PEGylated insulin-like growth factor-I affords protection and facilitates recovery of lost functions post-focal ischemia.
Insulin-like growth factor-I (IGF-I) is involved in the maturation and maintenance of neurons, and impaired IGF-I signaling has been shown to play a role in various neurological diseases including stroke. The aim of the present study was to investigate the efficacy of an optimized IGF-I variant by adding a 40 kDa polyethylene glycol (PEG) chain to IGF-I to form PEG-IGF-I. We show that PEG-IGF-I has a slower clearance which allows for twice-weekly dosing to maintain steady-state serum levels in mice. Using a photothrombotic model of focal stroke, dosing from 3 hrs post-stroke dose-dependently (0.3-1 mg/kg) decreases the volume of infarction and improves motor behavioural function in both young 3-month and aged 22-24 month old mice. Further, PEG-IGF-I treatment increases GFAP expression when given early (3 hrs post-stroke), increases Synaptophysin expression and increases neurogenesis in young and aged. Finally, neurons (P5-6) cultured in vitro on reactive astrocytes in the presence of PEG-IGF-I showed an increase in neurite length, indicating that PEG-IGF-I can aid in sprouting of new connections. This data suggests a modulatory role of IGF-I in both protective and regenerative processes, and indicates that therapeutic approaches using PEG-IGF-I should be given early and where the endogenous regenerative potential is still high.
Department of Anatomy and Brain Health Research Center, University of Otago, Dunedin 9054, New Zealand.
Kim
K
Parker
Department of Anatomy and Brain Health Research Center, University of Otago, Dunedin 9054, New Zealand.
Antonio
A
Berretta
F. Hoffmann-La Roche Ltd., pRED, Pharma Research & Early Development, Roche Innovation Center Basel, Grenzacherstrasse 124, CH-4070, Basel, Switzerland.
Stefanie
S
Saenger
F. Hoffmann-La Roche Ltd., pRED, Pharma Research & Early Development, Roche Innovation Center Basel, Grenzacherstrasse 124, CH-4070, Basel, Switzerland.
Manaswini
M
Sivaramakrishnan
Department of Anatomy and Brain Health Research Center, University of Otago, Dunedin 9054, New Zealand.
Simon A
SA
Shirley
F. Hoffmann-La Roche Ltd., pRED, Pharma Research & Early Development, Roche Innovation Center Basel, Grenzacherstrasse 124, CH-4070, Basel, Switzerland.
Friedrich
F
Metzger
Department of Anatomy and Brain Health Research Center, University of Otago, Dunedin 9054, New Zealand. andrew.clarkson@otago.ac.nz.|Brain Research New Zealand, University of Otago, Dunedin 9054, New Zealand. andrew.clarkson@otago.ac.nz.|Faculty of Pharmacy, The University of Sydney, Sydney, Australia. andrew.clarkson@otago.ac.nz.
Andrew N
AN
Clarkson
D000818:Animals; D004195:Disease Models, Animal; D007334:Insulin-Like Growth Factor I / Q000008:administration & dosage* / Q000493:pharmacokinetics; D007511:Ischemia / Q000628:therapy*; D008124:Locomotion; D051379:Mice; D044967:Serum / Q000737:chemistry; D020521:Stroke / Q000628:therapy*; D016896:Treatment Outcome
D007334:Insulin-Like Growth Factor I