Carnosic Acid and Carnosol Display Antioxidant and Anti-Prion Properties in In Vitro and Cell-Free Models of Prion Diseases

Abstract

Prion diseases are transmissible encephalopathies associated with the conversion of the physiological form of the prion protein (PrPC) to the disease-associated (PrPSc). Despite intense research, no therapeutic or prophylactic agent is available. The catechol-type diterpene Carnosic acid (CA) and its metabolite Carnosol (CS) from Rosmarinus officinalis have well-documented anti-oxidative and neuroprotective effects. Since oxidative stress plays an important role in the pathogenesis of prion diseases, we investigated the potential beneficial role of CA and CS in a cellular model of prion diseases (N2a22L cells) and in a cell-free prion amplification assay (RT-QuIC). The antioxidant effects of the compounds were confirmed when N2a22L were incubated with CA or CS. Furthermore, CA and CS reduced the accumulation of the disease-associated form of PrP, detected by Western Blotting, in N2a22L cells. This effect was validated in RT-QuIC assays, indicating that it is not associated with the antioxidant effects of CA and CS. Importantly, cell-free assays revealed that these natural products not only prevent the formation of PrP aggregates but can also disrupt already formed aggregates. Our results indicate that CA and CS have pleiotropic effects against prion diseases and could evolve into useful prophylactic and/or therapeutic agents against prion and other neurodegenerative diseases.

Αnti-prion effects of anthocyanins

“…Oxidative stress has been identified as a hallmark of neurodegeneration [ 32 , [129] , [130] , [131] ]. In accordance with other anti-oxidant compounds exhibiting anti-prion activity [ 72 , 124 , 126 , 128 , 132 , 133 ], Oenin and Myrtillin successfully decreased the levels of ROS in prion-infected cells. While Oenin didn't affect Nrf2 expression levels, it managed to activate the Keap1-Nrf2 pathway (albeit less effectively compared to Myrtillin).…”

“…Many compounds exert their anti-oxidant neuroprotective effects through Keap1-Nrf2 activation [ [69] , [70] , [71] , [72] , [73] , [74] , [75] , [76] ]. Consequently, it was tested whether the observed anti-oxidant effects of Oenin and Myrtillin in N2a22L cells also depended on Keap1-Nrf2 induction.…”

Prion therapeutics: Lessons from the past

“…CA, a catechol isolated from Rosmarinus officinalis (Rosemary), has been reported for its potential antioxidant, anti-inflammatory, and neuroprotective activities [ 225 ]. CA and its metabolite, carnosol (CS), have been shown to exert its potent antioxidant and anti-prion activity in N2a22L and N2a58 cells by reducing de novo generation of PrP Sc aggregates, as well as favouring removal of already formed PrP Sc clusters [ 226 ]. In addition, CA can cross BBB after oral administration [ 227 ], which was also confirmed by Light-BBB computational prediction [ 228 ].…”

Anticancer Effects of Rosmarinus officinalis Leaf Extract on KB Cell Lines

“…It is touted as a potent anti-inflammatory and antioxidant substance. From single molecules to the multicellular process that encompasses both invasion and metastasis in animal models, cell lines have been presented in the new domains of cancer biology [ 15 ]. The aim of this study is to investigate the potential anti-cancer effects of R. officinalis on KB cell lines.…”