Steroid receptors as targets for myelin regeneration by endogenous adult neural stem cells

The nerve fibres of the brain and spinal cord (the CNS) are surround by an insulting material called myelin that protects the fibres and allows them to carry electrical impulses very rapidly. Myelin is made by a cell called an oligodendrocyte. This cell is the primary target in several neurological diseases most notably multiple sclerosis (MS). Early in the disease the brains own stem cells are able to replace the lost oligodendrocytes and hence myelin can be restored (a regenerative process called remyelination). However, as the disease progresses and the patient ages remyelination becomes less efficient and the fibres are left without their myelin: in this state they are very vulnerable to irreversible degeneration themselves. Therapies that enhance remyelination would clearly have a major impact on the treatment of MS - however, none currently exist. In this short project UK and Chinese laboratories will collaborate to test the ability of a naturally-derived plant compound called diosgenin, which is already in clinical use, to enhance remyelination in ageing laboratory rodents and will initiate studies to understand the mechanisms of action of diosgenin in remyelination. It is intended that this application, if successful, will provide a platform for further more extensive Anglo-Chinese collaborative studies aimed at the development of remyelination-enhancing regenerative medicines for MS.

Remyelination is the process in which adult neural stem cells (OPCs) differentiate into oligodendrocytes that replace lost myelin sheaths, restoring function and protecting axons. In chronic demyelinating diseases such as multiple sclerosis remyelination slows and even fails with ageing, leaving axons vulnerable to irreversible degeneration. There is therefore a need to develop therapies that enhance remyelination and so prevent axon degeneration. This 12-month project brings together UK and Chinese research groups with complementary expertise in remyelination biology to further explore the remyelination enhancing properties of a plant steroid diosgenin. Using a combination of in vivo (toxin and immune-mediated rodent [transgenic] models of demyelination) and in vitro (myelinating co-cultures) approaches we will address two hypotheses: 1) diosgenin accelerates remyelination in the ageing CNS, 2) diosgenin exerts in pro-remyelination effects via direct effects on OPCs. The in vivo models we will use are 1) focal injection of lysolecithin into spinal cord white matter of ageing (>6 months) mice, and 2) focal injection of TNFa/IFNb into the spinal cord white matter of ageing (>9 months) Lewis rats previously sub-clinically immunised with rMOG. The extent of OPC recruitment, oligodendrocyte differentiation and remyelination in animals injected with diosgenin (20mg/kg and 100mg/kg, i.p.) will compared with controls at 5, 10 and 21 days after lesion induction. The role of the alpha and beta oestrogen receptors will be assessed using 1) knock-out mice deficient in either or both receptor and 2) OPC-dorsal root ganglion myelinating co-cultures, diosgenin administration and receptor knock-down with small interference RNA.

Both the UK and China applicants are engaged in programmes of research that aim to see fundamental aspects of remyelination biology translated into new regenerative therapies that will have substantial impact on the lives of individuals with demyelinating disease. The work described in this application is positioned towards the front end of the pipeline that leads from scientific discovery to clinical implementation, involving laboratory based studied to address pre-clinical questions. If the hypotheses addressed in this application are upheld it will not only lead to a further series of laboratory based studies on the role of sex steroid receptor mediated signalling in CNS remyelination but will also strengthen the case for 1) preliminary clinical trials with diosgenin for remyelination enhancement in MS patients (similar to the one currently been formulated by the Cambridge laboratory in collaboration with clinical colleagues in Cambridge, Edinburgh and UCL using the RXR agonist bexarotene), and 2) diosgenin as a chemical start point for a drug discovery programme towards more effective oestrogen receptor based drugs (for which the MRC Developmental Pathway Funding Scheme and/or Wellcome Trust Seeding Drug Discovery Scheme would provide suitable opportunities for advancing this work towards a clinical outcome).