title: Glial cell line-derived neurotrophic factor attenuates behavioural deficits and regulates nigrostriatal dopaminergic and peptidergic markers in 6-hydroxydopamine-lesioned adult rats: comparison of intraventricular and intranigral delivery.
abstract: The effects of intranigrally- or intraventricularly-administered glial cell line-derived neurotrophic factor were tested on low dose (0.05 mg/kg) apomorphine-induced rotations and tyrosine hydroxylase activity in the substantia nigra and striatum of stable 6-hydroxydopamine-lesioned rats. In addition, we determined if 6-hydroxydopamine lesions in the absence or presence of treatment affected neuropeptide (substance P, met-enkephalin, dynorphin) content in the striatum. Glial cell line-derived neurotrophic factor, when administered intranigrally, prevented apomorphine-induced rotational behaviour for 11 weeks following a single injection. In comparison, intraventricularly-administered glial cell line-derived neurotrophic factor produced a transient reduction in rotational behaviour that lasted for two to three weeks following a single injection. We also show that rotational behaviour is reduced following each subsequent intraventricular injection of glial cell line-derived neurotrophic factor given every six weeks, a time-point when baseline rotation deficits were re-established. Intranigrally- or intraventricularly-administered glial cell line-derived neurotrophic factor significantly reduced weight gain in all 6-hydroxydopamine-lesioned rats in this study. Following behavioural analysis where a confirmed improvement of behaviour was established, tissues were dissected for neurochemical analysis. In lesioned rats with intranigral injections of administered glial cell line-derived neurotrophic factor, significant increases of nigral, but not striatal tyrosine hydroxylase activity were measured. Additionally, 6-hydroxydopamine lesions significantly increased striatal dynorphin (61-139%) and met-enkephalin (81-139%), but not substance P levels. In these rats, intranigrally-administered glial cell line-derived neurotrophic factor injections reversed lesion-induced increases in nigral dynorphin A levels and increased nigral dopamine levels, but did not alter nigral met-enkephalin or substance P levels nor striatal dopamine levels. In lesioned rats with intraventricular injections of glial cell line-derived neurotrophic factor, tyrosine hydroxylase ispilateral to the lesion was increased in the substantia nigra, but not in the striatum. Intraventricularly-administered glial cell line-derived neurotrophic factor did not reverse lesion-induced increases in nigral dynorphin A or met-enkephalin levels nor did glial cell line-derived neurotrophic factor affect substance P levels in the striatum. These results suggest that in an animal model of Parkinson's disease, the neurotrophic factor glial cell line-derived neurotrophic factor reverses behavioural consequences of 6-hydroxydopamine administration, an effect that may involve both dopaminergic and peptidergic neurotransmission.
authors.affiliation: AMGEN INC., Department of Neuroscience, Thousand Oaks, CA 91320-1789, U.S.A.
authors.forename: P A
authors.initials: PA
authors.lastname: Lapchak
authors.forename: P J
authors.initials: PJ
authors.lastname: Miller
authors.forename: F
authors.initials: F
authors.lastname: Collins
authors.forename: S
authors.initials: S
authors.lastname: Jiao
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D015415:Biomarkers; D002851:Chromatography, High Pressure Liquid; D004298:Dopamine / Q000378:metabolism*; D005260:Female; D051100:Glial Cell Line-Derived Neurotrophic Factor; D007267:Injections; D007276:Injections, Intraventricular; D017072:Neostriatum / Q000187:drug effects* / Q000378:metabolism*; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins / Q000378:metabolism / Q000494:pharmacology*; D009479:Neuropeptides / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D016627:Oxidopamine / Q000008:administration & dosage / Q000633:toxicity; D051381:Rats; D017208:Rats, Wistar; D013239:Stereotyped Behavior / Q000187:drug effects; D013378:Substantia Nigra / Q000187:drug effects* / Q000378:metabolism*; D013566:Sympathomimetics / Q000008:administration & dosage / Q000633:toxicity; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D015430:Weight Gain / Q000187:drug effects
chemical_list: D015415:Biomarkers; C495041:Gdnf protein, rat; D051100:Glial Cell Line-Derived Neurotrophic Factor; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D009479:Neuropeptides; D018696:Neuroprotective Agents; D013566:Sympathomimetics; D016627:Oxidopamine; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine