title: Intranasal administration of glial-derived neurotrophic factor (GDNF) rapidly and significantly increases whole-brain GDNF level in rats.
abstract: Previous studies have shown that glial cell line-derived neurotrophic factor (GDNF) exerts significant neuroprotective effects on substantia nigra (SN) neurons in the rat 6-hydroxydopamine (6-OHDA) model of Parkinson's disease (PD). In this study we used enzyme-linked immunosorbent assay (ELISA) to determine GDNF brain levels and distribution to target regions (i.e. striatum and SN) following intranasal administration of GDNF at different time points after administration. Brain levels increased significantly within 1h following a single 50-μg dose of GDNF in a liposomal formulation, returning to baseline by 24h. In a second study, different doses of GDNF (10-150 μg) in phosphate-buffered saline (PBS) were studied at the 1-h time point. Dose-dependent increases in brain GDNF levels were observed with apparent saturation of uptake at doses above 100 μg. Liposomes delivered 10-fold more GDNF to brain than PBS despite yielding similar neuroprotective efficacy in the 6-OHDA model, suggesting incomplete release of GDNF from liposomes in tissue. In a third study, autoradiography was performed on brain sections taken 1h after intranasal (125)I-labeled GDNF. Radioactivity was detected throughout the brain along the rostral-to-caudal axis, indicating that nasally administered GDNF can reach target areas. Collectively, these results demonstrate that intranasal administration of GDNF in liposomes or PBS achieves significant increases in GDNF in target brain areas, supporting use of intranasal administration as a non-invasive means of delivering GDNF to the brain to protect dopamine neurons and arrest disease progression in PD.
authors.affiliation: Department of Pharmaceutical Sciences, Bouvé College of Health Sciences, 140 The Fenway, 360 Huntington Avenue, Northeastern University, Boston, MA 02115, USA.
authors.forename: T S
authors.initials: TS
authors.lastname: Bender
authors.affiliation: Department of Pharmaceutical Sciences, MCPHS University, 179 Longwood Avenue, Boston, MA 02115, USA.
authors.forename: M M
authors.initials: MM
authors.lastname: Migliore
authors.affiliation: Department of Pharmaceutical Sciences, MCPHS University, 19 Foster Street, Worcester, MA 01608, USA.
authors.forename: R B
authors.initials: RB
authors.lastname: Campbell
authors.affiliation: Department of Pharmaceutical Sciences, Bouvé College of Health Sciences, 140 The Fenway, 360 Huntington Avenue, Northeastern University, Boston, MA 02115, USA.
authors.forename: S
authors.initials: S
authors.lastname: John Gatley
authors.affiliation: Department of Pharmaceutical Sciences, Bouvé College of Health Sciences, 140 The Fenway, 360 Huntington Avenue, Northeastern University, Boston, MA 02115, USA. Electronic address: b.waszczak@neu.edu.
authors.forename: B L
authors.initials: BL
authors.lastname: Waszczak
mesh_terms: D000281:Administration, Intranasal; D000704:Analysis of Variance; D000818:Animals; D001345:Autoradiography; D001921:Brain / Q000187:drug effects* / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems; D004797:Enzyme-Linked Immunosorbent Assay; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000008:administration & dosage* / Q000378:metabolism*; D007456:Iodine Isotopes / Q000493:pharmacokinetics; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
chemical_list: D051100:Glial Cell Line-Derived Neurotrophic Factor; D007456:Iodine Isotopes
keywords: Parkinson’s disease; autoradiography; glial cell-line derived neurotrophic factor (GDNF); intranasal; liposomes; neuroprotection