Protection from oxidation enhances the survival of cultured mesencephalic neurons

Colton, Carol A.; Pagán, Fernando; Snell, Julie; Colton, Joel S.; Cummins, Alex; Gilbert, Daniel L.

doi:10.1016/0014-4886(95)90058-6

Cited by 53 publications

(27 citation statements)

References 26 publications

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“…However, neurons can maintain an intracellular glutathione poo1 by taking up cysteine provided by glial cells (Sagara et al, 1993). Protection from oxidation enhances the survival of mesencephalic cultures (Mena et al, 1993(Mena et al, , 1996Pardo et al, 1995), and the number of TH-positive neurons is increased if SOD, USH peroxidase, or L-NAC is added to the medium (Colton et al, 1995). We have shown that TH-positive neurons that overexpress SOD display increased neutite outgrowth and survival (Przedborski et al, 1996) and are protected from L-DOPA toxicity (Mena et al, 1997).…”

Section: Effect Of L-dopa On Glutathione Levelsmentioning

confidence: 87%

Neurotrophic Effects of l‐DOPA in Postnatal Midbrain Dopamine Neuron/Cortical Astrocyte Cocultures

Mena

Davila

Sulzer

1997

Journal of Neurochemistry

118

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L-DOPA IS toxic to catecholamine neurons in culture, but the toxicity is reduced by exposure to astrocytes. We tested the effect of L-DOPA on dopamine neurons using postnatal ventral midbrain neuron/cortical astrocyte cocultures in serum-free, glia-conditioned medium. L-DOPA (50 tiM) protected against dopamine neuronal cell death and increased the number and branching of dopamine processes. In contrast to embryonically derived glia-free cultures, where L-DOPA is toxic, postnatal midbrain cultures did not show toxicity at 200 1iM L-DOPA. The stereoisomer D-DOPA (50-400 btM) was not neurotrophic. The aromatic amino acid decarboxylase inhibitor carbidopa (25~zM) did not block the neurotrophic effect. These data suggest that the neurotrophic effect of L-DOPA is stereospecific but independent of the production of dopamine. However, L-DOPA increased the level of glutathione. Inhibition of glutathione peroxidase by Lbuthionine sulfoximine (3 1iM for 24 h) blocked the neurotrophic action of L-DOPA. N-Acetyl-L-cysteine (250 1iM for 48 h), which promotes glutathione synthesis, had a neurotrophic effect similar to that of L-DOPA. These data suggest that the neurotrophic effect of L-DOPA may be mediated, at least in part, by elevation of glutathione content. Key Words: L-DOPA-Glia-Glutathione-Parkinson's disease-Dopamine neurons.

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Section: Effect Of L-dopa On Glutathione Levelsmentioning

confidence: 87%

Neurotrophic Effects of l‐DOPA in Postnatal Midbrain Dopamine Neuron/Cortical Astrocyte Cocultures

Mena

Davila

Sulzer

1997

Journal of Neurochemistry

118

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“…In cultures of E14 rat primary (mesencephalic) neurons and PC12 cells, hypoxia increases tyrosine hydroxylase, the rate-limiting enzyme for catecholamine synthesis (37,38). In addition, embryonic precursors from both the peripheral nervous system and the central nervous system exhibit enhanced neuronal proliferation and differentiation in response to lowered oxygen tension (6,39).…”

Section: Discussionmentioning

confidence: 99%

Endogenous Erythropoietin Signaling Is Required for Normal Neural Progenitor Cell Proliferation

Chen

Asavaritikrai

Prchal

et al. 2007

Journal of Biological Chemistry

161

138

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Erythropoietin (Epo) and its receptor (EpoR), critical for erythropoiesis, are expressed in the nervous system. Prior to death in utero because of severe anemia EpoR-null mice have fewer neural progenitor cells, and differentiated neurons are markedly sensitive to hypoxia, suggesting that during development Epo stimulates neural cell proliferation and prevents neuron apoptosis by promoting oxygen delivery to brain or by direct interaction with neural cells. Here we present evidence that neural progenitor cells express EpoR at higher levels compared with mature neurons; that Epo stimulates proliferation of embryonic neural progenitor cells; and that endogenous Epo contributes to neural progenitor cell proliferation and maintenance. EpoRnull mice were rescued with selective EpoR expression driven by the endogenous EpoR promoter in hematopoietic tissue but not in brain. Although these mice exhibited normal hematopoiesis and erythrocyte production and survived to adulthood, neural cell proliferation and viability were affected. Embryonic brain exhibited increased neural cell apoptosis, and neural cell proliferation was reduced in the adult hippocampus and subventricular zone. Neural cells from these animals were more sensitive to hypoxia/glutamate neurotoxicity than normal neurons in culture and in vivo. These observations demonstrate that endogenous Epo/EpoR signaling promotes cell survival in embryonic brain and contributes to neural cell proliferation in adult brain in regions associated with neurogenesis. Therefore, Epo exerts extrahematopoietic function and contributes directly to brain development, maintenance, and repair by promoting cell survival and proliferation independent of insult, injury, or ischemia.

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“…One such variable that may be particularly important to Aß toxicity is the amount of time cultures are maintained in vitro before experimentation (Café et al, 1996). This is because accumulation ofoxidative stress is an inherent feature of cell culture (Brewer and Cotman, 1989;Colton et al, 1995), and thus, all other factors being equal, cells cultured for extended periods will likely exhibit higher basal levels of oxidative stress than those cultured for shorter periods. Consequently, it may be expected that antioxidants would be less effective in attenuating Aß toxicity in shortterm culture studies than in long-term ones.…”

Section: Discussionmentioning

confidence: 99%

β‐Amyloid Neurotoxicity In Vitro: Evidence of Oxidative Stress but Not Protection by Antioxidants

Pike

Ramezan‐Arab

Cotman

1997

Journal of Neurochemistry

120

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Recent data from several groups suggest that the primary mechanism of ß-amyloid neurotoxicity may be mediated by reactive oxygen species. To evaluate this hypothesis, we first compared the efficacy of antioxidant agents in preventing toxicity caused by oxidative insults (iron, hydrogen peroxide, and tert-butyl hydroperoxide) and ß-amyloid peptides in cultured rat hippocampal neurons. Tested antioxidants (propyl gallate, Trolox, probucol, and promethazine) generally provided significant protection against oxidative insults but not ß-amyloid peptides. Next, we examined whether ß-amyloid causes oxidative stress, by comparing levels of lipid peroxidation after exposure to either iron or ß-amyloid. In a cell-free system, iron but not ß-amyloid generated lipid peroxidation. In culture, both insults caused rapid increases in lipid peroxidation, with iron inducing higher levels at later time points. Pretreatment with the antioxidant probucol significantly reduced lipid peroxidation caused by both insults but only attenuated iron toxicity, suggesting that lipid peroxidation does not contribute directly to cell death induced by ß-amyloid. Finally, we observed that increasing basal levels of oxidative stress by pretreating cultures with subtoxic doses of iron significantly increased neuronal vulnerability to ß-amyloid. The ability of ß-amyloid to induce oxidative stress and the demonstration that oxidative stress potentiatesß-amyloid toxicity support the clinical use of antioxidants for AD. However, these data do not support the theory that the primary mechanism of ß-amyloid toxicity involves oxidative pathways, indicating a continued need to identify additional cellular responses to ß-amyloid that underlie its neurodegenerative actions. Key Words: ß-AmyloidAlzheimer's disease-Antioxidants-Free radicalsLipid peroxidation-Oxidative stress. J. Neurochem. 69,1601Neurochem. 69, -1611Neurochem. 69, (1997.sociated with neuritic dystrophy and reactive glia (Wisniewski and Terry, 1973;Probst et al., 1987;Rozemuller et al., 1989). The Aß hypothesis is further supported by our recent demonstration that the extent of Aß deposition in entorhinal cortex correlates with cognitive decline in AD patients (r '-.~-O.9) better than other pathological indices (Cummings et al., 1996). Causal contributions of Aß to AD neurodegeneration are also implied by analyses of genetic mutations linked to familial forms of AD. Specifically, several rare autosomal dominant mutations in the Aß precursor protein gene on chromosome 21 and relatively more prevalent mutations in the presenilin-1 and presenilin-2 genes on chromosomes 14 and 1, respectively, appear to precipitate AD at least in part by causing significant increases in either the overall production of Aß or the levels of particularly amyloidogenic X-42/43 Aß species (for review, see Selkoe, 1996).An important contributory role of Aß in AD neurodegeneration is also supported by in vitro and in vivo experimental paradigms that have demonstrated neurodegenerative actions of Aß peptides (for...

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Protection from oxidation enhances the survival of cultured mesencephalic neurons

Cited by 53 publications

References 26 publications

Neurotrophic Effects of l‐DOPA in Postnatal Midbrain Dopamine Neuron/Cortical Astrocyte Cocultures

Neurotrophic Effects of l‐DOPA in Postnatal Midbrain Dopamine Neuron/Cortical Astrocyte Cocultures

Endogenous Erythropoietin Signaling Is Required for Normal Neural Progenitor Cell Proliferation

β‐Amyloid Neurotoxicity In Vitro: Evidence of Oxidative Stress but Not Protection by Antioxidants

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