Biography:

Susan Duty completed her PhD from the University of Manchester and undertook postdoctoral studies at the Universities of Sydney and Manchester before achieving an academic appointment at King’s College London in 1995. She is now Head of Department of Pharmacology & Therapeutics and Primary Investigator in the Wolfson Centre for Age-Related Diseases. She has published more than 49 papers and is a long-standing committee member of the British Pharmacological Society. Research in Susan’s laboratory is currently funded by the European Union’s Horizon 2020 research and innovation programme under the Marie SkÅ‚odowska-Curie Grant Agreement No 764860, Parkinson’s UK and Innovate UK.

 

Abstract:

Parkinson’s disease is a neurodegenerative disorder accompanied by motor symptoms which result from degeneration of dopaminergic neurons in the nigrostriatal pathway. While current treatments aimed at replenishing lost dopamine transmission help restore movement, these treatments do not combat the ongoing neurodegeneration so motor symptoms continue to progressively worsen. There currently remains no neuroprotective treatment for use in Parkinson’s disease. We previously reported that direct intracerbral infusion of fibroblast growth factor 20 (FGF20), a neurotrophic factor which supports dopaminergic neurones, was neuroprotective in the 6-hydroxydopamine (6-OHDA) lesion rat model of Parkinson's disease. Given the difficulties associated with growth factor infusion in patients, we looked for an alternative way to boost endogenous FGF20 levels to achieve this neuroprotection. Specifically, we adopted a targeted repurposing approach to screen for candidate FDA-approved drugs with potential to enhance endogenous FGF20 production. In silico interrogation of the Broad Institute’s Connectivity Map database revealed 16 candidate drugs that increased FGF20 transcription, were blood brain barrier penetrant and not contra-indicated for use in Parkinson’s disease. Through in-vitro screening, 4 drugs were found to significantly elevate FGF20 protein levels, as determined by ELISA, in both MCF-7 cells and ventral mesencephalic primary cultures. Of these, salbutamol and triflusal significantly elevated FGF20 levels in the nigrostriatal tract in rats treated orally for 7 days and afforded a modest but significant protection against against nigral cell loss in the 6-OHDA-lesion rat. These daa support targeted repurposing as a powerful strategy to help the timely identification of neuroprotective treatments for Parkinson’s disease.  

 

Biography:

Professor Lazarovici graduated in pharmacology and toxicology at the Hebrew University, post graduated on neurobiology at the Weizmann Institute of Science and conducted neurochemical and molecular research at the National Institutes of Child Health and Human Development, NIH, Bethesda, USA. He was a visiting professor in the School of Biomedical Engineering, Science and Health Systems, Drexel University and Faculty of Engineering, Temple University, Philadelphia, USA.  Prof. Lazarovici is a member of 15 international and national academic societies, published about 250 scientific articles and reviews and edited six books.

 

Abstract:

Critical limb ischemia (CLI) is a severe form of peripheral artery disease caused by a poor supply of blood to the affected muscle. The ultimate failure of surgical revascularization in patients has led to attempts to develop alternative angiogenic therapies, including administration of angiogenic growth factors either as recombinant protein or as gene therapy. Vascular Endothelial Growth Factor (VEGF), is crucial for new blood vessels formation and Nerve Growth Factor (NGF) has  been also reported to play an important role in angiogenesis although, less investigated. Based on these observations, we hypothesized that NGF may induce the formation of functional blood vessels in a hindlimb ischemic rabbit model. Results: Hindlimb ischemia was induced in 34 rabbits bilaterally, by endovascular embolization of femoral arteries. On the 7th, 14th, and 20th post-embolization days, NGF was injected intramuscularly, in one ischemic limb, and vehicle was injected in the contralateral control limb. On the 40th day, newly developed collateral vessels were quantified by trans-auricular, intra-arterial subtraction angiography. Perfusion analysis of an in vivo dynamic computed tomography (CT) study was performed, to investigate the hemodynamic recovery of the distal ischemic tissues. Functional estimation of limb perfusion showed a statistically significant increase of blood flow and blood volume upon NGF therapy. However, the increase of the collateral vessels was not detectable angiographically, explaining NGF-stimulated, capillary angiogenic network formation but not increase of arteriogenesis. The combination of NGF with either tropomyosin-related kinase type A receptor or vascular endothelial growth factor receptor 2 antagonists, abolished the NGF-induced hemodynamic recovery. Conclusions: These findings provide new insights into understanding the involvement of NGF in vascular formation and its applications in therapeutic angiogenesis of CLI.

P. Lazarovici holds The Jacob Gitlin Chair in Physiology and is affiliated and partially supported by the David R. Bloom Center for Pharmacy and the Dr. Adolf and Klara Brettler Center for Research in Molecular Pharmacology and Therapeutics at The Hebrew University of Jerusalem, Israel.