose) polymerase, and p53 (4). The identification of signaling molecules that control delayed neuronal death has led to the hope that some of these death-signaling elements may serve as useful therapeutic targets for the reduction of neuropathology and behavioral deficits associated with stroke injury. The mechanism by which stroke-evoked delayed death occurs, however, is not fully understood.The cell cycle is a highly coordinated process regulated by the appropriate and timely activation of cyclin-dependent kinases (CDKs) (5). Regulation of CDKs is complex and includes binding to their obligate cyclin partner, activating and inhibitory phosphorylation events, and endogenous inhibitors of CDK activity. Distinct CDKs regulate progressive phases of the cell cycle. Generally, it is thought that the Cdk4͞6͞cyclin D1 complex regulates the G 0 to G 1 , Cdk2͞cyclin E and Cdk3 control G 1 to S, and Cdk2͞cyclin A and Cdk1͞cyclin B control G 2 and M progressions. Although the downstream targets of CDKs are not fully characterized, one important substrate is the tumor suppresser retinoblastoma protein (pRb), which is phosphorylated by activated Cdk4͞6͞cyclin D complex (6). Once hyperphosphorylated, pRb is released from the transcription factor complex E2F͞DP, which then activates genes required for S phase transition (7-9).Paradoxically, increasing evidence suggests that CDKs may have functions beyond that of cell cycle regulation. Numerous reports indicate the requirement of CDK signals for death of cultured postmitotic neurons exposed to select death insults. For example, inappropriate cyclin B and cyclin D1 transcripts have been observed in neuronal P...

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“…Apoptosis has been detected in the brains of several mammalian species, including human infants, after HI (Linnik et al, 1993;MacManus et al, 1993MacManus et al, , 1995Mehmet et al, 1994;Li et al, 1995;Beilharz et al, 1995;ChariautMarlangue et al, 1995;Edwards et al, 1997;Yue et al, 1996). Recent in vitro data have stressed the role of energy metabolism and the mitochondria in controlling apoptosis (Liu et al, 1996;Yang et al, 1997), but suggested that apoptosis results from a mild cellular insult, while severe stress induces necrosis .…”

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confidence: 99%

Relation of impaired energy metabolism to apoptosis and necrosis following transient cerebral hypoxia-ischaemia

et al. 1998

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This study investigated whether both mild and severe hypoxia-ischaemia (HI) caused significant numbers of cells to die by apoptosis in the developing brain in vivo. Newborn piglets were subjected to transient global HI and the fraction of all cells in the cingulate gyrus that were apoptotic or necrotic counted 48 h after resuscitation. The mean (S.D.) proportion of apoptotic cells was 11.9% (6.7%) (sham operated controls 4.1% (2.7%)), while 11.4% (8.4%) were necrotic (controls 0.7% (1.3%)) (P50.05). Apoptotic and necrotic cell counts were both linearly related to the severity of impaired cerebral energy metabolism measured by magnetic resonance spectroscopy (P50.05), as shown by: (1) the decline in the ratio of nucleotide triphosphates to the exchangeable phosphate pool during HI; (2) the fall in the ratio of phosphocreatine to inorganic phosphate 8 ± 48 h after HI; and (3) an increased ratio of lactate to total creatine at both these times. Thus both apoptosis and necrosis occurred in the cingulate gyrus after both severe and mild HI in vivo in proportion to the severity of the insult.

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Differences in DNA Fragmentation following Transient Cerebral or Decapitation Ischemia in Rats

Cited by 113 publications

References 50 publications

Detection of Higher-Order 50- and 10-kbp DNA Fragments before Apoptotic Internucleosomal Cleavage after Transient Cerebral Ischemia

Detection of Higher-Order 50- and 10-kbp DNA Fragments before Apoptotic Internucleosomal Cleavage after Transient Cerebral Ischemia

Cyclin-dependent kinases as a therapeutic target for stroke

Relation of impaired energy metabolism to apoptosis and necrosis following transient cerebral hypoxia-ischaemia

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