Etoposide induces programmed death in neurons cultured from the fetal rat central nervous system

Nakajima, Miki; Kashiwagi, Kumiko; Ohta, Jitsuo; Furukawa, Shoei; Hayashi, Kyozo; Kawashima, Takuji; Hayashi, Yokichi

doi:10.1016/0006-8993(94)90165-1

Cited by 36 publications

(22 citation statements)

References 18 publications

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“…It has been suggested that de novo protein synthesis may be essential for activation of caspase-regulated apoptosis. 32,55,56 Consistent with the studies using caspase inhibitors, inhibition of protein synthesis did not protect cortical neurons from the neurotoxic effects of anandamide. In contrast, parallel studies using treatment with etoposide, a classical method of inducing caspase-3-mediated neuronal apoptosis, showed cycloheximide blockade of apoptosis.…”

Section: Discussionsupporting

confidence: 63%

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Anandamide-induced cell death in primary neuronal cultures: role of calpain and caspase pathways

et al. 2004

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Anandamide (arachidonoylethanolamide or AEA) is an endocannabinoid that acts at vanilloid (VR1) as well as at cannabinoid (CB1/CB2) and NMDA receptors. Here, we show that AEA, in a dose-dependent manner, causes cell death in cultured rat cortical neurons and cerebellar granule cells. Inhibition of CB1, CB2, VR1 or NMDA receptors by selective antagonists did not reduce AEA neurotoxicity. Anandamideinduced neuronal cell loss was associated with increased intracellular Ca 2 þ , nuclear condensation and fragmentation, decreases in mitochondrial membrane potential, translocation of cytochrome c, and upregulation of caspase-3-like activity. However, caspase-3, caspase-8 or caspase-9 inhibitors, or blockade of protein synthesis by cycloheximide did not alter anandamide-related cell death. Moreover, AEA caused cell death in caspase-3-deficient MCF-7 cell line and showed similar cytotoxic effects in caspase-9 dominantnegative, caspase-8 dominant-negative or mock-transfected SH-SY5Y neuroblastoma cells. Anandamide upregulated calpain activity in cortical neurons, as revealed by a-spectrin cleavage, which was attenuated by the calpain inhibitor calpastatin. Calpain inhibition significantly limited anandamide-induced neuronal loss and associated cytochrome c release. These data indicate that AEA neurotoxicity appears not to be mediated by CB1, CB2, VR1 or NMDA receptors and suggest that calpain activation, rather than intrinsic or extrinsic caspase pathways, may play a critical role in anandamide-induced cell death.

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Section: Discussionsupporting

confidence: 63%

“…In contrast, the same dose of CHX was protective against etoposide-induced cell death (Figure 5b), a well-established model of caspase-mediated neuronal apoptosis. 32 Anandamide induces cell death in caspase-9 and -8 dominant-negative SH-SY5Y cells and caspase-3-deficient MCF-7 cells…”

Section: The Metabolically Stable Anandamide Analog Methanandamide Camentioning

confidence: 99%

Anandamide-induced cell death in primary neuronal cultures: role of calpain and caspase pathways

et al. 2004

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“…EGF has been shown to prevent programmed cell death in PC12, mammary epithelial, and colorectal carcinoma cells and to lessen nitric oxide-induced cytotoxicity in neurons (33)(34)(35). Of interest in the fetal kidney, exogenous EGF administration decreases apoptotic cell death in the nephrogenic zone of the developing kidney cortex and in the developing medullary papilla (36,37).…”

Section: Resultsmentioning

confidence: 99%

The Membrane-bound Form of Heparin-binding Epidermal Growth Factor-like Growth Factor Promotes Survival of Cultured Renal Epithelial Cells

Takemura

Kondo

Homma

et al. 1997

Journal of Biological Chemistry

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“…Other insults including uv radiation (44) and growth factor withdrawal (45,46) may also cause apoptosis through APCD. However, apoptosis has also been demonstrated in neurons exposed to oxidative stress (47), etoposide (48), heat shock (49), and decreased extracellular Kϩ (50), indicating that non-APCD apoptotic pathways also exist in neurons. Alternate pathways of apoptosis can be discerned by their differential sensitivity to blockade by bcl-2, crmA, and various caspase inhibitors (20,51).…”

Section: Discussionmentioning

confidence: 99%

Multiple Pathways of Apoptosis in PC12 Cells

Ivins¹,

Ivins

Sharp³

et al. 1999

Journal of Biological Chemistry

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Stable transfectants of PC12 cells expressing bcl-2 or crmA were generated and tested for their susceptibility to various apoptotic insults. Bcl-2 expression conferred resistance to apoptosis induced by staurosporine and by oxidative insults including hydrogen peroxide and peroxynitrite, but was less effective in inhibition of activation-induced programmed cell death induced by concanavalin A. Concanavalin A-induced apoptosis was abated, however, in cells expressing very high levels of bcl-2. In contrast, cells expressing crmA were protected from concanavalin A-induced apoptosis, but were as susceptible as control cells to apoptosis induced by staurosporine and oxidative insults. Therefore, at least two apoptotic pathways in PC12 cells can be discerned by their differential sensitivity to blockade by bcl-2 and crmA. The ability of ␤-amyloid (A␤) to induce apoptosis in these cells was assessed. CrmA transfectants were protected from apoptosis induced by A␤ 1-42 , but only cells expressing very high levels of bcl-2 were similarly protected. These results suggest that the apoptotic pathway activated by A␤ 1-42 in PC12 cells can be differentiated from the apoptotic pathway activated by oxidative insults. Gene transfer experiments also demonstrated that expression of crmA in primary cultures of hippocampal neurons is protective against cell death induced by A␤ 1-42 . Together these results support the hypothesis that A␤-induced apoptosis occurs through activation-induced programmed cell death. Alzheimer's disease (AD)1 is characterized by a pronounced loss of neurons in susceptible regions of the brain (1). Evidence suggests that this neuronal loss occurs through apoptosis (2, 3), a type of cell death with distinct morphological and biochemical characteristics. The principle component of senile plaques in AD brain is ␤-amyloid (A␤), a 39 -43-amino acid peptide derived from amyloid precursor protein. A␤ has been shown to be neurotoxic in vivo (4) and in vitro (5-8), and is generally believed to contribute to the etiology of AD. Understanding how A␤ induces neuronal apoptosis, therefore, may be important for clinical interventions in AD.A␤ must aggregate into a ␤-pleated sheet structure to induce the death of cultured hippocampal neurons (6), and A␤ is not toxic when immobilized as a neuronal substrate (9). These findings have led to the suggestion that aggregated A␤ might cross-link transmembrane plasma membrane receptors to initiate a death program, in a type of activation-induced programmed cell death (APCD) (10). Studies of A␤ effects on cells have documented changes in tyrosine phosphorylation of cellular substrates (11,12), suggesting that activation of signal transduction pathways might also be involved. Because A␤ causes oxidative stress in neurons, A␤ has been proposed to cause death through an oxidative mechanism (13), and antioxidants have sometimes (13) but not always (14) been reported to block A␤-induced cell death. Other studies have suggested that A␤ perturbs calcium homeostasis in neurons to cause cell...

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Etoposide induces programmed death in neurons cultured from the fetal rat central nervous system

Cited by 36 publications

References 18 publications

Anandamide-induced cell death in primary neuronal cultures: role of calpain and caspase pathways

Anandamide-induced cell death in primary neuronal cultures: role of calpain and caspase pathways

The Membrane-bound Form of Heparin-binding Epidermal Growth Factor-like Growth Factor Promotes Survival of Cultured Renal Epithelial Cells

Multiple Pathways of Apoptosis in PC12 Cells

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