Effects of novel neuroprotective and neurorestorative multifunctional drugs on iron chelation and glucose metabolism

Yulia Pollak, Danit Mechlovich, Tamar Amit, Orit Bar-Am, Irena Manov, Silvia A. Mandel, Orly Weinreb, Esther G. Meyron-Holtz, Theodore C. Iancu, Moussa B.H. Youdim

Research output: Contribution to journalArticlepeer-review


Iron accumulation and iron-related oxidative stress are involved in several pathological conditions and provide a rationale for the development of iron chelators as novel promising therapeutic strategies. Thus, we have recently synthesized multifunctional non-toxic, brain permeable iron chelating compounds, M30 and HLA20, possessing the neuroprotective N-propargyl moiety of the anti-Parkinsonian drug, monoamine oxidase (MAO)-B inhibitor, rasagiline and the antioxidant-iron chelating moiety of an 8-hydroxyquinoline derivative of the iron chelator, VK28. Here, we examined the hepatic regulatory effects of these novel compounds using two experimental approaches: chelation activity and glucose metabolism parameters. The present study demonstrated that M30 and HLA20 significantly decreased intracellular iron content and reduced ferritin expression levels in iron-loaded hepatoma Hep3B cells. In electron microscopy analysis, M30 was shown to reduce the electron-dense deposits of siderosomes by ~30 %, as well as down-regulate cytosolic ferritin particles observed in iron-overloaded cells. In vivo studies demonstrated that M30 administration (1 mg/kg, P.O. three times a week) reduced hepatic ferritin levels; increased hepatic insulin receptor and glucose transporter-1 levels and improved glucose tolerance in C57BL/6 mice and in a mouse model of type-2 diabetes, the ob/ob (leptin-/-). The results clearly indicate that the novel multifunctional drugs, especially M30, display significant capacity of chelating intracellular iron and regulating glucose metabolism parameters. Such effects can have therapeutic significance in conditions with abnormal local or systemic iron metabolism, including neurological diseases.

Original languageEnglish
Pages (from-to)37-48
Number of pages12
JournalJournal of Neural Transmission
Issue number1
StatePublished - Jan 2013
Externally publishedYes

Bibliographical note

Funding Information:
The authors thank Dr. Lana Kupershmidt for her assistance and Avital Weiss for her technical assistance on immunocytochemistry and helpful comments on the manuscript. The electron-microscopic study was partially supported by the Dan David Foundation (grant 05-2010). We are grateful to Technion Research and Development and Rappaport Family Research Institute (Haifa) for their support.


  • Electron microscopy
  • Glucose metabolism
  • Iron chelation
  • Iron-preloaded cells
  • M30

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology
  • Psychiatry and Mental health
  • Biological Psychiatry


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