Poster Presentation 10th Australian Peptide Conference 2013

The BDNF mimetic cyclo-dPAKKR promotes myelination and remyelination in the periphery. (9863)

Richard A Hughes 1 , Junhua Xiao 2 , Giang Tran 3 , Suzanne Hodgkinson 3 , Agnes W Wong 2 , Simon S Murray 2
  1. Pharmacology, University of Melbourne, Parkville, Vic, Australia
  2. Anatomy and Neuroscience, University of Melbourne, Parkville, Vic, Australia
  3. University of New South Wales, Sydney, NSW, Australia

The neurotrophins are proteins that are essential for the development of the peripheral nervous system including the process of myelination. The neurotrophin BDNF has been shown to exert contrasting influences upon myelination via its two receptors - acting through neuronal p75NTR to enhance myelination, but inhibiting it via neuronal trkB.  We previously described the cyclic pentapeptide cyclo-dPAKKR, a structural mimic of a region of BDNF that binds to p75NTR that acts to promote neuronal survival in vitro. Here we investigated whether cyclo-dPAKKR, by selectively targeting p75NTR, could exert a unified promyelinating response. In vitro, we found that like BDNF, cyclo-dPAKKR promoted myelination of NGF-dependent neurons, its effect dependent on the expression of p75NTR on neurons.  However, whereas BDNF inhibited the myelination of BDNF-dependent neurons, cyclo-dPAKKR significantly enhanced it.  Local injection of cyclo-dPAKKR adjacent to the neonatal sciatic nerve in vivo significantly increased both myelin protein expression and the number of myelinated axons, as well as significantly upregulating the expression of neuregulin 1 type-III, a key factor in the induction of peripheral myelination. To investigate whether cyclo-dPAKKR could also promote the remyelination of peripheral neurons, we examined the effects of cyclo-dPAKKR in the EAN rodent model of peripheral demyelinating neuropathy.  Administration of cyclo-dPAKKR significantly delayed the disease onset and reduced the severity of clinical symptoms in EAN. Consistent with these positive effects, cyclo-dPAKKR substantially reduced the extent of myelin damage in that takes place on myelinated peripheral nerves in the EAN model.  The data demonstrate that cyclo-dPAKKR, promotes peripheral myelin development and can protect against myelin damage, suggesting that selectively targetting p75NTR is a strategy worthy of consideration for the treatment of peripheral demyelinating diseases.