bcl-2 Prolongs neuronal survival during hypoxia-induced apoptosis

Banasiak, Kenneth; Cronin, Tara; Haddad, Gabriel G.

doi:10.1016/s0169-328x(99)00189-8

Cited by 46 publications

(17 citation statements)

References 37 publications

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“…Other forms of cell death after longer incubation periods were partly inhibited by lack of proper caspase-9 function. In keeping with our data earlier reports described protective effects of Bcl-2 and Bcl-xL against hypoxiainduced apoptosis (Shimizu et al, 1995;Banasiak et al, 1999), and showed that chemical inhibition of caspase-9 protects against hypoxia (Zhu et al, 2000;Alarcon et al, 2001;Malhotra et al, 2001).…”

Section: Discussionsupporting

confidence: 93%

Molecular ordering of hypoxia-induced apoptosis: critical involvement of the mitochondrial death pathway in a FADD/caspase-8 independent manner

et al. 2004

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Section: Discussionsupporting

confidence: 93%

Molecular ordering of hypoxia-induced apoptosis: critical involvement of the mitochondrial death pathway in a FADD/caspase-8 independent manner

et al. 2004

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“…Our finding that TPCK given prior to injury reduces inducible nitric oxide synthase activity [19], another NF-ÎB-dependent activity, is consistent with this pathway. Hypoxic ischemia increases bcl-2, probably acting through hypoxia-inducible factor [26], in a not always successful attempt to prevent damage [32,33]. Overexpression of bcl-2 has been shown to delay or block apoptosis induced by numerous physiological and pathological mechanisms [34].…”

Section: Resultsmentioning

confidence: 99%

“…Overexpression of bcl-2 has been shown to delay or block apoptosis induced by numerous physiological and pathological mechanisms [34]. Usually mechanisms that reduce bcl-2 [35] and raise bax levels are dominant [21], where cells are fated to die an apoptotic death, but this is not always the case [32,33]. bcl-2 can be damaged by oxyradicals, inactivated by binding to proapoptotic bcl-2-like proteins (bax) or split by caspase-3 into a 22-kD apoptosis-promoting fragment.…”

Section: Resultsmentioning

confidence: 99%

Treatment of Hypoxic-Ischemic Brain Injury in Newborn Rats with TPCK 3 h after Hypoxia Decreases Caspase-9 Activation and Improves Neuropathologic Outcome

Feng¹,

LeBlanc²

2003

Dev Neurosci

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N-Tosyl-L-phenylalanyl-chloromethyl ketone (TPCK) reduces apoptosis in vitro. Pretreatment with TPCK reduces brain injury. Would treatment after injury reduce damage? Seven-day-old rats had the right carotid artery ligated and were subjected to 2.5 h of 8% oxygen and were treated intraperitoneally 3 h after hypoxia with 10 mg/kg of TPCK or vehicle. Brain damage was measured 22 days after injury. bcl-2, bax, and cytochrome c where measured by Western blot 24 h after injury. Caspase-9 and caspase-3 activity were measured enzymatically 24 h after injury. Treatment with TPCK reduced the loss of the right hemisphere caused by injury from 27.6 ± 2.8% SEM (vehicle, n = 56) to 19.8 ± 2.8% (TPCK, n = 61, p < 0.05). Hypoxic ischemia increased cytosolic cytochrome c from 0.25 ± 0.04 to 0.4 ± 0.04 optical density (OD; p < 0.05), but TPCK had no effect (0.31 ± 0.03 OD). TPCK reduced caspase-9 activity from 72 ± 30 to 43 ± 5 fluorescence units/h/mg (p < 0.05 vs. vehicle), and caspase-3 activity from 66 ± 10 to 39 ± 3.7 fluorescence units/h/mg (p < 0.05 vs. vehicle). Treatment with TPCK 3 h after hypoxic ischemia reduced brain infarct size. TPCK may act by reducing caspase-9 activation by cytochrome c.

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“…It would be important to know which cells are demonstrating these effects -especially in the context of the extent and type of cell damage and its time course. Bcl-2 is increased in many models of cell stress [16], and although generally having a protective action [19], the increase in bcl-2 is not always adequate to prevent cell death [20]. This is probably the role bcl-2 plays in our model.…”

Section: Feng/leblancmentioning

confidence: 86%

N-Tosyl-<i>L</i>-Phenylalanyl-Chloromethyl Ketone Eliminates the Increase in Caspase-3 and Bcl-2 Caused by Brain Injury in the Newborn Rat

Feng

LeBlanc

2002

Pharmacology

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N-Tosyl-L-phenylalanyl-chloromethyl ketone (TPCK) is neuroprotective in rat pups. We measured bcl-2, Bax and caspase-3 to determine the mechanisms. Seven-day-old rats had the right carotid artery ligated and were subjected to 2.5 h of 8% oxygen. Ten mg/kg of PTCK or vehicle was given intraperitoneally 15 min prior to hypoxia. At 24 h after hypoxia the brains were removed. Bcl-2 in the hippocampus increased from 0.149 ± (SE) 0.023 in the shams to 0.289 ± 0.037 with injury and vehicle (p < 0.05 vs. shams), which was reduced to 0.177 ± 0.030 by TPCK ( p < 0.05 vs. vehicle). Bcl-2 in the cortex increased from 0.180 ± 0.037 in the shams to 0.655 ± 0.078 with injury and vehicle (p < 0.01 vs. shams), which was reduced to 0.354 ± 0.035 by TPCK (p < 0.01 vs. vehicle). Bax, measured only in the mitochondrial enriched fraction of the cortex, was unchanged. Caspase-3 activity increased with injury to 245 ± 38% of baseline in the hippocampus (p < 0.01) and to 261 ± 69% in the cortex (p < 0.01). Treatment with TPCK reduced this to 132 ± 16% in the hippocampus (p < 0.01 vs. vehicle) and 140 ± 14% in the cortex (p < 0.05 vs. vehicle). In this experiment TPCK reduces bcl-2 and caspase-3 concentration in animals who have been shown in our previous studies to be protected by TPCK from hypoxic ischemic brain injury. This is consistent with the hypothesis that TPCK produces neuroprotection by blocking the apoptotic cascade between bcl-2 and caspase-3.

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bcl-2 Prolongs neuronal survival during hypoxia-induced apoptosis

Cited by 46 publications

References 37 publications

Molecular ordering of hypoxia-induced apoptosis: critical involvement of the mitochondrial death pathway in a FADD/caspase-8 independent manner

Molecular ordering of hypoxia-induced apoptosis: critical involvement of the mitochondrial death pathway in a FADD/caspase-8 independent manner

Treatment of Hypoxic-Ischemic Brain Injury in Newborn Rats with TPCK 3 h after Hypoxia Decreases Caspase-9 Activation and Improves Neuropathologic Outcome

N-Tosyl-<i>L</i>-Phenylalanyl-Chloromethyl Ketone Eliminates the Increase in Caspase-3 and Bcl-2 Caused by Brain Injury in the Newborn Rat

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