3α,7-Dihydroxy-14(13→12)abeo-5β,12α(H),13β(H)-cholan-24-oic Acids Display Neuroprotective Properties in Common Forms of Parkinson’s Disease

Abstract

Parkinson’s Disease is the most common neurodegenerative movement disorder globally, with prevalence increasing. There is an urgent need for new therapeutics which are disease-modifying rather than symptomatic. Mitochondrial dysfunction is a well-documented mechanism in both sporadic and familial Parkinson’s Disease. Furthermore, ursodeoxycholic acid (UDCA) has been identified as a bile acid which leads to increased mitochondrial function in multiple in vitro and in vivo models of Parkinson’s Disease. Here, we describe the synthesis of novel C-nor-D-homo bile acid derivatives and the 12-hydroxy-methylated derivative of lagocholic acid (7) and their biological evaluation in fibroblasts from patients with either sporadic or LRRK2 mutant Parkinson’s Disease. These compounds boost mitochondrial function to a similar level or above that of UDCA in many assays; notable, however, is their ability to boost mitochondrial function to a higher level and at lower concentrations than UDCA specifically in the fibroblasts from LRRK2 patients. Our study indicates that novel bile acid chemistry could lead to the development of more efficacious bile acids which increase mitochondrial function and ultimately cellular health at lower concentrations proving attractive potential novel therapeutics for Parkinson’s Disease.

Study on synthesis of ursodeoxycholic acid by reduction of 7-ketolithocholic acid in double aprotic solvents and molecular simulations

“…Ursodeoxycholic acid is a fundamental treatment drug for numerous hepatobiliary diseases that also has adjuvant therapeutic effects on certain cancers and neurological diseases, in addition, it also can be beneficial in neonatal jaundice needing phototherapy (Lazarus et al 2022 ; Huang and Cao 2015 ; Xiaolei and Xuejun 2014 ; Liu et al 2006 ; Santos et al 2003 ). Since there is no side effect, ursodeoxycholic acid is also widely used in kidney injury (Acute Kidney Injury) and Parkinson’s Disease (Sathe et al 2020 ; Qi et al 2021 ; Luxenburger et al 2023 ), has important clinical value. At the beginning, it was too cruel to extract ursodeoxycholic acid by killing bear bile or extracting bile duct drainage, so there were many methods to product ursodeoxycholic acid, and now many methods have been very mature.…”