Abstract |
Neuronal cell fate is majorly governed by the actions of growth factors, such
as neurotrophins. These specific ligands and their receptors activity are regulated by
multiple cellular parameters. Indeed, we have recently shown that neurosteroid
dehydroepiandrosterone (DHEA) prevents neuronal apoptosis through binding to
NGF receptors, namely TrkA and p75NTR. In this study we provide evidence that
DHEA interacts with the other two mammalian neurotrophin receptors, i.e., the TrkB
and TrkC, as well as their invertebrate counterparts (orthologs) in mollusks Lymnaea
and Aplysia, and in cephalochordate fish Amphioxus, supporting the hypothesis that
during evolution DHEA may have served as a primordial neurotrophic factor,
promoting neuronal survival in species with less complex nervous systems. A large
number of experimental and clinical studies suggest that endogenous neurotrophins
are involved in the pathopysiology of many neurodegenerative diseases. However,
despite their demonstrated beneficial effects on neuronal survival and protection, the
therapeutic usefulness of neurotrophins is compromised by their polypeptide nature
and their restricted penetrance to the blood-brain barrier (BBB). To overcome this
limitation, small molecules –like DHEA- which could mimic the effects of neurotrophic
factors would be therapeutically ideal. However, DHEA is metabolized in vivo to sex
steroids, affecting the endocrine system. We have recently synthesized 17-spiro
analogs of DHEA with anti-apoptotic, neuroprotective properties (IC50 at nanomolar
levels), deprived of androgenic-estrogenic actions. In the present study, we report
that synthetic DHEA derivative, BNN27, specifically interacts with both NGF
receptors, TrkA and p75NTR, at nanomolar concentrations. BNN27 induces TrkA
tyrosine phosphorylation, affecting downstream signaling of Akt and MAPKs in
sympathetic neurons and regulates TrkA internalization, however in a different time
pattern than that of NGF. Moreover, BNN27 was shown to promote the interaction of
p75NTR receptors with its effector factors RhoGDI, RIP2 and TRAF6. It also
significantly reverses apoptosis of NGF-dependent embryonic sensory neurons of
NGF null mice. BNN27 itself was not effective in to mimicking NGF in the induction of
neurite elongation, perhaps due to its differential endosome’s turn over. However,
combination of BNN27 with NGF results in enhancement of neurites’ length. BNN27
may serve as a lead molecule to develop BBB permeable, neurotrophin-like small
molecules (microneurotrophins) with potential applications in the treatment of
neurodegenerative diseases and brain disorders.
|