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Experimental Brain Research

, Volume 234, Issue 7, pp 1863–1873 | Cite as

IGF-1 protects dopamine neurons against oxidative stress: association with changes in phosphokinases

  • Amina El Ayadi
  • Michael J. Zigmond
  • Amanda D. SmithEmail author
Research Article

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.

Keywords

6-OHDA Akt CREB Parkinson’s disease Striatum ERK1/2 GSK-3Beta 

Notes

Acknowledgments

The study was funded by Career Development Award (NS45698) to ADS, Rita Levi-Montalcini Fellowship to AE and both a Udall Center of Excellence in Parkinson’s Disease Research (NS19608) and a Research Project Grant Award (NS070825) to MJZ.

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Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  • Amina El Ayadi
    • 1
    • 3
  • Michael J. Zigmond
    • 1
  • Amanda D. Smith
    • 1
    • 2
    Email author
  1. 1.Pittsburgh Institute for Neurodegenerative DiseaseUniversity of PittsburghPittsburghUSA
  2. 2.VA Pittsburgh Healthcare SystemUniversity of PittsburghPittsburghUSA
  3. 3.Department of SurgeryUniversity of Texas Medical BranchGalvestonUSA

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