title: Pegylated granulocyte colony-stimulating factor conveys long-term neuroprotection and improves functional outcome in a model of Parkinson's disease.
abstract: Recent proof-of-principle data showed that the haematopoietic growth factor granulocyte colony-stimulating factor (filgrastim) mediates neuroprotection in rodent models of Parkinson's disease. In preparation for future clinical trials, we performed a preclinical characterization of a pegylated derivative of granulocyte colony-stimulating factor (pegfilgrastim) in the mouse 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of Parkinson's disease. We determined serum and cerebrospinal fluid drug levels after subcutaneous injection. A single injection of pegfilgrastim was shown to achieve stable levels of granulocyte colony-stimulating factor in both serum and cerebrospinal fluid with substantially higher levels compared to repetitive filgrastim injections. Leucocyte blood counts were only transiently increased after repeated injections. We demonstrated substantial dose-dependent long-term neuroprotection by pegfilgrastim in both young and aged mice, using bodyweight-adjusted doses that are applicable in clinical settings. Importantly, we found evidence for the functionally relevant preservation of nigrostriatal projections by pegfilgrastim in our model of Parkinson's disease, which resulted in improved motor performance. The more stable levels of pegylated neuroprotective proteins in serum and cerebrospinal fluid may represent a general advantage in the treatment of chronic neurodegenerative diseases and the resulting longer injection intervals are likely to improve patient compliance. In summary, we found that pegylation of a neuroprotective growth factor improved its pharmacokinetic profile over its non-modified counterpart in an in vivo model of Parkinson's disease. As the clinical safety profile of pegfilgrastim is already established, these data suggest that evaluation of pegfilgrastim in further Parkinson's disease models and ultimately clinical feasibility studies are warranted.
authors.affiliation: Department of Neurology, University Medical Centre, Georg-August-University, 37075 Göttingen, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Frank
authors.forename: Florian
authors.initials: F
authors.lastname: Klinker
authors.forename: Björn H
authors.initials: BH
authors.lastname: Falkenburger
authors.forename: Rico
authors.initials: R
authors.lastname: Laage
authors.forename: Fred
authors.initials: F
authors.lastname: Lühder
authors.forename: Bettina
authors.initials: B
authors.lastname: Göricke
authors.forename: Armin
authors.initials: A
authors.lastname: Schneider
authors.forename: Hartmud
authors.initials: H
authors.lastname: Neurath
authors.forename: Herbert
authors.initials: H
authors.lastname: Desel
authors.forename: David
authors.initials: D
authors.lastname: Liebetanz
authors.forename: Mathias
authors.initials: M
authors.lastname: Bähr
authors.forename: Jochen H
authors.initials: JH
authors.lastname: Weishaupt
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000009:adverse effects; D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002851:Chromatography, High Pressure Liquid; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D000069585:Filgrastim; D016179:Granulocyte Colony-Stimulating Factor / Q000378:metabolism / Q000627:therapeutic use*; D006719:Homovanillic Acid / Q000378:metabolism; D007279:Injections, Subcutaneous; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D010300:Parkinson Disease / Q000097:blood / Q000134:cerebrospinal fluid / Q000188:drug therapy* / Q000209:etiology; D011092:Polyethylene Glycols / Q000378:metabolism / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000378:metabolism / Q000627:therapeutic use; D045442:Rotarod Performance Test; D013997:Time Factors; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D018696:Neuroprotective Agents; D011994:Recombinant Proteins; D015102:3,4-Dihydroxyphenylacetic Acid; D016179:Granulocyte Colony-Stimulating Factor; C455861:pegfilgrastim; D011092:Polyethylene Glycols; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D014446:Tyrosine 3-Monooxygenase; C423652:pegylated granulocyte colony-stimulating factor; D000069585:Filgrastim; D006719:Homovanillic Acid