The identification of cianidanol as a selective estrogen receptor beta agonist and evaluation of its neuroprotective effects on Parkinson's disease models.

Aim: The present study aims to identify selective estrogen receptor beta (ERβ) agonists and to evaluate the neuroprotective mechanism in Parkinson's disease (PD) models.

Main Methods: In-silico studies were carried out using Maestro and GROMACS. Neuroprotective activity and apoptosis were evaluated using cytotoxicity assay and flow cytometry respectively. Gene expression studies were carried out by reverse transcription polymerase chain reaction. Motor and cognitive functions were assessed by actophotometer, rotarod, catalepsy, and elevated plus maze. The neuronal population in the substantia nigra and striatum of rats was assessed by hematoxylin and eosin staining.

Key Findings: Cianidanol was identified as a selective ERβ agonist through virtual screening. The cianidanol-ERβ complex is stable during the 200 ns simulation and was able to retain the interactions with key amino acid residues. Cianidanol (25 μM) prevents neuronal toxicity and apoptosis induced by rotenone in differentiated SH-SY5Y cells. Additionally, cianidanol (25 μM) increases the expression of ERβ, cathepsin D, and Nrf2 transcripts. The neuroprotective effects of cianidanol (25 μM) were reversed in the presence of a selective ERβ antagonist. In this study, we found that selective activation of ERβ could decrease the transcription of α-synuclein gene. Additionally, cianidanol (10, 20, 30 mg/kg, oral) improves the motor and cognitive deficit in rats induced by rotenone.

Significance: Cianidanol shows neuroprotective action in PD models and has the potential to serve as a novel therapeutic agent for the treatment of PD.