Neurotrophic and neuroprotective efficacy of intranasal GDNF in a rat model of Parkinson's disease.
Glial cell line-derived neurotrophic factor (GDNF) exerts neurotrophic and neuroprotective effects on substantia nigra (SN) dopamine neurons and has great therapeutic potential for Parkinson's disease (PD). Hindering this potential is the fact that GDNF cannot cross the blood-brain barrier. The aim of this study was to assess the effects of GDNF administered by the intranasal route in normal rats, and in the unilateral 6-hydroxydopamine (6-OHDA) model of PD. In the first study, rats received single intranasal doses of 50-μg GDNF in phosphate-buffered saline (PBS) or cationic liposomes, but no 6-OHDA. In the second study, rats were nasally administered 10, 50 or 150 μg of GDNF in PBS or cationic liposomes 1h before injection of 6-OHDA. All groups were sacrificed 3-4 weeks later. Both intranasal GDNF treatments induced a neurotrophic effect in the SN insofar as the number of tyrosine hydroxylase (TH)-positive neurons was significantly higher than in controls given intranasal PBS liposomes. Dopamine cell counts were also higher in the intact SN of 6-OHDA-lesioned rats compared to controls given PBS liposomes. Most importantly, intranasal GDNF provided significant neuroprotective efficacy indicated by greater TH immunostaining density in the lesioned versus intact SN of rats given single 50-μg doses of GDNF in PBS, or 150-μg doses of liposomal GDNF, compared to lesioned rats given PBS liposomes. Three 50-μg doses given at daily intervals (1 day before, 1h before, and 1 day after 6-OHDA) provided even greater protection than single 150-μg doses. Multiple doses at short intervals may therefore provide greater neuroprotection than single bolus doses. These results demonstrate both a neurotrophic effect of intranasal GDNF in the intact SN as well as neuroprotective efficacy in the unilateral 6-OHDA model, supporting pursuit of this approach as a potential treatment for PD.
Department of Pharmaceutical Sciences, MCPHS University, 179 Longwood Avenue, Boston, MA 02115, USA.
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Migliore
Department of Pharmaceutical Sciences, Bouvé College of Health Sciences, 140 The Fenway, 360 Huntington Avenue, Northeastern University, Boston, MA 02115, USA.
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Ortiz
Department of Pharmaceutical Sciences, Bouvé College of Health Sciences, 140 The Fenway, 360 Huntington Avenue, Northeastern University, Boston, MA 02115, USA.
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Dye
Department of Pharmaceutical Sciences, MCPHS University, 19 Foster Street, Worcester, MA 01608, USA.
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Campbell
Department of Pharmaceutical Sciences, Bouvé College of Health Sciences, 140 The Fenway, 360 Huntington Avenue, Northeastern University, Boston, MA 02115, USA.
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Amiji
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.
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Waszczak
D000281:Administration, Intranasal; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002452:Cell Count; D004195:Disease Models, Animal; D059290:Dopaminergic Neurons / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000008:administration & dosage*; D008081:Liposomes; D008297:Male; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D016627:Oxidopamine; D010300:Parkinson Disease / Q000188:drug therapy* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013378:Substantia Nigra / Q000187:drug effects* / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D051100:Glial Cell Line-Derived Neurotrophic Factor; D008081:Liposomes; D018696:Neuroprotective Agents; D016627:Oxidopamine; D014446:Tyrosine 3-Monooxygenase
6-hydroxydopamine; Parkinson’s disease; glial cell line derived neurotrophic factor; intranasal; substantia nigra; tyrosine hydroxylase