Staurosporine, a Novel Protein Kinase C Inhibitor, Prevents Postischemic Neuronal Damage in the Gerbil and Rat

Hara, Hideaki; Oda, Hiroshi; Yoshidomi, Mikio; Matsuda, Yuzuru; Kogure, Kyuya

doi:10.1038/jcbfm.1990.117

Cited by 152 publications

(60 citation statements)

References 41 publications

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“…36 The finding that calcium antagonists influence PKC activity during ischemia could be important, because PKC inhibition has been found to be beneficial in protecting the heart, lung, and brain from ischemia. 37,38 The link between ischemia and increased endothelial cell-layer permeability is also relevant. For instance, the prevention of ischemia-induced permeability increases could be useful therapeutically.…”

Section: Discussionmentioning

confidence: 99%

Calcium Antagonists Ameliorate Ischemia-Induced Endothelial Cell Permeability by Inhibiting Protein Kinase C

et al. 1999

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Background-Dihydropyridines block calcium channels; however, they also influence endothelial cells, which do not express calcium channels. We tested the hypothesis that nifedipine can prevent ischemia-induced endothelial permeability increases by inhibiting protein kinase C (PKC) in cultured porcine endothelial cells. Methods and Results-Ischemia was induced by potassium cyanide/deoxyglucose, and permeability was measured by albumin flux. Ion channels were characterized by patch clamp. [Ca 2ϩ ] i was measured by fura 2. PKC activity was measured by substrate phosphorylation after cell fractionation. PKC isoforms were assessed by Western blot and confocal microscopy. Nifedipine prevented the ischemia-induced increase in permeability in a dose-dependent manner. Ischemia increased [Ca 2ϩ ] i , which was not affected by nifedipine. Instead, ischemia-induced PKC translocation was prevented by nifedipine. Phorbol ester also increased endothelial cell permeability, which was dose dependently inhibited by nifedipine. The effects of non-calcium-channel-binding dihydropyridine derivatives were similar. Analysis of the PKC isoforms showed that nifedipine prevented ischemia-induced translocation of PKC-␣ and PKC-. Specific inhibition of PKC isoforms with antisense oligodeoxynucleotides demonstrated a major role for PKC-␣. Conclusions-Nifedipine exerts a direct effect on endothelial cell permeability that is independent of calcium channels.The inhibition of ischemia-induced permeability by nifedipine seems to be mediated primarily by PKC-␣ inhibition. Anti-ischemic effects of dihydropyridine calcium antagonists could be due in part to their effects on endothelial cell permeability. (Circulation. 1999;99:2523-2529.)

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Section: Discussionmentioning

confidence: 99%

Calcium Antagonists Ameliorate Ischemia-Induced Endothelial Cell Permeability by Inhibiting Protein Kinase C

et al. 1999

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“…62 STS administration in rats also facilitates recovery from deficits induced by basal forebrain lesions 63 and prevents neuronal damage after ischemic injury. 64 The exact mechanism by which 1 nM STS inhibits the sympathetic neuronal PCD pathway is not known. Since the NGF-deprived, 1 nM STS-saved neurons did not show an increase in c-jun phosphorylation ( Figure 9B), 1 nM STS presumably inhibited the sympathetic neuronal PCD pathway either at or prior to increase in c-jun phosphorylation.…”

Section: Neuroprotection With 1 Nm Stsmentioning

confidence: 99%

Staurosporine-induced neuronal death: multiple mechanisms and methodological implications

Deshmukh

Johnson

2000

Cell Death Differ

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To examine whether multiple pathways of cell death exist in sympathetic neurons, we studied the cell death pathway induced by staurosporine (STS) in sympathetic neurons and compared it with the well-characterized NGF deprivationinduceddeathpathway.IncreasingconcentrationsofSTSwere found to induce sympathetic neuronal death with different biochemical and morphological characteristics. One hundred nM STS induced metabolic changes, loss of cytochrome c, and caspase-dependent morphological degeneration which closely resembled the apoptotic death induced by NGF deprivation. In contrast, sympathetic neurons treated with 1 mM STS showed no loss of cytochrome c but exhibited extensive, caspase-independent, chromatin changes that were not TUNEL positive. One mM STS-treated sympathetic neurons had greatly reduced metabolic activities and became committed to die rapidly, yet maintained soma structure and appeared viable by other criteria even up to 48 h after STS treatment, illustrating the need to assess cell death by multiple criteria. Lastly, in contrast to the cell death-inducing activities of 100 nM STS or 1 mM STS, very low concentrations of STS (1 nM STS) inhibited sympathetic neuronal death by acting either at or prior to c-jun phosphorylation in the NGF deprivation-induced PCD pathway. Cell Death and Differentiation (2000) 7, 250 ± 261.

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“…Inhibitors or vehicle [5% dimethyl sulfoxide (DMSO) in saline] were injected into the bilateral CAl region of the hippocampus (1 fLl over a 5-min period) (one injection spreading bilaterally). The site of injection was as described by Hara et al (1990), 1.8 mm posterior to the bregma, 2.0 mm lateral to the midline, and 1.4 mm into the dural surface according to the atlas of the gerbil brain (Loskota et aI., 1974). Thirty minutes following injection, the carotid arteries were exposed, clamped for 5 min then released for the period of time indicated for each exper iment.…”

Section: Gerbil Modelmentioning

confidence: 99%

“…The Mongolian gerbil has been extensively used as a model to examine the effects of ischemia and reperfusion injury on the brain (Hara et al, 1990;Kindy et al, 1991). Several reports have demon strated selective increases in lipid metabolism, pro tein oxidation, and gene expression after ischemia and reperfusion insult (Dempsey et al, 1985(Dempsey et al, , 1986Cao et al, 1988;Kindy et al, 1991).…”

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confidence: 99%

Inhibition of Tyrosine Phosphorylation Prevents Delayed Neuronal Death following Cerebral Ischemia

Kindy

1993

J Cereb Blood Flow Metab

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Protein tyrosine phosphorylation plays an important role in the regulation of neuronal function. We examined the effects of inhibition of tyrosine phosphorylation on ischemic neuronal damage in the CA1 region of the hippocampus. In the gerbil hippocampus, genistein and lavendustin A, tyrosine kinase inhibitors, were administered 30 min before initiation of 5-min ischemia and reperfusion. Both genistein and lavendustin A blocked tyrosine phosphorylation and prevented delayed neuronal death (DND). However, genistin, an inactive analogue of genistein, did not block DND. Genistein was dose-dependent in the inhibition of DND after ischemia and reperfusion. Administration of genistein 5 to 10 min after ischemia and reperfusion was ineffective in blocking DND in the CA1 region of the hippocampus. The tyrosine kinase inhibitors selectively blocked the phosphorylation of microtubule-associated protein (MAP)-2 kinase following ischemia and reperfusion injury. These results suggest that tyrosine phosphorylation in the ischemic brain is important for neuronal injury and that MAP-2 kinase may play a role in the onset of delayed neuronal death.

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Staurosporine, a Novel Protein Kinase C Inhibitor, Prevents Postischemic Neuronal Damage in the Gerbil and Rat

Cited by 152 publications

References 41 publications

Calcium Antagonists Ameliorate Ischemia-Induced Endothelial Cell Permeability by Inhibiting Protein Kinase C

Calcium Antagonists Ameliorate Ischemia-Induced Endothelial Cell Permeability by Inhibiting Protein Kinase C

Staurosporine-induced neuronal death: multiple mechanisms and methodological implications

Inhibition of Tyrosine Phosphorylation Prevents Delayed Neuronal Death following Cerebral Ischemia

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