title: GDNF reduces drug-induced rotational behavior after medial forebrain bundle transection by a mechanism not involving striatal dopamine.
abstract: Parkinson's disease (PD) is characterized by the progressive loss of the substantia nigra (SN) dopaminergic neurons projecting to the striatum. Neurotrophic factors may have the potential to prevent or slow down the degenerative process occurring in PD. To that end, we examined whether low amounts of glial cell line-derived neurotrophic factor (GDNF) continuously released from polymer-encapsulated genetically engineered cells are able to prevent the loss of tyrosine hydroxylase immunoreactivity (TH-IR) in SN neurons and ameliorate the amphetamine-induced rotational asymmetry in rats that have been subjected to a unilateral medial forebrain bundle (MFB) axotomy. Baby hamster kidney (BHK) cells transfected with the cDNA for GDNF were encapsulated in a polymer fiber and implanted unilaterally at a location lateral to the MFB and rostral to the SN. ELISA assays before implantation show that the capsules release approximately 5 ng of GDNF/capsule per day. One week later, the MFB was axotomized unilaterally ipsilateral to the capsule placement. Seven days later, the animals were tested for amphetamine-induced rotational asymmetry and killed. The striatum was excised and analyzed either for catecholamine content or TH-IR, while the SN was immunostained for the presence of TH-IR. GDNF did not prevent the loss of dopamine in the striatum. However, GDNF significantly rescued TH-IR neurons in the SN pars compacta. Furthermore, GDNF also significantly reduced the number of turns per minute ipsilateral to the lesion under the influence of amphetamine. Improvement of rotational behavior in the absence of dopaminergic striatal reinnervation may reflect neuronal plasticity in the SN, as suggested by the dendritic sprouting observed in animals receiving GDNF. These results illustrate that the continuous release of low levels of GDNF close to the SN is capable of protecting the nigral dopaminergic neurons from an axotomy-induced lesion and significantly improving pharmacological rotational behavior by a mechanism other than dopaminergic striatal reinnervation.
authors.affiliation: Gene Therapy Center and Division of Surgical Research, Centre Hospitalier Universitaire Vaudois, Lausanne University Medical School, 1011 Lausanne, Switzerland.
authors.forename: J L
authors.initials: JL
authors.lastname: Tseng
authors.forename: E E
authors.initials: EE
authors.lastname: Baetge
authors.forename: A D
authors.initials: AD
authors.lastname: Zurn
authors.forename: P
authors.initials: P
authors.lastname: Aebischer
mesh_terms: D000818:Animals; D000831:Animals, Newborn / Q000378:metabolism; D002214:Capsules; D003342:Corpus Striatum / Q000378:metabolism*; D006224:Cricetinae; D003714:Denervation; D004298:Dopamine / Q000502:physiology*; D005260:Female; D051100:Glial Cell Line-Derived Neurotrophic Factor; D007150:Immunohistochemistry; D007668:Kidney / Q000166:cytology / Q000378:metabolism; D008474:Medial Forebrain Bundle / Q000502:physiology*; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins / Q000008:administration & dosage* / Q000378:metabolism / Q000494:pharmacology; D018696:Neuroprotective Agents / Q000008:administration & dosage* / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013239:Stereotyped Behavior / Q000187:drug effects*; D013378:Substantia Nigra / Q000378:metabolism; D014162:Transfection; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D002214:Capsules; C495041:Gdnf protein, rat; D051100:Glial Cell Line-Derived Neurotrophic Factor; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine