Abstract
The neurotrophin, brain-derived neurotrophic factor (BDNF) promotes central nervous system (CNS) myelination during development and after injury. This is achieved via activation of oligodendrocyte-expressed tropomyosin-related kinase (Trk) B receptors. However, while administration of BDNF has shown beneficial effects, BDNF itself has a poor pharmacokinetic profile. Here, we compare two TrkB-targeted BDNF-mimetics, the structural-mimetic, tricyclic dimeric peptide-6 (TDP6) and the non-peptide small molecule TrkB agonist LM22A-4 in a cuprizone model of central demyelination in female mice. Both mimetics promoted remyelination, increasing myelin sheath thickness and oligodendrocyte densities after 1-week recovery. Importantly, LM22A-4 exerts these effects in an oligodendroglial TrkB-dependent manner. However, analysis of TrkB signaling by LM22A-4 suggests rather than direct activation of TrkB, LM22A-4 exerts its effects via indirect transactivation of Trk receptors. Overall, these studies support the therapeutic strategy to selectively targeting TrkB activation to promote remyelination in the brain.
Highlights
The neurotrophin, brain-derived neurotrophic factor (BDNF) is an attractive therapeutic for many neurodegenerative diseases due to its broad neuroprotective effects promoting neuronal survival, synaptic plasticity and central nervous system (CNS) myelination (Chao, 2003; Longo and Massa, 2013; Fletcher et al, 2018a)
electron microscopy (EM) analysis indicated that mice treated with tricyclic dimeric peptide-6 (TDP6) exhibited a trend (p = 0.09) increase towards more remyelinated axons compared to those receiving artificial cerebrospinal fluid (aCSF), whereas for those receiving LM22A-4, no increase was observed (p = 0.46; Figure 1C)
Linear regression analysis of g-ratio against axon diameter (Figure 1E) indicated that both TDP6 and LM22A-4 treatments increase myelin sheath thickness during remyelination (Figure 1D), TDP6 exerted a more consistent effect with a significant decrease in y-intercept (p = 0.0032), but no change in slope (p = 0.35) indicating that g-ratio was reduced across all axonal diameters, whereas for LM22A-4 there was a significant increase in slope (p = 0.006), indicative of reduced g-ratio and thicker myelin on smaller diameter axons
Summary
The neurotrophin, brain-derived neurotrophic factor (BDNF) is an attractive therapeutic for many neurodegenerative diseases due to its broad neuroprotective effects promoting neuronal survival, synaptic plasticity and central nervous system (CNS) myelination (Chao, 2003; Longo and Massa, 2013; Fletcher et al, 2018a). BDNF itself has poor pharmacokinetic properties; it is non-selective, acting through the pan-neurotrophic receptor p75NTR, has a short-half life and has high molecular weight, limiting its ability to penetrate the blood-brain barrier (Poduslo and Curran, 1996; Longo and Massa, 2013). To overcome these limitations a range of small molecule BDNF-mimetics that selectively target the TrkB receptor have been developed (Longo and Massa, 2013). This includes tricyclic dimeric peptide-6 (TDP6; O’Leary and Hughes, 2003) and the partial TrkB agonist, LM22A-4 (Massa et al, 2010).
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