Neurotrophic factors are among the most promising treatments aiming at slowing 
or stopping and even reversing Parkinson's disease (PD). However, in most cases, 
they cannot readily cross the human blood-brain-barrier (BBB). Herein, we 
propose as a therapeutic for PD the small molecule 
17-beta-spiro-[5-androsten-17,2'-oxiran]-3beta-ol (BNN-20), a synthetic analogue 
of DHEA, which crosses the BBB and is deprived of endocrine side-effects. Using 
the "weaver" mouse, a genetic model of PD, which exhibits progressive 
dopaminergic neurodegeneration in the Substantia Nigra (SN), we have shown that 
long-term administration (P1-P21) of BNN-20 almost fully protected the 
dopaminergic neurons and their terminals, via i) a strong anti-apoptotic effect, 
probably mediated through the Tropomyosin receptor kinase B (TrkB) neurotrophin 
receptor's PI3K-Akt-NF-κB signaling pathway, ii) by exerting an efficient 
antioxidant effect, iii) by inducing significant anti-inflammatory activity and 
iv) by restoring Brain-Derived Neurotrophic Factor (BDNF) levels. By 
intercrossing "weaver" with NGL mice (dual GFP/luciferase-NF-κΒ reporter mice, 
NF-κΒ.GFP.Luc), we obtained Weaver/NGL mice that express the NF-κB reporter in 
all somatic cells. Acute BNN-20 administration to Weaver/NGL mice induced a 
strong NF-κB-dependent transcriptional response in the brain as detected by 
bioluminescence imaging, which was abolished by co-administration of the TrkB 
inhibitor ANA-12. This indicates that BNN-20 exerts its beneficial action (at 
least in part) through the TrkB-PI3K-Akt-NF-κB signaling pathway. These results 
could be of clinical relevance, as they suggest BNN-20 as an important 
neuroprotective agent acting through the TrkB neurotrophin receptor pathway, 
mimicking the action of the endogenous neurotrophin BDNF. Thus BNN-20 could be 
proposed for treatment of PD.