title: IGF-1 protects dopamine neurons against oxidative stress: association with changes in phosphokinases.
abstract: Insulin-like growth factor-1 (IGF-1) is an endogenous peptide transported across the blood brain barrier that is protective in several brain injury models, including an acute animal model of Parkinson's disease (PD). Motor deficits in PD are due largely to the progressive loss of nigrostriatal dopaminergic neurons. Thus, we examined the neuroprotective potential of IGF-1 in a progressive model of dopamine deficiency in which 6-hydroxydopamine (6-OHDA) is infused into the striatum. Rats received intrastriatal IGF-1 (5 or 50 µg) 6 h prior to infusion of 4 µg 6-OHDA into the same site and were euthanized 1 or 4 weeks later. Both concentrations of IGF-1 protected tyrosine hydroxylase (TH) immunoreactive terminals in striatum at 4 weeks but not at 1 week, indicating that IGF-induced restoration of the dopaminergic phenotype occurred over several weeks. TH-immunoreactive cell loss was only attenuated with 50 µg IGF-1. We then examined the effect of striatal IGF-1 on the Ras/ERK1/2 and PI3K/Akt pathways to ascertain whether their activation correlated with IGF-1-induced protection. Striatal and nigral levels of phospho-ERK1/2 were maximal 6 h after IGF-1 infusion and, with the exception of an increase in nigral pERK2 at 48 h, returned to basal levels by 7 days. Phospho-Akt (Ser473) was elevated 6-24 h post-IGF-1 infusion in both striatum and substantia nigra concomitant with inhibition of pro-death GSK-3β, a downstream target of Akt. These results suggest that IGF-1 can protect the nigrostriatal pathway in a progressive PD model and that this protection is preceded by activation of key pro-survival signaling cascades.
authors.affiliation: Pittsburgh Institute for Neurodegenerative Disease, University of Pittsburgh, 3501 Fifth Avenue, 7026 Biomedical Science Tower 3, Pittsburgh, PA, 15261, USA.|Department of Surgery, University of Texas Medical Branch, Galveston, TX, 77550, USA.
authors.forename: Amina El
authors.initials: AE
authors.lastname: Ayadi
authors.affiliation: Pittsburgh Institute for Neurodegenerative Disease, University of Pittsburgh, 3501 Fifth Avenue, 7026 Biomedical Science Tower 3, Pittsburgh, PA, 15261, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Zigmond
authors.affiliation: Pittsburgh Institute for Neurodegenerative Disease, University of Pittsburgh, 3501 Fifth Avenue, 7026 Biomedical Science Tower 3, Pittsburgh, PA, 15261, USA. smithad@pitt.edu.|VA Pittsburgh Healthcare System, University of Pittsburgh, Pittsburgh, PA, USA. smithad@pitt.edu.
authors.forename: Amanda D
authors.initials: AD
authors.lastname: Smith
mesh_terms: D018663:Adrenergic Agents / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D004195:Disease Models, Animal; D059290:Dopaminergic Neurons / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta / Q000187:drug effects / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000008:administration & dosage / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D017072:Neostriatum / Q000187:drug effects / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000494:pharmacology*; D018384:Oxidative Stress; D016627:Oxidopamine / Q000008:administration & dosage / Q000494:pharmacology; D020734:Parkinsonian Disorders / Q000188:drug therapy / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism*; D014446:Tyrosine 3-Monooxygenase / Q000187:drug effects / Q000378:metabolism
chemical_list: D018663:Adrenergic Agents; D018696:Neuroprotective Agents; D007334:Insulin-Like Growth Factor I; D016627:Oxidopamine; D014446:Tyrosine 3-Monooxygenase; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt
keywords: 6-OHDA; Akt; CREB; ERK1/2; GSK-3Beta; Parkinson’s disease; Striatum