The Role of Astroglia on the Survival of Dopamine Neurons

Mena, María A.; Bernardo, Sonsoles de; Casarejos, Marı́a José; Canals, Santiago; Rodrı́guez-Martı́n, Eulalia

doi:10.1385/mn:25:3:245

Cited by 63 publications

(62 citation statements)

References 116 publications

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“…59 Further understanding the mechanism underlying the neurotrophic acton of VPA will provide an avenue to disclose both the pathogenesis and therapeutic mechanisms underlying bipolar mood disorder. 2,60,61 The results of our study underline the emerging role of glia as active participants in neuronal survival and plasticity, with astrocytes being strongly implicated as the major player in these responses. It reinforces the view that disturbances of astroglial function could conceivably contribute to pathogenesis of various forms of brain disorders and that astrocytes may serve as an appropriate target for the development of novel therapeutics.…”

Section: Discussionmentioning

confidence: 61%

Valproate protects dopaminergic neurons in midbrain neuron/glia cultures by stimulating the release of neurotrophic factors from astrocytes

et al. 2006

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Valproate (VPA), one of the mood stabilizers and antiepileptic drugs, was recently found to inhibit histone deacetylases (HDAC). Increasing reports demonstrate that VPA has neurotrophic effects in diverse cell types including midbrain dopaminergic (DA) neurons. However, the origin and nature of the mediator of the neurotrophic effects are unclear. We have previously demonstrated that VPA prolongs the survival of midbrain DA neurons in lipopolysaccharide (LPS)-treated neuron-glia cultures through the inhibition of the release of pro-inflammatory factors from microglia. In this study, we report that VPA upregulates the expression of neurotrophic factors, including glial cell line-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF) from astrocytes and these effects may play a major role in mediating VPA-induced neurotrophic effects on DA neurons. Moreover, VPA pretreatment protects midbrain DA neurons from LPS or 1-methyl-4-phenylpyridinium (MPP þ )-induced neurotoxicity. Our study identifies astrocyte as a novel target for VPA to induce neurotrophic and neuroprotective actions in rat midbrain and shows a potential new role of cellular interactions between DA neurons and astrocytes. The neurotrophic and neuroprotective effects of VPA also suggest a utility of this drug for treating neurodegenerative disorders including Parkinson's disease. Moreover, the neurotrophic effects of VPA may contribute to the therapeutic action of this drug in treating bipolar mood disorder that involves a loss of neurons and glia in discrete brain areas.

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Section: Discussionmentioning

confidence: 61%

Valproate protects dopaminergic neurons in midbrain neuron/glia cultures by stimulating the release of neurotrophic factors from astrocytes

et al. 2006

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“…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: 97%

“…Astrocytes, the most abundant glial cells, support the differentiation, survival, pharmacological properties, and resistance to injury of dopamine neurons (Mena et al, 2002;Takuma et al, 2004). The role of glia is mediated by the secretion of chemical substances into the media (Mena et al, 1997a(Mena et al, , 2002de Bernardo et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

“…The role of glia is mediated by the secretion of chemical substances into the media (Mena et al, 1997a(Mena et al, , 2002de Bernardo et al, 2003). Dysfunctional astrocytes enhance neuronal degeneration by a diminished secretion of trophic factors (Riederer et al, 1989;Engele et al, 1991Engele et al, , 1996Damier et al, 1993;Makar et al, 1994;Muller et al, 1995;Mena et al, 1997aMena et al, , 1998bMena et al, , 2002Kinor et al, 2001), the release of cytokines, and the increased production of reactive oxidative molecules (Hirsch et al, 1999;Liberatore et al, 1999;Hirsch and Hunot, 2000;Vila et al, 2001;Wu et al, 2002;Canals et al, 2003b;de Bernardo et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

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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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“…Several studies point to a role of activated glia and inflammation in the pathogenesis of neurodegenerative diseases, especially in PD (Hirsch et al, 2005;Liu et al, 2003;Mena et al, 2002;Mirza et al, 2000). Activation of both, microglia and astroglia is seen in animal models of PD and they are considered active participants in the nigrostriatal degeneration (Halliday and Stevens, 2011;Mena and Garcia de, 2008;Teismann and Schulz, 2004;Wu et al, 2002).…”

Section: Midbrain Astroglia Responsesmentioning

confidence: 99%

Nanomicellar formulation of coenzyme Q10 (Ubisol-Q10) effectively blocks ongoing neurodegeneration in the mouse 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model: potential use as an adjuvant treatment in Parkinson's disease

Sikorska

Lanthier

Miller

et al. 2014

Neurobiology of Aging

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Although the support for the use of antioxidants, such as coenzyme Q 10 (CoQ 10 ), to treat Parkinson's disease (PD) comes from the extensive scientific evidence, the results of conducted thus far clinical trials are inconclusive. It is assumed that the efficacy of CoQ 10 is hindered by insolubility, poor bioavailability, and lack of brain penetration. We have developed a nanomicellar formulation of CoQ 10 (Ubisol-Q 10 ) with improved properties, including the brain penetration, and tested its effectiveness in mouse MPTP (1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine) model with the objectives to assess its potential use as an adjuvant therapy for PD. We used a subchronic MPTP model (5-daily MPTP injections), characterized by 50% loss of dopamine neurons over a period of 28 days. Ubisol-Q 10 was delivered in drinking water. Prophylactic application of Ubisol-Q 10 , started 2 weeks before the MPTP exposure, significantly offset the neurotoxicity (approximately 50% neurons died in MPTP group vs. 17% in MPTP+ Ubisol-Q 10 group by day 28). Therapeutic application of Ubisol-Q 10 , given after the last MPTP injection, was equally effective. At the time of intervention on day 5 nearly 25% of dopamine neurons were already lost, but the treatment saved the remaining 25% of cells, which otherwise would have died by day 28. This was confirmed by cell counts, analyses of striatal dopamine levels, and improved animals' motor skill on a beam walk test. Similar levels of neuroprotection were obtained with 3 different Ubisol-Q 10 concentrations tested, that is, 30 mg, 6 mg, or 3 mg CoQ 10 /kg body weight/day, showing clearly that high doses of CoQ 10 were not required to deliver these effects. Furthermore, the Ubisol-Q 10 treatments brought about a robust astrocytic activation in the brain parenchyma, indicating that astroglia played an active role in this neuroprotection. Thus, we have shown for the first time that Ubisol-Q 10 was capable of halting the neurodegeneration already in progress;

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The Role of Astroglia on the Survival of Dopamine Neurons

Cited by 63 publications

References 116 publications

Valproate protects dopaminergic neurons in midbrain neuron/glia cultures by stimulating the release of neurotrophic factors from astrocytes

Valproate protects dopaminergic neurons in midbrain neuron/glia cultures by stimulating the release of neurotrophic factors from astrocytes

Glial Dysfunction in Parkin Null Mice: Effects of Aging

Nanomicellar formulation of coenzyme Q10 (Ubisol-Q10) effectively blocks ongoing neurodegeneration in the mouse 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model: potential use as an adjuvant treatment in Parkinson's disease

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