In VivoMicrodialysis Studies of Somatodendritic Dopamine Release in the Rat Substantia Nigra: Effects of Unilateral 6-OHDA Lesions and GDNF

Hoffman, Alexander F.; Horne, Craig G. van; Eken, Servet; Hoffer, Barry J.; Gerhardt, Greg A.

doi:10.1006/exnr.1997.6571

Cited by 50 publications

(36 citation statements)

References 35 publications

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“…Support for this hypothesis comes from several reports that GDNF can phosphorylate TH and increase its activity both in vitro (Kobori et al 2004) and in vivo (Salvatore et al 2004). A GDNF-induced increase in DA content (Hudson et al, 1995; Beck et al, 1996; Martin et al, 1996, Rosenblad et al, 2003) and in the stimulus-evoked release of DA (Herbert et al, 1996; Herber & Gerhardt, 1997; Hoffman et al, 1997) has also been reported.…”

Section: Discussionmentioning

confidence: 97%

Effects of intrastriatal GDNF on the response of dopamine neurons to 6-hydroxydopamine: Time course of protection and neurorestoration

2011

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Glial cell line-derived neurotrophic factor (GDNF) protects dopamine (DA) neurons from 6-hydroxydopamine (6-OHDA) toxicity. We have now explored this protection over 8 weeks following toxin administration. Infusion of Fluoro-Gold (FG) into striatum was followed 1 week later by GDNF (9 μg) or its vehicle. Six hours later, animals received 6-OHDA (4 μg) into the same site. 6-OHDA caused a loss of cells in the substantia nigra that expressed both FG and tyrosine hydroxylase (TH) and striatal terminals expressing TH, the high affinity dopamine transporter (DAT), and the vesicular monoamine transporter 2 (VMAT2) as assessed 2-8 weeks later. Loss of FG + cells, and striatal DA was completely blocked by GDNF by 2 weeks. In contrast, GDNF only slightly attenuated the loss of TH, DAT, or VMAT2 in striatum at 2 wks, but had restored these markers by 4-8 weeks. Thus, GDNF prevents DA cell death and loss of striatal DA content, but several weeks are required to fully restore the dopaminergic phenotype. These results provide insight into the mechanism of GDNF protection of DA neurons, and may help avoid incorrect interpretations of temporary phenotypic changes.

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Section: Discussionmentioning

confidence: 97%

Effects of intrastriatal GDNF on the response of dopamine neurons to 6-hydroxydopamine: Time course of protection and neurorestoration

2011

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“…DNSP-11, an 11 amino acid peptide possibly derived from the human GDNF prosequence, is a stable, easy to synthesize and purify molecule that opens up a new area of neurotrophic factor development. It shares many physiological and neurotrophic properties analogous to mature GDNF including: neuroprotection and promoting differentiation in primary dopamine neuron cell cultures; increasing dopamine release and metabolism in vivo ; and decreasing apomorphine-induced rotations and enhancing dopamine function in the substantia nigra of 6-OHDA lesioned rats [7], [16], [49]. In addition, Immonen and colleagues have shown that the rat homolog of DNSP-11, called brain excitatory peptide (BEP), produces an increase in synaptic excitability in rat CA1 pyramidal neurons through possible involvement of a G-protein coupled receptor [15].…”

Section: Discussionmentioning

confidence: 99%

Dopamine Neuron Stimulating Actions of a GDNF Propeptide

et al. 2010

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BackgroundNeurotrophic factors, such as glial cell line-derived neurotrophic factor (GDNF), have shown great promise for protection and restoration of damaged or dying dopamine neurons in animal models and in some Parkinson's disease (PD) clinical trials. However, the delivery of neurotrophic factors to the brain is difficult due to their large size and poor bio-distribution. In addition, developing more efficacious trophic factors is hampered by the difficulty of synthesis and structural modification. Small molecules with neurotrophic actions that are easy to synthesize and modify to improve bioavailability are needed.Methods and FindingsHere we present the neurobiological actions of dopamine neuron stimulating peptide-11 (DNSP-11), an 11-mer peptide from the proGDNF domain. In vitro, DNSP-11 supports the survival of fetal mesencephalic neurons, increasing both the number of surviving cells and neuritic outgrowth. In MN9D cells, DNSP-11 protects against dopaminergic neurotoxin 6-hydroxydopamine (6-OHDA)-induced cell death, significantly decreasing TUNEL-positive cells and levels of caspase-3 activity. In vivo, a single injection of DNSP-11 into the normal adult rat substantia nigra is taken up rapidly into neurons and increases resting levels of dopamine and its metabolites for up to 28 days. Of particular note, DNSP-11 significantly improves apomorphine-induced rotational behavior, and increases dopamine and dopamine metabolite tissue levels in the substantia nigra in a rat model of PD. Unlike GDNF, DNSP-11 was found to block staurosporine- and gramicidin-induced cytotoxicity in nutrient-deprived dopaminergic B65 cells, and its neuroprotective effects included preventing the release of cytochrome c from mitochondria.ConclusionsCollectively, these data support that DNSP-11 exhibits potent neurotrophic actions analogous to GDNF, making it a viable candidate for a PD therapeutic. However, it likely signals through pathways that do not directly involve the GFRα1 receptor.

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“…We found that, in addition to increasing stimulus-evoked overflow of DA in the striatum, both NTN and GDNF produced substantial increases in nigral DA levels. It has been reported that intracerebral administration of GDNF can augment DA release in the substantia nigra [11, 30], suggesting that GDNF-induced increases in tissue levels of DA in the nigra may lead to enhanced somatodendritic release of DA. Thus, it will be important in future studies to define the behavioral effects of NTN and the role of striatal versus nigral release of DA on any observed behavioral changes.…”

Section: Discussionmentioning

confidence: 99%

Neurturin Effects on Nigrostriatal Dopamine Release and Content: Comparison with GDNF

Cass

Peters

2010

Neurochem Res

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Neurturin (NTN) is a member of the glial cell line-derived neurotrophic factor (GDNF) family; and, while GDNF has been shown to increase dopamine (DA) release in normal animals, the ability of NTN to alter DA release has not been previously reported. The purpose of the present study was to determine if NTN could alter striatal DA release, and to compare the effects of NTN to GDNF. Male Fischer-344 rats were given a single injection of vehicle or 5 μg NTN or GDNF into the right substantia nigra. Three weeks later microdialysis experiments were conducted to assess striatal DA release. Basal extracellular levels of striatal DA were not affected by either NTN or GDNF. However, both NTN and GDNF led to increases in amphetamine-evoked overflow of DA from the ipsilateral striatum, and there was a trend for potassium-evoked overflow to be augmented. Postmortem tissue levels of DA were decreased by approximately 20% in the striatum, and increased by approximately 100% in the substantia nigra, on the ipsilateral side of the brain compared to the contralateral side following both NTN and GDNF injection. Thus, NTN, like GDNF, can augment striatal DA release, and the magnitude of the NTN effects are similar to those of GDNF.

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In VivoMicrodialysis Studies of Somatodendritic Dopamine Release in the Rat Substantia Nigra: Effects of Unilateral 6-OHDA Lesions and GDNF

Cited by 50 publications

References 35 publications

Effects of intrastriatal GDNF on the response of dopamine neurons to 6-hydroxydopamine: Time course of protection and neurorestoration

Effects of intrastriatal GDNF on the response of dopamine neurons to 6-hydroxydopamine: Time course of protection and neurorestoration

Dopamine Neuron Stimulating Actions of a GDNF Propeptide

Neurturin Effects on Nigrostriatal Dopamine Release and Content: Comparison with GDNF

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