Title : Hibiscus sabdariffa extract protects against high glucose-induced toxicity via SIRT-1/AKT/FOXO-1 pathway in Neuro-2a cells and suppressing A? expression in transgenic Caenorhabditis elegans strain of Alzheimer’s disease
Alzheimer’s disease (AD) is one of the most common types of dementia, which accounts for an estimated 60 to 80% of all dementia cases. Though pathways including alteration in the cholinergic system, amyloid precursor protein (APP) processing and tau hyperphosphorylation are identified as the major hallmarks of the disease, still there is inefficiency in the identification of suitable drug candidate which could offer neuroprotection against the disease condition. This may be due to the fact that multiple intricate pathways and metabolic diseases including diabetes contributes to the disease progression and hence targeting one pathway will not show the desired outcome in patients. Pioneering studies have shown the interlink between diabetes and AD as well as the influence of hyperglycemia towards the generation of amyloid beta and neurofibrillary tangles in the brain, making the treatment complicated. This study was aimed to explore and the effect of ethanol extract of Hibiscus sabdariffa red calyces against high glucose-induced neurotoxicity in Neuro-2a cells and Caenorhabditis elegans and elucidate the mechanism of action. High glucose (175 mM) increased the generation of reactive oxygen species, altered mitochondrial membrane potential with increase in Cyp-D expression, modulated the expression of genes/proteins involved in oxidative stress response (Nrf-2, NQO-1, HO-1, FOXO-1), unfolded protein response genes (Grp-78, CHOP), lipid metabolism (LXRs, Seladin-1, ABCA-1), cell signalling (AKT/p-AKT, JNK, p-JNK), and apoptosis (P53, Caspase-3). Pre-treatment with H. sabdariffa extract restored the normal homeostasis by reversing the effects caused by high glucose treatment. Further, LC-MS/MS analysis showed the presence of compounds including allo-Aromadendrene, N-Feruloyltyramine, 11-Hydroxycanthin-6-one, Pelargonidin 3-rhamnoside 5-glucoside, Anisocoumarin H, Hibiscus acid, and Sinapoyl aldehyde. Of the identified compounds, molecular docking studies showed that allo-Aromadendrene, 11-Hydroxycanthin-6-one and Pelargonidin 3-rhamnoside 5-glucoside could interact with target sites of the proteins (AChE, FOXO-1, GSK-3β, LXR’s) with high binding score compared to that of the respective positive controls. In addition, studies with the simple model organism C. elegans (both wild type and transgenic strain of AD) showed that H. sabdariffa extract could extend the lifespan of the organism against high glucose-induced toxicity accompanied with the reduction in Aβ expression in CL2006 strain indicating the neuroprotective effect. Our results conclude that H. sabdariffa calyx extract with its phytoconstituents can be considered as promising therapeutic agent to treat neurodegenerative diseases associated with diabetes.
Keywords: Alzheimer’s disease; diabetes; allo-Aromadendrene; C. elegans; lipid metabolism
Outcome of the presentation
- Thai medicinal plants are an important component of local health care systems in Thailand. However, the lack of qualitative studies, clinical trials and documentation makes it difficult to integrate with the modern health care systems. Hibiscus sabdariffa has been prevalently used by Thai communities in food, beverages and as herbal medicine against diabetes. The current study provides insight in to the potential use of the ethanol extract of H. sabdariffa for its effect against hyperglycemia associated Alzheimer’s disease.
- The bioactive compounds identified in the research will be of scientific interest for further exploration of their activity, elucidating the mechanism of action and to the development as drugs against neurodegenerative diseases.
- The research also provides insight in to the importance and use of the simple nematode Caenorhabditis elegans that can be used as a potent model organism for studying the mechanisms of neurodegenerative disorders using transgenic/mutant strains and screening of drugs against diseases.