Technology Opportunities

Studying the physiological and pharmacological effects of a family of new steroid drugs consisting of digitalis-like compounds endogenous in mammalian tissue with particular emphasis on the functions of these hormones on the brain and cardiovascular system

Laboratory of Cell Physiology, Department of Medical Neurobiology, Institute for Medical Research-Israel-Canada, Faculty of Medicine

Research Background

Research in this laboratory is aimed at the elucidation of the physiological role of endogenous digitalis-like compounds, which are sodium pump (Na,K-ATPase) inhibitors used as therapeutics in the treatment of congestive heart failure and atrial fibrillation. They are endogenously present in mammals and function as hormones. Steroids of this family are synthesized in and released from the adrenal gland. Although a vast amount of literature has demonstrated the involvement of these compounds in several pathological states, their physiological role is still obscure. Work in the laboratory is focused on the possible function of the steroids in the regulation of cardiovascular function, behaviour, and cell growth.

Research Capabilities

• Studies are being carried out on a new family of steroids that interact with sodium-potassium-ATPase at the molecular, cellular and whole experimental animal levels
• The physiological role of the digitalis-like steroids on the cardiovascular system is investigated in- vitro in heart muscle preparation and in-vivo in rats, mice, and zebra fish. The effects of the compounds on brain function are studied at cellular level, using neuronal tissue cultured cells (PC12, NT2) and on animal behavior models using the forced swimming test. The molecular mechanisms underlining these responses are investigated using conventional biochemical and molecular techniques.
• Understanding the physiological role of this family of steroids may point to new targets for the development of drugs for the treatment of cardiac, neurological and psychiatric diseases. Furthermore, the synthesis of new derivatives of these hormones may result in new drugs that have beneficial effects through interaction with the Na+, K+-ATPase. Such compounds have already been discovered in the laboratory.

Advantages

This laboratory is recognised as one of the world leaders for the study of endogenous and exogenous digitalis steroids. Since increasing evidence demonstrates that the interaction of these steroids with the Na+, K+-ATPase elicits numerous cell and tissue specific pharmacological responses, this family of steroids may be considered as a novel platform for drug development. The effect of one of the newly synthesised compounds on FSL rats in the Forced Swimming Test is shown in the figure. The results clearly prove that the compound has robust anti-depressive effect.

Effect of synthetic digitalis-like compound on behavior in FSL rats:

FSL rats treated chronically for 14 days with ip injections of the steroid (n=10) or pluronic 1% (n=7) as control (both 2 mg/kg/day). At day 15, anti-depressive behavior was measured by FST. The attenuation of the depressive-like behavior was manifested by marked reduction in immobility time (*p<0.02), significant increase in climbing (*p<0.02) and mobility time (**p<0.01).

Researcher and Research Interests

Professor David Lichtstein, Jacob Gitlin Chair of Physiology. Professor Lichtstein is currently the Chairman of the Institute for Medical Research Israel-Canada, at the faculty of Medicine. He is the former chairman of the Department of Physiology and former President of the Israeli Society for Physiology and Pharmacology. His research focus on the regulation of Na+, K+-ATPase activity and its biological and pharmacological consequences, a topic in which he is one of the world leaders.

Collaborators:

Professor Haim Rosen

Professor Joseph Deutsch

Available Resources

The following technologies are currently employed in the laboratory:

• Measurements of cardiovascular function, in-vivo, in rats, mice and zebra fish
• Measurements of cardiac and smooth muscle contractility in ex-vivo preparations (Langedorf, Atrial and Purkinje Fibers) from rats, mice and guinea pigs
• Measurement of animal behaviour in Forced Swimming and Open Field tests
• Determination of ion homeostasis in-vivo in rats and mice using metabolic cages
• Analysis of intracellular signalling pathways activity by the determination of phosphorylated proteins
• Determination of Na+, K+-ATPase activity by the measurement of ion transport and ATP hydrolysis

Laboratory Contact