Neurosteroids and microneurotrophins signal through NGF receptors to induce prosurvival signaling in neuronal cells.
The neurosteroid dehydroepiandrosterone (DHEA) exerts a portion of its neuroprotective effects by directly interacting with the nerve growth factor (NGF) receptors TrkA and p75(NTR) to induce prosurvival signaling. DHEA is an intermediate in the biosynthesis of estrogens and androgens that affects the endocrine system and potentially increases the risk for developing estrogen- and androgen-dependent tumors. We have synthesized 17-spiro analogs of DHEA that lack estrogenic or androgenic properties and bind to and activate NGF receptors, thus exerting potent neuroprotective effects without the tumor risk. These synthetic DHEA derivatives may serve as lead molecules to develop small agonists of NGF receptors that can penetrate the blood-brain barrier (microneurotrophins) with potential applications in the treatment of neurodegenerative diseases. The neuroprotective properties of microneurotrophins are now being tested in various animal models of neurodegenerative diseases.
Foundation of Research and Technology-Hellas (IESL-FORTH), Heraklion, Greece. gravanis@med.uoc.gr
Achille
A
Gravanis
Theodora
T
Calogeropoulou
Vily
V
Panoutsakopoulou
Kyriaki
K
Thermos
Constantinos
C
Neophytou
Ioannis
I
Charalampopoulos
D000728:Androgens / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D001812:Blood-Brain Barrier; D002470:Cell Survival; D003687:Dehydroepiandrosterone / Q000494:pharmacology; D004967:Estrogens / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007700:Kinetics; D051379:Mice; D008822:Mice, Transgenic; D009369:Neoplasms / Q000378:metabolism; D009414:Nerve Growth Factors / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D018377:Neurotransmitter Agents / Q000378:metabolism*; D016716:PC12 Cells; D051381:Rats; D020917:Receptor, trkA / Q000378:metabolism; D017475:Receptors, Nerve Growth Factor / Q000378:metabolism*; D015398:Signal Transduction
D000728:Androgens; D004967:Estrogens; D009414:Nerve Growth Factors; D018377:Neurotransmitter Agents; D017475:Receptors, Nerve Growth Factor; D003687:Dehydroepiandrosterone; D020917:Receptor, trkA