JM-20, a Benzodiazepine-Dihydropyridine Hybrid Molecule, Inhibits the Formation of Alpha-Synuclein-Aggregated Species.

Studies showed that JM-20, a benzodiazepine-dihydropyridine hybrid molecule, protects against rotenone and 6-hydroxydopamine neurotoxicity. However, its protective effects against cytotoxicity induced by endogenous neurotoxins involved in Parkinson's disease (PD) pathogenesis have never been investigated. In this study, we evaluated the ability of JM-20 to inhibit alpha-synuclein (aSyn) aggregation. We also evaluated the interactions of JM-20 with aSyn by molecular docking and molecular dynamics and assessed the protective effect of JM-20 against aminochrome cytotoxicity. We demonstrated that JM-20 induced the formation of heterogeneous amyloid fibrils, which were innocuous to primary cultures of mesencephalic cells. Moreover, JM-20 reduced the average size of aSyn positive inclusions in H4 cells transfected with SynT wild-type and synphilin-1-V5, but not in HEK cells transfected with synphilin-1-GFP. In silico studies showed the interaction between JM-20 and the aSyn-binding site. Additionally, we showed that JM-20 protects SH-SY5Y cells against aminochrome cytotoxicity. These results reinforce the potential of JM-20 as a neuroprotective compound for PD and suggest aSyn as a molecular target for JM-20.

The Flavonoid Agathisflavone from Poincianella pyramidalis Prevents Aminochrome Neurotoxicity.

Flavonoids have been suggested to protect dopaminergic neurons in Parkinson's disease based on studies that used exogenous neurotoxins. In this study, we tested the protective ability of agathisflavone in SH-SY5Y cells exposed to the endogenous neurotoxin aminochrome. The ability of aminochrome to induce loss of lysosome acidity is an important mechanism of its neurotoxicity. We demonstrated that the flavonoid inhibited cellular death and lysosomal dysfunction induced by aminochrome. In addition, we demonstrated that the protective effect of agathisflavone was suppressed by antagonists of estrogen receptors (ERα and ERß). These results suggest lysosomal protection and estrogen signaling as mechanisms involved in agathisflavone neuroprotection in a Parkinson's disease study model.