Investigation of the in vitro antidiabetic and neuroprotective effects of selected Helichrysum species against high monosaccharide-induced toxicity

Abstract

Chronic hyperglycaemia (glucotoxicity), a common complication in diabetes mellitus (DM), is known to cause cognitive decline in some of these patients, often affecting their overall quality of life. Some medicinal plants used in folk medicine for DM have also been reported effective in treating some of its co-morbidities, including cognitive decline. Plants of the Helichrysum genus (Asteraceae family) are well known in South African traditional medicine for their diverse health benefits, which make them potential sources of biologically active compounds. Thus, in the current study, the composition of bioactive compounds, as well as the antidiabetic and neuroprotective effects of selected Helichrysum plants viz: Helichrysum pandurifolium Schrank, Helichrysum foetidum, Helichrysum petiolare and Helichrysum cymocum, were investigated. Liquid chromatography-mass spectrometry (LC-MS) analysis was first used to characterise the aqueous acetone extracts of each plant, followed by bioactivity evaluation. LC-MS analysis and phytochemical screening revealed H. petiolare extract has the highest content of phenolics, saturated fatty acids, polyunsaturated fatty acids and total flavonoids. The best nitric oxide scavenging activity and total antioxidant capacity compared with other species were also demonstrated. Furthermore, the flavonoid composition varied in all extracts, with H. petiolare and H. pandurifolium Schrank extracts having the highest number of flavonoids. Thus, the aqueous acetone extract of H. petiolare (AAHPE) was further investigated for antidiabetic and neuroprotective potentials. The AutoDock Vina tool was used for molecular docking simulation. Treatment with AAHPE (25-75 µg/mL) improved the cell viability and increased the concentration-dependent percentage glucose uptake in the insulin-resistant HepG2 cell line significantly compared with the control. The highest AAHPE concentration (75 µg/mL) showed higher glucose uptake activity than the standard drug, metformin. Furthermore, AAHPE was found to inhibit both α-amylase and α-glucosidase enzymes in vitro, as corroborated by molecular docking results that showed strong binding (ΔG) of AAHPE flavonoids to α-amylase and αglucosidase compared with the drug, acarbose (ΔG for flavonoids = -7.2 to -9.6 Kcal/mol vs ΔG for acarbose = -6.1 Kcal/mol) for α-amylase; (ΔG for flavonoids = -7.3 to -9.0 Kcal/mol vs ΔG for acarbose = -6.3 Kcal/mol) for α-glucosidase. Analysis of in vitro neuroprotective effects of AHHPE against glucotoxicity induced on SH-SY5Y cells showed improved cell viability at all treatment concentrations (25-100 µg/ml). It also showed reduced reactive oxygen species production (ROS) and increased production of adenosine triphosphate (ATP) compared with cells treated with the standard acetylcholinesterase (AChE) inhibitor drug, donepezil (1 mM) or untreated cells (300 mM glucose). Molecular docking analysis showed that selected AAHPE flavonoids exhibited tight binding forces (better inhibitory profiles) with AChE compared with donepezil (-8.3 Kcal/mol). The flavonoids include 3, 5- dicaffeoylquinic acid (-9.9 Kcal/mol), isorhamnetin 3-galactoside (-8.8 Kcal/mol), 4,5- dicaffeoylquinic acid (-8.6 Kcal/mol), methyl 3, 5-di-O-caffeoyl quinate (-8.6 Kcal/mol), 3- caffeoylquinic acid (-8.4 Kcal/mol), quercetin-3-glucoside (-8.4 Kcal/mol) and sinocrassosideA1 (-8.4 Kcal/mol). Thus, the AAHPE and its bioactive phytocompounds, especially flavonoids, with their potential antioxidant effects, more effective glycaemic control than metformin, and better neuroprotective effects than donepezil against DM-associated disorders (e.g cognitive decline). Hence, they could be developed as commercially available dietary herbal supplements for managing postprandial hyperglycaemia.