The effect of glia-conditioned medium on dopamine neurons in culture. Modulation of apoptosis, tyrosine hydroxylase expression and 1-methyl-4-phenylpyridinium toxicity

Mena, María A.; Casarejos, Marı́a José; Yébenes, Justo Garcı́a de

doi:10.1007/s007020050227

Cited by 21 publications

(17 citation statements)

References 28 publications

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“…The density of astrocytes in the substantia nigra, which is primarily affected by PD pathology, is the lowest in the brain (Mena and Garcia de Yebenes, 2008). This may explain specific vulnerability of substantia nigra neurons to stress factors; in addition, astroglial cells are known to protect dopaminergic neurones in vitro and are instrumental for neuronal utilization of L -DOPA (Mena et al, 1996, 1999; Mena and Garcia de Yebenes, 2008). …”

Section: Astrocytes In Parkinson's Diseasementioning

confidence: 99%

Neurological Diseases as Primary Gliopathies: A Reassessment of Neurocentrism

et al. 2012

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Diseases of the human brain are almost universally attributed to malfunction or loss of nerve cells. However, a considerable amount of work has, during the last decade, expanded our view on the role of astrocytes in CNS (central nervous system), and this analysis suggests that astrocytes contribute to both initiation and propagation of many (if not all) neurological diseases. Astrocytes provide metabolic and trophic support to neurons and oligodendrocytes. Here, we shall endeavour a broad overviewing of the progress in the field and forward the idea that loss of homoeostatic astroglial function leads to an acute loss of neurons in the setting of acute insults such as ischaemia, whereas more subtle dysfunction of astrocytes over periods of months to years contributes to epilepsy and to progressive loss of neurons in neurodegenerative diseases. The majority of therapeutic drugs currently in clinical use target neuronal receptors, channels or transporters. Future therapeutic efforts may benefit by a stronger focus on the supportive homoeostatic functions of astrocytes.

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Section: Astrocytes In Parkinson's Diseasementioning

confidence: 99%

Neurological Diseases as Primary Gliopathies: A Reassessment of Neurocentrism

et al. 2012

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“…GCM protects DA neurons from apoptosis, MPP ϩ -induced cell death (Mena et al, 1999), and nitric oxide (Canals et al, 2001b). In addition, GCM greatly increases astrocytic GFAP ϩ processes.…”

Section: Effects Of Wt and Pk-ko Glia-conditioned Medium On Fetal Midmentioning

confidence: 99%

“…We have shown previously that GCM from mesencephalic rat astrocytes is neuroprotective for neuronal-enriched mesencephalic cultures (Mena et al, 1997a(Mena et al, , 1998b(Mena et al, , 1999(Mena et al, , 2002Canals et al, 2001a;Rodriguez-Martin et al, 2001). In this study, we investigated the differential effects of PK-KO-and WT-GCM on WT midbrain neuronal cultures.…”

Section: Effects Of Wt and Pk-ko Glia-conditioned Medium On Fetal Midmentioning

confidence: 99%

Glial Dysfunction in Parkin Null Mice: Effects of Aging

Solano¹,

Casarejos²,

et al. 2008

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Parkin mutations in humans produce parkinsonism whose pathogenesis is related to impaired protein degradation, increased free radicals, and abnormal neurotransmitter release. The role of glia in parkin deficiency is little known. We cultured midbrain glia from wild-type (WT) and parkin knock-out (PK-KO) mice. After 18 -20 d in vitro, PK-KO glial cultures had less astrocytes, more microglia, reduced proliferation, and increased proapoptotic protein expression.PK-KO glia had greater levels of intracellular glutathione (GSH), increased mRNA expression of the GSH-synthesizing enzyme ␥-glutamylcysteine synthetase, and greater glutathione S-transferase and lower glutathione peroxidase activities than WT. The reverse happened in glia cultured in serum-free defined medium (EF12) or in old cultures. PK-KO glia was more susceptible than WT to transference to EF12 or neurotoxins (1-methyl-4-phenylpyridinium, blockers of GSH synthesis or catalase, inhibitors of extracellular signal-regulated kinase 1/2 and phosphatidylinositol 3 kinases), aging of the culture, or combination of these insults. PK-KO glia was less susceptible than WT to Fe 2ϩ plus H 2 O 2 and less responsive to protection by deferoxamine. Old WT glia increased the expression of heat shock protein 70, but PK-KO did not. Glia conditioned medium (GCM) from PK-KO was less neuroprotective and had lower levels of GSH than WT. GCM from WT increased the levels of dopamine markers in midbrain neuronal cultures transferred to EF12 more efficiently than GCM from PK-KO, and the difference was corrected by supplementation with GSH. PK-KO-GCM was a less powerful suppressor of apoptosis and microglia in neuronal cultures. Our data prove that abnormal glial function is critical in parkin mutations, and its role increases with aging.

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“…The function of astrocyte-derived NO is not yet clear. However, it is well established that astrocytes comprise an effective antioxidant system [12][13][14][15][16] and are highly resistant to elevated concentrations of the deleterious NO-derived oxidant, peroxynitrite [17]. However, these cells are not immune to MPTP toxicity [18,19].…”

Section: Neurotrophic and Neurotoxic Effects Of Nitric Oxide On Dopammentioning

confidence: 99%

Nitric Oxide and Dopamine Neurons. Implications for Parkinsons Disease

Mena¹,

Casarejos²,

Canals

2005

CMCCNSA

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There is evidence suggesting that nitric oxide (NO) may play an important role in dopamine (DA) cell death. NO may act as a neuroprotector or neurotoxic agent in dopamine neurons, depending on cell redox status. Glutathione (GSH) depletion is the earliest biochemical alteration shown to date in brains of Parkinson's disease (PD) patients. However, data from animal models show that GSH depletion by itself is not sufficient to induce nigral degeneration. Low NO concentrations have neurotrophic effects on DA cells via a cGMP-independent mechanism that may implicate up-regulation of GSH. On the other hand, higher levels of NO induce cell death in both DA neurons and mature oligodendrocytes that is totally reverted by soluble factors released from glia. Alterations in GSH levels change the neurotrophic effects of NO in dopamine function into neurotoxic, under these conditions, NO triggers a programmed cell death with markers of both apoptosis and necrosis characterised by an early production of free radicals followed by late activation of the sGC/cGMP/PKG pathway. Arachidonic acid metabolism through the 12-lipoxygenase (12-LOX) pathway is also central for this GSH-NO interaction. Neurotrophism of NO switches into neurotoxicity after GSH depletion, due to persistent activation of the ERK-1/2 signaling pathway in glial cells. The implication of these cell death signaling pathways in pathological conditions like Parkinson's disease, where GSH depletion, glial dysfunction and NO overproduction have been documented, are discussed.

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The effect of glia-conditioned medium on dopamine neurons in culture. Modulation of apoptosis, tyrosine hydroxylase expression and 1-methyl-4-phenylpyridinium toxicity

Cited by 21 publications

References 28 publications

Neurological Diseases as Primary Gliopathies: A Reassessment of Neurocentrism

Neurological Diseases as Primary Gliopathies: A Reassessment of Neurocentrism

Glial Dysfunction in Parkin Null Mice: Effects of Aging

Nitric Oxide and Dopamine Neurons. Implications for Parkinsons Disease

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