Page 69 - University of Pretoria RESEARCH REVIEW 2016

BRAIN-BODY DIALOGUES
AND THE PRODUCTION OF HORMONES
The Centre for Neuroendocrinology: Brain-Body Dialogues is a new Research Centre in the Faculty of Health Sciences, established in 2015.
Directed by Professor Robert Millar, and supported by principal investigators, Dr Claire Newton (Deputy Director), Dr Ross Anderson and recently Dr Iman van den Bout, the Centre has in a short span of time already recruited 15 members of staff and students.
Research in the Centre addresses the way in which the external and internal (body) environments
are detected by the brain and integrated in the hypothalamic area to produce hormones that regulate all aspects of body health including stress, metabolism, appetite, growth and reproduction. Disturbance of this homeostasis results in debilitating diseases such as obesity and diabetes, a failure to grow, infertility, and cancers of the prostate, breast and female reproductive tract.
Research is characterised by the continuum of basic through to clinical research with a major emphasis on the development of new therapeutics or diagnostic tools. Three research highlights in 2016 include:
A new treatment for hot flushes
in post-menopausal women
Professor Robert Millar has worked with Euroscreen, a biotech company in Belgium, to develop an antagonist of Neurokinin B, a hypothalamic hormone. Professor Millar hypothesised that a Neurokinin B antagonist would provide treatment for polycystic ovarian syndrome (which affects 30% of women) and hot flushes (which affects 60–80% of post-menopausal women). This compound has now proven to be successful in reducing the frequency and severity of menopausal hot flushes in a Phase IIa clinical trial, and a large-scale Phase IIb trial is now being planned.
Identifying a drug that restores function to inactivating mutations of receptors
A primary focus of the Centre’s research revolves around the breakthrough discovery that function can be restored to inactivating genetic mutations in human G-protein-coupled receptors (GPCRs),
which are responsible for cell communication.
Dr Claire Newton and Dr Ross Anderson have
fully characterised inactivating mutations in the human luteinising hormone receptor, the conduit for stimulation of the ovaries and testes, which
have been identified in patients suffering from reproductive dysfunction. They found that most of the mutations result in a failure of the receptors to traffic to the cell surface, preventing interaction with their hormone signal and therefore rendering the receptors non-functional. They have also discovered a novel small-molecule compound that is able to enter cells and stabilise such mutant receptors
so that they are expressed on the cell surface, therefore restoring their function. Clinical proof-of- concept studies are now being initiated with patents harbouring mutations, which they have shown can be rescued in vitro.
Development of a novel
prostate-cancer therapeutic
A research highlight is the development of a Gonadotropin-releasing hormone (GnRH) analogs
that ameliorates the negative side-effects of current therapeutics. GnRH analogs are the mainstay of prostate cancer treatment by depleting
androgen. However, the concomitant
depletion of oestrogens, which are
synthesised from androgens, produces
adverse side-effects of hot flashes and
loss of bone and libido. Researchers at
the Centre proposed that GnRH analogs
conjugated to oestrogens could retain
both GnRH and oestrogen activities in a
single molecule, thereby achieving both
androgen deprivation and oestrogen
replacement with resultant amelioration
of side-effects. They have demonstrated
that conjugates of GnRH analogues to
estradiol or the phytoestrogen, genistein,
are active at binding and activating
the GnRH receptor, and also activate
oestrogen receptors in vitro. They now
propose to undertake more detailed in
vitro studies and also to demonstrate that
the compounds are anti-androgenic and
oestrogenic in male rats. Robert Millar
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