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Journal of Molecular Neuroscience

, Volume 56, Issue 3, pp 681–687 | Cite as

Insulin-like Growth Factor 1 Differentially Affects Lithium Sensitivity of Lymphoblastoid Cell Lines from Lithium Responder and Non-responder Bipolar Disorder Patients

  • Elena Milanesi
  • Adva Hadar
  • Elisabetta Maffioletti
  • Haim Werner
  • Noam Shomron
  • Massimo Gennarelli
  • Thomas G. Schulze
  • Marta Costa
  • Maria Del Zompo
  • Alessio Squassina
  • David Gurwitz
Article

Abstract

Bipolar disorder (BD) is a chronic psychiatric illness with an unknown etiology. Lithium is considered the cornerstone in the management of BD, though about 50–60 % of patients do not respond sufficiently to chronic treatment. Insulin-like growth factor 1 (IGF1) has been identified as a candidate gene for BD susceptibility, and its low expression has been suggested as a putative biomarker for lithium unresponsiveness. In this study, we examined the in vitro effects of insulin-like growth factor 1 (IGF-1) on lithium sensitivity in lymphoblastoid cell lines (LCLs) from lithium responder (R) and non-responder (NR) bipolar patients. Moreover, we evaluated levels of microRNA let-7c, a small RNA predicted to target IGF1. We found that exogenous IGF-1 added to serum-free media increased lithium sensitivity selectively in LCLs from NR BD patients. However, no significant differences were observed when comparing let-7c expression in LCLs from R vs. NR BD patients. Our data support a key role for IGF-1 in lithium resistance/response in the treatment of bipolar disorder.

Keywords

Insulin-like growth factor 1 (IGF-1) Somatomedin C Let-7c Lithium Bipolar disorder Lymphoblastoid cell lines (LCLs) 

Abbreviations

BD

Bipolar disorder

IGF-1

Insulin-like growth factor 1

LCLs

Lymphoblastoid cell lines

R

Responders

NR

Non-responders

IGF1R

IGF-1 receptor

IR

Insulin receptor

LRP1

Receptor-related protein 1

IGFBP2

Insulin-like growth factor binding protein 2

miRNAs

MicroRNAs

IGFBP1

Insulin-like growth factor binding protein 1

IGFBP3

Insulin-like growth factor binding protein 3

qRT-PCR

Quantitative real-time-PCR

Notes

Acknowledgments

The authors thank the patients involved in the study for the generous collaboration. This study was supported by the US Israel Binational Science Foundation (BSF) Grant No. 2013223 (to DG). DG is supported by the Shalom and Varda Yoran Institute for Human Genome Research at Tel Aviv University. Elena Milanesi is a post-doctoral fellow supported by the Shabbetai Donnolo Fellowships between Italy and Israel. MG and Elisabetta Maffioletti are supported by grants from the Italian Ministry of Health (Ricerca Corrente). AS is a post-doctoral fellow funded by a grant from the Sardinia Regional Government (P.O.R. Sardegna F.S.E. Operational Program of the Autonomous Region of Sardinia, European Social Fund 2007-2013–Axis IV Human Resources, Objective l.3, Line of Activity l.3.1.).

Supplementary material

12031_2015_523_MOESM1_ESM.docx (63 kb)
Fig. S1 (A) Growth inhibition (%) induced by 10 μM paroxetine (72 h) in media containing 10 % FBS or 4 % Biogro-2. Bars indicate the average ± SD of the growth inhibition of three replicates. (B) Average of growth inhibition induced by 10 μM paroxetine in 4 % Biogro-2 and 10 % FBS media. Bars indicate the average ± SD of the growth inhibition. (DOCX 63 kb)
12031_2015_523_MOESM2_ESM.docx (23 kb)
Fig. S2 Effect of 10 % FBS on lithium sensitivity, Bars indicate the average of Delta 1 ± SD in R and NR BD patients. (DOCX 22 kb)
12031_2015_523_MOESM3_ESM.docx (40 kb)
Fig. S3 Relative expression levels of IGF-1. Relative expression levels were measured by means of the comparative Ct method (ΔΔ Ct) using GAPDH as endogenous control. Fold change of the difference between R and NR was calculated with 2 − ΔΔCt equation. Differences between R and NR were analyzed with the Mann–Whitney U test. (For more details see Squassina et al., 2013) (DOCX 40 kb)
12031_2015_523_MOESM4_ESM.docx (22 kb)
Fig. S4 Expression of let-7c in LCLs from 10 healthy controls, 10 R BD and 10 NR BD patients. U6 assay was used as endogenous control. Bars represent the fold difference compared with healthy controls ± SD. (DOCX 21 kb)

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Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Elena Milanesi
    • 1
    • 2
  • Adva Hadar
    • 1
  • Elisabetta Maffioletti
    • 3
  • Haim Werner
    • 1
  • Noam Shomron
    • 2
    • 4
  • Massimo Gennarelli
    • 3
    • 5
  • Thomas G. Schulze
    • 6
  • Marta Costa
    • 7
  • Maria Del Zompo
    • 7
    • 8
  • Alessio Squassina
    • 7
  • David Gurwitz
    • 1
    • 4
  1. 1.Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of MedicineTel Aviv UniversityTel AvivIsrael
  2. 2.Department of Cell and Developmental Biology, Sackler Faculty of MedicineTel Aviv UniversityTel AvivIsrael
  3. 3.Genetic UnitIRCCS Istituto Centro San Giovanni di Dio FatebenefratelliBresciaItaly
  4. 4.Sagol School of NeuroscienceTel Aviv UniversityTel AvivIsrael
  5. 5.Departement of Molecular and Translational MedicineUniversity of BresciaBresciaItaly
  6. 6.Institute of Psychiatric Phenomics and GenomicsLudwig-Maximilians-UniversityMunichGermany
  7. 7.Section of Neuroscience and Clinical Pharmacology, Department of Biomedical SciencesUniversity of CagliariCagliariItaly
  8. 8.Unit of Clinical Pharmacology of the University Hospital of CagliariCagliariItaly

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