Regulation of Natural Cell Death in Dopaminergic Neurons of the Substantia Nigra by Striatal Glial Cell Line-Derived Neurotrophic Factor<i>In Vivo</i>

Oo, Tinmarla F.; Kholodilov, Nikolai; Burke, Robert E.

doi:10.1523/jneurosci.23-12-05141.2003

Cited by 108 publications

(90 citation statements)

References 55 publications

(78 reference statements)

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“…We have shown that GDNF is able to support DA neurons by suppressing apoptosis in a postnatal primary culture model, established during the natural cell death period for these neurons (Burke et al, 1998). We have also shown in vivo that direct intrastriatal injection of GDNF suppresses the first phase of natural cell death on PND 2, whereas injection of neutralizing antibodies augments it (Oo et al, 2003), suggesting a regulatory role for endogenous GDNF.…”

Section: Introductionmentioning

confidence: 72%

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Regulation of the Development of Mesencephalic Dopaminergic Systems by the Selective Expression of Glial Cell Line-Derived Neurotrophic Factor in Their Targets

Kholodilov¹,

Yarygina²,

Oo³

et al. 2004

J. Neurosci.

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Glial cell line-derived neurotrophic factor (GDNF) has been shown to protect and restore dopamine (DA) neurons in injury models and is being evaluated for the treatment of Parkinson's disease. Nevertheless, little is known of its physiological role. We have shown that GDNF suppresses apoptosis in DA neurons of the substantia nigra (SN) postnatally both in vitro and during their first phase of natural cell death in vivo. Furthermore, intrastriatal injection of neutralizing antibodies augments cell death, suggesting that endogenous GDNF plays a role as a target-derived factor. Such a role would predict that overexpression of GDNF in striatum would increase the surviving number of SN DA neurons. To test this hypothesis, we used the tetracycline-dependent transcription activator (tTA)/tTA-responsive promoter system to create mice that overexpress GDNF selectively in the striatum, cortex, and hippocampus. These mice demonstrate an increased number of SN DA neurons after the first phase of natural cell death. However, this increase does not persist into adulthood. As adults, these mice also do not have increased dopaminergic innervation of the striatum. They do, however, demonstrate increased numbers of ventral tegmental area (VTA) neurons and increased innervation of the cortex. This morphologic phenotype is associated with an increased locomotor response to amphetamine. We conclude that striatal GDNF is necessary and sufficient to regulate the number of SN DA neurons surviving the first phase of natural cell death, but it is not sufficient to increase their final adult number. GDNF in VTA targets, however, is sufficient to regulate the adult number of DA neurons.

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Section: Introductionmentioning

confidence: 72%

“…However, the striatal TH-positive fiber staining evaluated at the regional level by optical density measurements (Burke et al, 1990;Oo et al, 2003) in adult mice revealed no difference between double transgenics and controls (Fig. 7A), nor did Western analysis of TH in striata (Fig.…”

Section: Striatal Dopaminergic Innervation Is Not Increased In Cblg-dmentioning

confidence: 94%

Regulation of the Development of Mesencephalic Dopaminergic Systems by the Selective Expression of Glial Cell Line-Derived Neurotrophic Factor in Their Targets

Kholodilov¹,

Yarygina²,

Oo³

et al. 2004

J. Neurosci.

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“…VPA upregulate GDNF and BDNF expression in astrocytes GDNF has been shown to promote DA neurons survival, induce neurite outgrowth and sprouting, [31][32][33] upregulate TH expression and enhance synaptic efficacy. 34 The presence of GDNF messenger RNA (mRNA) in the astrocytes of substantia nigra, 35,36 and the high sensitivity of DA neurons to this neurotrophin make GDNF a likely candidate for the yet unidentified VPA-induced, astrocytes-secreted neurotrophic substance.…”

Section: Resultsmentioning

confidence: 99%

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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“…Apoptotic profiles were identified in the SN on T Himmunoperoxidase stained and thionin-counterstained sections as previously described (39).…”

Section: Determination Of the Number Of Apoptotic Profiles Within Thementioning

confidence: 99%

Oncoprotein Akt/PKB induces trophic effects in murine models of Parkinson's disease

Ries

Henchcliffe²,

Kareva³

et al. 2006

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

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152

156

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Despite promising preclinical studies, neurotrophic factors have not yet achieved an established role in the treatment of human neurodegenerative diseases. One impediment has been the difficulty in providing these macromolecules in sufficient quantity and duration at affected sites. An alternative approach is to directly activate, by viral vector transduction, intracellular signaling pathways that mediate neurotrophic effects. We have evaluated this approach in dopamine neurons of the substantia nigra, neurons affected in Parkinson's disease, by adeno-associated virus 1 transduction with a gene encoding a myristoylated, constitutively active form of the oncoprotein Akt/PKB. Adeno-associated virus Myr-Akt has pronounced trophic effects on dopamine neurons of adult and aged mice, including increases in neuron size, phenotypic markers, and sprouting. Transduction confers almost complete protection against apoptotic cell death in a highly destructive neurotoxin model. Activation of intracellular neurotrophic signaling pathways by vector transfer is a feasible approach to neuroprotection and restorative treatment of neurodegenerative disease.apoptosis ͉ dopamine ͉ neurotrophic ͉ programmed cell death ͉ substantia nigra

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Regulation of Natural Cell Death in Dopaminergic Neurons of the Substantia Nigra by Striatal Glial Cell Line-Derived Neurotrophic FactorIn Vivo

Cited by 108 publications

References 55 publications

Regulation of the Development of Mesencephalic Dopaminergic Systems by the Selective Expression of Glial Cell Line-Derived Neurotrophic Factor in Their Targets

Regulation of the Development of Mesencephalic Dopaminergic Systems by the Selective Expression of Glial Cell Line-Derived Neurotrophic Factor in Their Targets

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

Oncoprotein Akt/PKB induces trophic effects in murine models of Parkinson's disease

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