Apoptosis in Focal Cerebral Ischemia

Chopp, Michael; Li, Y.

doi:10.1007/978-3-7091-9465-2_4

Cited by 59 publications

(69 citation statements)

References 34 publications

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“…Consistent with the notion that apoptosis is a gene-directed self-destruction program, alterations in gene expression are associated with apoptosis (for review, see Bredesen, 1995). Recent studies suggest that apoptosis contributes to neuronal cell death after cerebral ischemia (Nitatori et al, 1995;Chopp and Li, 1996;Du et al, 1996), in Alzheimer's disease (Cotman and Anderson, 1995;Lassmann et al, 1995;Anderson et al, 1996), and in Huntington's disease (Portera-Cailliau et al, 1995).…”

mentioning

confidence: 83%

Mechanisms of Cell Death Induced by the Mitochondrial Toxin 3-Nitropropionic Acid: Acute Excitotoxic Necrosis and Delayed Apoptosis

1997

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Impaired energy metabolism may play an important role in neuronal cell death after brain ischemia and in late-onset neurodegenerative diseases. Both excitotoxic necrosis and apoptosis have been implicated in cell death induced by metabolic impairment. However, the factors that determine whether cells undergo apoptosis or necrosis are not known. In the present study, metabolic impairment was induced by 3-nitropropionic acid (3-NP), a suicide inhibitor of succinate dehydrogenase. Treatment of cultured rat hippocampal neurons with 3-NP resulted in two types of cell death with distinct morphological, pharmacological, and biochemical features. A rapid necrotic cell death, characterized by cell swelling and nuclear shrinkage, could be completely prevented by the NMDA receptor antagonist MK-801 (10 M) and dose-dependently potentiated by low micromolar levels of extracellular glutamate. A slowly evolving apoptotic death, characterized by nuclear fragmentation, was not attenuated by MK-801 but was prevented by cycloheximide (1 g/ml). The combination of MK-801 and cycloheximide resulted in an almost complete protection against 3-NP-induced cell death. DNA fragmentation, detected by the terminal deoxynucleotidyl transferase-mediated dUTP-X 3Ј nick end-labeling technique, was a late event in apoptosis and also occurred after necrotic cell death. ATP depletion was an early event in the 3-NP-induced neuronal degeneration, and the decline in ATP was exacerbated by glutamate. We conclude that 3-NP triggers two separate cell death pathways: an excitotoxic necrosis as a result of NMDA receptor activation and a delayed apoptosis that is NMDA receptor-independent. Mildly elevated levels of extracellular glutamate shift the cell death mechanism from apoptosis to necrosis.Key words: energy metabolism; succinate dehydrogenase; 3-nitropropionic acid; excitotoxicity; apoptosis; necrosis; nuclear fragmentation; TUNEL; ATP Neuronal function and survival depend on a continuous supply of glucose and oxygen, used to generate ATP through glycolysis and mitochondrial respiration. A perturbation in energy metabolism during conditions such as ischemia, stroke, and brain trauma may cause irreversible neuronal injury. An age-related decline in energy metabolism also may contribute to neuronal loss during normal aging, as well as in neurodegenerative diseases (Wallace, 1994;Beal, 1995).There are discrepancies in the findings regarding the mechanisms of neuronal cell death after metabolic impairment. A large body of evidence supports the "secondary excitotoxicity" hypothesis that a loss of ATP leads to membrane depolarization, removal of the voltage-dependent Mg 2ϩ block of the NMDA receptor, and subsequent activation of NMDA receptor (for review, see Beal, 1992). Both in vivo and in vitro studies have shown that metabolic inhibitors potentiate glutamate and NMDA toxicity (Weller and

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confidence: 83%

Mechanisms of Cell Death Induced by the Mitochondrial Toxin 3-Nitropropionic Acid: Acute Excitotoxic Necrosis and Delayed Apoptosis

1997

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“…The presence of apoptotic cell death was determined by morphology, TUNEL staining and DNA laddering on agarose gel electrophoresis. Whether cell death occurs by necrosis or apoptosis, is now widely believed to depend on the intensity of the insult (Bonfoco et al, 1995;Cheung et al, 1998b;Chopp et al, 1996;Dirnagl et al, 1999;Leist et al, 1998). Mild insults induce apoptosis, whereas more severe insults induce necrotic cell death.…”

Section: A B C D E Fmentioning

confidence: 99%

“…In cerebral ischaemia, neurons at the core of the occlusion, where blood¯ow is severely reduced, are thought to die rapidly and mainly by necrosis, whereas neurons in the surrounding penumbra, where blood¯ow is less severely reduced, die by apoptosis (Dirnagl et al, 1999). Many investigators have localized apoptotic neurons to the border of the ischaemic lesion where energy depletion and excitotoxic stimulation are less severe and prolonged (Chopp et al, 1996;Du et al, 1996;Guegan et al, 1998;Linnik et al, 1995). The ability of AM-36 to inhibit apoptosis due to persistent Na + channel opening may contribute to the potent neuroprotection found in vivo in a rat model of cerebral ischaemia .…”

Section: A B C D E Fmentioning

confidence: 99%

“…Both Na + channel antagonists and free radical scavengers individually have been shown to reduce neuronal damage after cerebral ischaemia in experimental animals Rataud et al, 1994;Smith et al, 1996;Takamatsu et al, 1998;Umemura et al, 1994;Zhao et al, 1994). The importance of the role of free radicals is exempli®ed by the fact that even delayed treatment with antioxidants can be e ective in reducing neuronal damage of the ischaemic lesion and the ensuing neuronal death involve apoptotic mechanisms (Chopp et al, 1996;Du et al, 1996;Guegan et al, 1998;Linnik et al, 1995). ROS have been suggested to play a central role in the induction of apoptosis following exposure to a range of cytotoxic insults (Dirnagl et al, 1999;Jabs, 1999;Leist et al, 1998;Stoian et al, 1996).…”

Section: Introductionmentioning

confidence: 99%

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Incorporation of sodium channel blocking and free radical scavenging activities into a single drug, AM‐36, results in profound inhibition of neuronal apoptosis

Callaway¹,

Beart²,

Jarrott³

et al. 2001

British J Pharmacology

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1 AM-36 is a novel neuroprotective agent incorporating both antioxidant and Na + channel blocking actions. In cerebral ischaemia, loss of cellular ion homeostasis due to Na + channel activation, together with increased reactive oxygen species (ROS) production, are thought to contribute to neuronal death. Since neuronal death in the penumbra of the ischaemic lesion is suggested to occur by apoptosis, we investigated the ability of AM-36, antioxidants and Na + channel antagonists to inhibit toxicity induced by the neurotoxin, veratridine in cultured cerebellar granule cells (CGC's). 2 Veratridine (10 ± 300 mM) concentration-dependently reduced cell viability of cultured CGC's. Under the experimental conditions employed, cell death induced by veratridine (100 mM) possessed the characteristics of apoptosis as assessed by morphology, TUNEL staining and DNA laddering on agarose gels. 3 Neurotoxicity and apoptosis induced by veratridine (100 mM) were inhibited to a maximum of 50% by the antioxidants, U74500A (0.1 ± 10 mM) and U83836E (0.03 ± 10 mM), and to a maximum of 30% by the Na + channel blocker, dibucaine (0.1 ± 100 mM). In contrast, AM-36 (0.01 ± 10 mM) completely inhibited veratridine-induced toxicity ( IC 50 1.7 (1.5 ± 1.9) mM, 95% con®dence intervals (CI) in parentheses) and concentration-dependently inhibited apoptosis. 4 These ®ndings suggest veratridine-induced toxicity and apoptosis are partially mediated by generation of ROS. AM-36, which combines both Na + channel blocking and antioxidant activity, provided superior neuroprotection compared with agents possessing only one of these actions. This bifunctional pro®le of activity may underlie the potent neuroprotective e ects of AM-36 recently found in a stroke model in conscious rats.

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“…12,13 These stresses induce an intracellular molecular cascade that ultimately results in self-destruction of tissue. Apoptosis is responsible for the long-term loss of neuronal tissue after cerebral ischemia, 14 but its potential role in cerebral injury induced by HCA and CPB at different Hct levels has not been established. We therefore hypothesized that low Hct levels worsen cerebral injury after prolonged hypothermic circulatory arrest in rats, which possibly involves variable expression of the genes C-Fos, Bcl-2 and Bax.…”

mentioning

confidence: 99%

Un niveau réduit d’hématocrite aggrave les lésions cérébrales après un arrêt circulatoire hypothermique prolongé chez le rat

Wang

Zheng

et al. 2006

Can J Anesth/J Can Anesth

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Purpose: This study tests the hypothesis that low hematocrit (Hct) worsens cerebral injury after prolonged hypothermic circulatory arrest (HCA) in rats, and the mechanism involves variable expression of the genes C-Fos, Bcl-2 and Bax.Methods: A rat HCA model was developed, and 40 animals were randomly assigned to four groups: Sham (sham) group, or Hct groups of Hct 10%, Hct 20% and Hct 30%. After 90 min of HCA at 18°C, physiologic variables were recorded and brain morphological changes were evaluated with light and electron microscopy. Expressions of C-Fos, Bcl-2, Bax in various brain areas were measured by the reverse transcriptase polymerase chain reaction and standard immunohistochemistry techniques. Results:The number of injured neurons in the hippocampus CA1 and parietal cortex in the Hct 10% group (CA1: 11.44 ± 2.52; cortex: 13.65 ± 2.31) exceeded the mean number of injured neurons in the Hct 20% group (CA1: 8.29 ± 1.31; cortex: 10.68 ± 1.24; P < 0.05) and the Hct 30% group. Mean mitochondrial injury scores were greatest at lower Hct levels, while the expression of C-Fos and Bax were highest in the Hct 10% group and lowest in the Hct30% group (P < 0.05). In contrast, the expression of the Bcl-2 mRNA was greatest in the Hct 30% group (P < 0.05). Conclusion:Low Hct worsens cerebral injury after prolonged HCA and CPB in rats, which may relate in part to the variable expression of the genes C-Fos, Bcl-2 and Bax. Hct 10 % (CA1: 11,44 ± 2,52; cortex: 13,65 ± 2,31) que dans le groupe Hct 20 % (CA1 : 8,29 ± 1,31 ; cortex : 10,68 ± 1,24 ; P < 0,05) Méthode : Un modèle d'ACH a été développé chez le rat et on a réparti de façon aléatoire 40 animaux dans quatre groupes : un groupe sans intervention et des groupes Hct de 10 %, 20 % et 30 %. Après un ACH pendant 90 min à 18°C, on a mesuré les variables physiologiques et on a évalué les changements morphologiques dans le cerveau avec la microscopie optique et électronique. On a mesuré l'expression de C-Fos, Bcl-2 et Bax dans différentes régions du cerveau par la réaction en chaîne transcriptase inverse -polymérase et par des techniques habituelles d'immunohistochimie. Résultats : Les neurones CA1 de l'hippocampe et du cortex pariétal ont été atteints en plus grand nombre dans le groupe

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Apoptosis in Focal Cerebral Ischemia

Cited by 59 publications

References 34 publications

Mechanisms of Cell Death Induced by the Mitochondrial Toxin 3-Nitropropionic Acid: Acute Excitotoxic Necrosis and Delayed Apoptosis

Mechanisms of Cell Death Induced by the Mitochondrial Toxin 3-Nitropropionic Acid: Acute Excitotoxic Necrosis and Delayed Apoptosis

Incorporation of sodium channel blocking and free radical scavenging activities into a single drug, AM‐36, results in profound inhibition of neuronal apoptosis

Un niveau réduit d’hématocrite aggrave les lésions cérébrales après un arrêt circulatoire hypothermique prolongé chez le rat

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