Levodopa induces apoptosis in cultured neuronal cells—A possible accelerator of nigrostriatal degeneration in Parkinson's disease?

Ziv, Ilan; Zilkha‐Falb, Rina; Offen, Daniel; Shirvan, Anat; Barzilai, Ari; Melamed, Eldad

doi:10.1002/mds.870120105

Cited by 85 publications

(43 citation statements)

References 32 publications

(38 reference statements)

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“…Additional evidence that cell death in this model proceeds through apoptotic mechanisms is suggested by the up-regulation of p53 and Bax protein expression after 6-OHDA exposure (12) and the observation that cell death can be blocked by addition of a caspase inhibitor (13). Cell death with characteristics of apoptosis also has been demonstrated after exposure to L-dopamine in PC-12 cells (14) and sympathetic neurons (15), suggesting that endogenous oxidative stressors may produce similar toxicity to these cells.…”

mentioning

confidence: 78%

Herpes simplex virus vector-mediated expression of Bcl-2 prevents 6-hydroxydopamine-induced degeneration of neurons in the substantia nigra in vivo

Yamada

Oligino²,

Mata³

et al. 1999

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

109

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ABSTRACT6-Hydroxydopamine (6-OHDA) is widely used to selectively lesion dopaminergic neurons of the substantia nigra (SN) in the creation of animal models of Parkinson's disease. In vitro, the death of PC-12 cells caused by exposure to 6-OHDA occurs with characteristics consistent with an apoptotic mechanism of cell death. To test the hypothesis that apoptotic pathways are involved in the death of dopaminergic neurons of the SN caused by 6-OHDA, we created a replication-defective genomic herpes simplex virusbased vector containing the coding sequence for the antiapoptotic peptide Bcl-2 under the transcriptional control of the simian cytomegalovirus immediate early promoter. Transfection of primary cortical neurons in culture with the Bcl-2-producing vector protected those cells from naturally occurring cell death over 3 weeks. Injection of the Bcl-2-expressing vector into SN of rats 1 week before injection of 6-OHDA into the ipsilateral striatum increased the survival of neurons in the SN, detected either by retrograde labeling of those cells with f luorogold or by tyrosine hydroxylase immunocytochemistry, by 50%. These results, demonstrating that death of nigral neurons induced by 6-OHDA lesioning may be blocked by the expression of Bcl-2, are consistent with the notion that cell death in this model system is at least in part apoptotic in nature and suggest that a Bcl-2-expressing vector may have therapeutic potential in the treatment of Parkinson's disease.

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mentioning

confidence: 78%

Herpes simplex virus vector-mediated expression of Bcl-2 prevents 6-hydroxydopamine-induced degeneration of neurons in the substantia nigra in vivo

Yamada

Oligino²,

Mata³

et al. 1999

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

109

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“…KOSTRZEWA 1995;Walkinshaw and Waters, 1995;Ziv et al, 1997c), but was not by inhibiting L-DOPA conversion to DA (Walkinshaw and Waters, 1995). These findings indicate that generation of ROS is a key step in DOPA-and DA-induced neuronal cell death.…”

Section: Evidence Linking Ros With Neuronal Cell Deathmentioning

confidence: 69%

“…In Vitro Evidence for L-DOPA and DA-induced Apoptosis L-DOPA incubation with postmitotic chick sympathetic neurons (Ziv et al, 1997c) or PC12 cells (Walkinshaw and Waters, 1995), and DA incubation with thymocytes (Often et al, 1995) or PC12 cells (Often et al, 1996), is accompanied by histochemical evidence of DNA fragmentation (in situ end-labelling of DNA; TUNEL) and chromatin condensation -suggestive of an apoptotic process. One view is that PD arises from damage to pcSN neurons at the nuclear level because DA is genotoxic and triggers apoptosis in neuronal cells, while Bcl-2 transfection of PC12 cells prevents apoptosis (Ziv et al, 1997a).…”

Section: Evidence For Neurotoxin-induced Apoptosismentioning

confidence: 97%

Review on apoptosis vs. necrosis of substantia nigrapars compacta in parkinson’s disease

Kostrzewa

2000

neurotox res

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The discovery that melanized neurons of the pars compacta of substantia nigra (pcSN) degenerate in the midbrain of human Parkinsonians is nearly a century old, but only in this decade have we gained insights into mechanisms underlying this neuronal loss. Although it had long been assumed that pcSN neurons underwent necrosis, recent (1) in vitro studies on isolated neurons, (2) in vivo studies in animals treated with neurotoxins, and (3) postmortem study of human Parkinsonian brain provide strong evidence that pcSN cells may be lost more from apoptosis (i.e., cell suicide) than from necrosis. This paper gives some historical perspective, but focuses primarily on mechanisms involved in both necrosis and apoptosis of neurons, primarily dopaminergic, and reviews the recent literature relating to apoptosis and apoptotic factors now identified in neurons undergoing neurotoxin-induced death and in postmortem human Parkinsonian brain. The weight of evidence in favor of apoptosis and apoptotic factors in these neurons, provides us with tools needed to develop anti-apoptotic factors that can be targeted to proteins on genes, so that it may be possible to decelerate or prevent the progressive neuronal cell loss in human Parkinsonians or in humans with other neurodegenerative disorders.

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“…5 Apoptosis is an active and genetically controlled cell suicide program that occurs naturally to maintain the appropriate cellular composition of each organ. 6 In chronic wounds, excessive apoptosis delays wound healing. Caspase is a key effector molecule that initiates the apoptotic process that results in the morphological and biochemical changes.…”

Section: Introductionmentioning

confidence: 99%

Expression of cytokines, growth factors and apoptosis-related signal molecules in chronic pressure ulcer wounds healing

et al. 2013

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Objectives: Many complex mechanisms responsible for the pathogenesis of pressure ulcers (PUs) currently remain poorly understood. The objective of this study was to discover the major roles for inflammatory cytokines, growth factors and several apoptosis-related signal molecules in chronic PU wound. Methods: We investigated expression of inflammatory cytokines, growth factors and their corresponding receptors, and the apoptosis signal of caspase-3 in chronic stage III/IV chronic PU wound, acute wounds as well as normal skin controls. Tissues were stained by hematoxylin and eosin (HE) for histopathology and Masson's trichrome for collagen. Vascular endothelial growth factor (VEGF), fibroblast growth factors 2 (bFGF) and caspase-3 were detected by immunohistochemical analysis. Expression of mRNAs for interleukin (IL)-1b, tumor necrosis factor-a (TNF-a), VEGF, KDR, bFGF and FGFR1 was determined by real-time reverse transcription PCR. Results: Stage III and IV chronic PUs stained had increased inflammatory cell infiltration and decreased collagen compared with controls. Levels of mRNAs for inflammatory cytokines IL-1b and TNF-a were elevated in PUs compared with acute wounds and normal skin. VEGF and bFGF, together with their receptors KDR and FGFR1, respectively, were significantly decreased compared with controls. However, the expression levels of caspase-3 were elevated in the PUs. Conclusion: Our series of studies have shown that chronic PUs displayed high levels of inflammation and disruption of the collagen matrix, along with increased indications of apoptosis and decreased levels of growth factors and their receptors. These characteristics can be used to comprehensively evaluate the etiology and treatment of chronic PUs.

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Levodopa induces apoptosis in cultured neuronal cells—A possible accelerator of nigrostriatal degeneration in Parkinson's disease?

Cited by 85 publications

References 32 publications

Herpes simplex virus vector-mediated expression of Bcl-2 prevents 6-hydroxydopamine-induced degeneration of neurons in the substantia nigra in vivo

Herpes simplex virus vector-mediated expression of Bcl-2 prevents 6-hydroxydopamine-induced degeneration of neurons in the substantia nigra in vivo

Review on apoptosis vs. necrosis of substantia nigrapars compacta in parkinson’s disease

Expression of cytokines, growth factors and apoptosis-related signal molecules in chronic pressure ulcer wounds healing

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