The actions of GDNF on injured and intact dopamine neurons

The actions of GDNF on injured and intact dopamine neurons

Field: Disorders of the nervous system

Authors: Kirik, Deniz
Rosenblad, Carl
Winkler, Christian
Mandel, Ron
Björklund, Anders

Address of presenting
author: Department of Physiology,
Section of Neurobiology,
Wallenberg Neuroscience Center,
Sölvegatan 17, S 223 62 Lund Sweden

E-mail: deniz.kirik@mphy.lu.se

Phone: +46 46 222 05 27

Fax: +46 46 222 05 61

Text of abstract: Glial cell line-derived neurotrophic factor (GDNF) is a potent survival promoting factor for the dopaminergic cells. We have used the intrastratal 6-OHDA lesion model to study the effects of GDNF, because this type of lesion produced a retrograde degeneration of axons followed by a delayed and protracted degeneration of cell bodies in the susbtantia nigra. Data from direct injection or continues infusion of the GDNF protein as well as long-term exression of GDNF in the nigra or the striatum by recombinant AAV-GDNF vectors show that GDNF has four distinct and complementary actions on the nigral DA neurons. (1) Expression of GDNF in striatum or nigra in intact animals causes an upregulation of DA turnover and induces contralateral side bias within 4 weeks after transduction with the AAV vectors; (2) GDNF can effectively protect nigral DA cell bodies from 6-OHDA toxicity both when it acts on the nigral DA cell bodies themselves or is delivered at the level of the terminals in the striatum; (3) Protection of the terminal DA innervation against the intrastriatal 6-OHDA lesion can be achieved only when the GDNF is delivered in the striatum (i.e. at the site of insult); (4) Functional regeneration from already damaged axons can be achieved only when GDNF is present in the striatum but not in the nigra. In addition, the recovery of normal motor functions is critically dependent on preservation or reinnervation of the striatum by DA terminals. Our data strongly suggest that in the rat PD model GDNF has to be delivered in the striatum in order to promote regeneration/sprouting of terminals in the striatum and alleviate motor impairments.

Keywords: parkinson's, glial-cell-line-derived-neurotrophic-factor, degeneration, neuroprotection

	The actions of GDNF on injured and intact dopamine neurons
Field:	Disorders of the nervous system
Authors:	Kirik, Deniz Rosenblad, Carl Winkler, Christian Mandel, Ron Björklund, Anders
Address of presenting author:	Department of Physiology, Section of Neurobiology, Wallenberg Neuroscience Center, Sölvegatan 17, S 223 62 Lund Sweden
E-mail:	deniz.kirik@mphy.lu.se
Phone:	+46 46 222 05 27
Fax:	+46 46 222 05 61
Text of abstract:	Glial cell line-derived neurotrophic factor (GDNF) is a potent survival promoting factor for the dopaminergic cells. We have used the intrastratal 6-OHDA lesion model to study the effects of GDNF, because this type of lesion produced a retrograde degeneration of axons followed by a delayed and protracted degeneration of cell bodies in the susbtantia nigra. Data from direct injection or continues infusion of the GDNF protein as well as long-term exression of GDNF in the nigra or the striatum by recombinant AAV-GDNF vectors show that GDNF has four distinct and complementary actions on the nigral DA neurons. (1) Expression of GDNF in striatum or nigra in intact animals causes an upregulation of DA turnover and induces contralateral side bias within 4 weeks after transduction with the AAV vectors; (2) GDNF can effectively protect nigral DA cell bodies from 6-OHDA toxicity both when it acts on the nigral DA cell bodies themselves or is delivered at the level of the terminals in the striatum; (3) Protection of the terminal DA innervation against the intrastriatal 6-OHDA lesion can be achieved only when the GDNF is delivered in the striatum (i.e. at the site of insult); (4) Functional regeneration from already damaged axons can be achieved only when GDNF is present in the striatum but not in the nigra. In addition, the recovery of normal motor functions is critically dependent on preservation or reinnervation of the striatum by DA terminals. Our data strongly suggest that in the rat PD model GDNF has to be delivered in the striatum in order to promote regeneration/sprouting of terminals in the striatum and alleviate motor impairments.

Keywords:	parkinson's, glial-cell-line-derived-neurotrophic-factor, degeneration, neuroprotection

Index

Created 2000-03-14

Department of Physiological Sciences, Lund University

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