A small peptide mimetic of brain‐derived neurotrophic factor promotes peripheral myelination. (24th February 2013)

• Record Type: Journal Article
• Authors: Xiao, Junhua; Hughes, Richard A.; Lim, Joe Y.; Wong, Agnes W.; Ivanusic, Jason J.; Ferner, Anita H.; Kilpatrick, Trevor J.; Murray, Simon S.
• Is Part Of: Journal of neurochemistry. Volume 125:Number 3(2013:May)
• Page Start: 386
• Page End: 398
• Publication Date: 2013-02-24
• Subjects: Neurochemistry -- Periodicals; 616.8042
• DOI: 10.1111/jnc.12168
• Languages: English
• ISSNs: 0022-3042

Abstract

<abstract abstract-type="main" xml:lang="en" id="jnc12168-abs-0001"> <title>Abstract</title> <p>The expression of the neurotrophins and their receptors is essential for peripheral nervous system development and myelination. We have previously demonstrated that brain‐derived neurotrophic factor (BDNF) exerts contrasting influences upon Schwann cell myelination <italic>in vitro</italic> – promoting myelination via neuronally expressed p75NTR, but inhibiting myelination via neuronally expressed TrkB. We have generated a small peptide called cyclo‐<sc>d</sc>PAKKR that structurally mimics the region of BDNF that binds p75NTR. Here, we have investigated whether utilizing cyclo‐<sc>d</sc>PAKKR to selectively target p75NTR is an approach that could exert a unified promyelinating response. Like BDNF, cyclo‐<sc>d</sc>PAKKR promoted myelination of nerve growth factor‐dependent neurons <italic>in vitro</italic>, an effect dependent on the neuronal expression of p75NTR. Importantly, cyclo‐<sc>d</sc>PAKKR also significantly promoted the myelination of tropomyosin‐related kinase receptor B‐expressing neurons <italic>in vitro</italic>, whereas BDNF exerted a significant inhibitory effect. This indicated that while BDNF exerted a contrasting influence upon the myelination of distinct subsets of dorsal root ganglion (DRG) neurons <italic>in vitro</italic>, cyclo‐<sc>d</sc>PAKKR uniformly promoted their myelination. Local injection of cyclo‐<sc>d</sc>PAKKR adjacent to the developing sciatic nerve <italic>in vivo</italic> significantly enhanced myelin protein expression and significantly increased the number of myelinated axons. These results demonstrate that cyclo‐<sc>d</sc>PAKKR promotes peripheral myelination <italic>in vitro</italic> and <italic>in vivo</italic>, suggesting it is a strategy worthy of further investigation for the treatment of peripheral demyelinating diseases.</p> </abstract>