Glial cell line‐derived neurotrophic factor prevents death, but not reductions in tyrosine hydroxylase, of injured nigrostriatal neurons in adult rats
Identifieur interne : 003B84 ( Main/Exploration ); précédent : 003B83; suivant : 003B85Glial cell line‐derived neurotrophic factor prevents death, but not reductions in tyrosine hydroxylase, of injured nigrostriatal neurons in adult rats
Auteurs : Xin Lu [Canada] ; Theo Hagg [Canada]Source :
- Journal of Comparative Neurology [ 0021-9967 ] ; 1997-11-24.
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Abstract
Glial cell line‐derived neurotrophic factor (GDNF) promotes survival of mesencephalic dopaminergic neurons in vitro and when injected locally into the brains of lesioned adult animals. Here, we show that GDNF (3 μg per day and higher) can promote the survival of all (retrogradely labeled) axotomized nigrostriatal dopaminergic neurons of adult rats when continuously infused for 2 weeks close to the substantia nigra, compared to only ∼30% survival with control infusions. Based on our previous observations, GDNF was as potent as ciliary neurotrophic factor and neurotrophin‐4 and approximately five to ten times more potent than brain‐derived neurotrophic factor and was most effective in promoting survival. GDNF prevented neuronal death induced by 6‐hydroxydopamine to a lesser extent than after axotomy. GDNF treatments begun 1 week after axotomy could maintain those neurons that had not yet died. When a 2 week GDNF treatment was interrupted, most of the GDNF‐rescued neurons died over the following 2 weeks. This suggests that longer trophic factor treatments or nigrostriatal connections are needed to achieve permanent survival. Measurements of tyrosine hydroxylase (TH) immunoreactivity of the rescued neuronal cell bodies suggest that GDNF cannot prevent the lesion‐induced loss of this rate‐limiting enzyme for dopamine synthesis. In fact, GDNF induced a decrease in TH in normal animals, suggesting an active down‐regulation of TH synthesis. Levels of TH immunoreactivity were recovered between 7 and 14 days after withdrawal of a 2 week GDNF infusion, in the neurons that survived axotomy. These results may have implications for developing new treatment strategies for Parkinson's disease. J. Comp. Neurol. 388:484–494, 1997. © 1997 Wiley‐Liss, Inc.
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DOI: 10.1002/(SICI)1096-9861(19971124)388:3<484::AID-CNE10>3.0.CO;2-M
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Comp. Neurol.</title><idno type="ISSN">0021-9967</idno><idno type="eISSN">1096-9861</idno><imprint><publisher>John Wiley & Sons, Inc.</publisher><pubPlace>New York</pubPlace><date type="published" when="1997-11-24">1997-11-24</date><biblScope unit="volume">388</biblScope><biblScope unit="issue">3</biblScope><biblScope unit="page" from="484">484</biblScope><biblScope unit="page" to="494">494</biblScope></imprint><idno type="ISSN">0021-9967</idno></series><idno type="istex">7AFB831016512720F30C55C6BAB3F28F39A6B1B9</idno><idno type="DOI">10.1002/(SICI)1096-9861(19971124)388:3<484::AID-CNE10>3.0.CO;2-M</idno><idno type="ArticleID">CNE10</idno></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0021-9967</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Parkinson's disease</term><term>axotomy</term><term>degeneration</term><term>dopaminergic</term><term>neurotoxicity</term></keywords></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Glial cell line‐derived neurotrophic factor (GDNF) promotes survival of mesencephalic dopaminergic neurons in vitro and when injected locally into the brains of lesioned adult animals. Here, we show that GDNF (3 μg per day and higher) can promote the survival of all (retrogradely labeled) axotomized nigrostriatal dopaminergic neurons of adult rats when continuously infused for 2 weeks close to the substantia nigra, compared to only ∼30% survival with control infusions. Based on our previous observations, GDNF was as potent as ciliary neurotrophic factor and neurotrophin‐4 and approximately five to ten times more potent than brain‐derived neurotrophic factor and was most effective in promoting survival. GDNF prevented neuronal death induced by 6‐hydroxydopamine to a lesser extent than after axotomy. GDNF treatments begun 1 week after axotomy could maintain those neurons that had not yet died. When a 2 week GDNF treatment was interrupted, most of the GDNF‐rescued neurons died over the following 2 weeks. This suggests that longer trophic factor treatments or nigrostriatal connections are needed to achieve permanent survival. Measurements of tyrosine hydroxylase (TH) immunoreactivity of the rescued neuronal cell bodies suggest that GDNF cannot prevent the lesion‐induced loss of this rate‐limiting enzyme for dopamine synthesis. In fact, GDNF induced a decrease in TH in normal animals, suggesting an active down‐regulation of TH synthesis. Levels of TH immunoreactivity were recovered between 7 and 14 days after withdrawal of a 2 week GDNF infusion, in the neurons that survived axotomy. These results may have implications for developing new treatment strategies for Parkinson's disease. J. Comp. 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