Pharmacokinetics and Pharmacodynamics of Key Components of a Standardized Centella asiatica Product in Cognitively Impaired Older Adults: A Phase 1, Double-Blind, Randomized Clinical Trial

Abstract

Centella asiatica is reputed in Eastern medicine to improve cognitive function in humans. Preclinical studies have demonstrated that aqueous extracts of C. asiatica improve cognition in mouse models of aging and Alzheimer’s disease (AD) through the modulation of mitochondrial biogenesis and nuclear factor-erythroid-2-related factor 2 (Nrf2)-dependent antioxidant response genes. This randomized, double-blind, crossover Phase I trial explored the oral bioavailability and pharmacokinetics of key compounds from two doses (2 g and 4 g) of a standardized C. asiatica aqueous extract product (CAP), over 10 h, in four mildly demented older adults on cholinesterase inhibitor therapy. The analysis focused on triterpenes (TTs) and caffeoylquinic acids (CQAs), which are known to contribute to C. asiatica’s neurological activity. The acute safety of CAP and the effects on NRF2 gene expression in peripheral blood mononuclear cells were evaluated. Single administration of 2 g or 4 g of CAP was safe and well-tolerated. The TT aglycones, asiatic acid and madecassic acid, were identified in plasma and urine, while the parent glycosides, asiaticoside and madecassoside, although abundant in CAP, were absent in plasma and had limited renal excretion. Similarly, mono- and di-CQAs showed delayed absorption and limited presence in plasma or urine, while the putative metabolites of these compounds showed detectable plasma pharmacokinetic profiles and urinary excretion. CAP elicited a temporal change in NRF2 gene expression, mirroring the TT aglycone’s pharmacokinetic curve in a paradoxical dose-dependent manner. The oral bioavailability of active compounds or their metabolites, NRF2 target engagement, and the acute safety and tolerability of CAP support the validity of using CAP in future clinical studies.

Mode of administration influences plasma levels of active Centella asiatica compounds in 5xFAD mice while markers of neuroinflammation remain unaltered

“…Plasma samples were prepared in duplicate for analysis by HPLC–MS/MS using methods previously described ( Cheng et al, 2003 ; Wright et al, 2022 ). Plasma samples (50 μL) and an ascorbic acid solution (1%; 10 μL) were combined with A. aerogenes sulfatase (2.5 μL; 0.025–0.05 units; Sigma-Aldrich) and E. coli glucuronidase (2.5 μL; 12.5–125 units; Sigma-Aldrich) dissolved in 50% aqueous glycerol.…”

Identification of Asiaticoside from Centella erecta (Apiaceae) as Potential Apyrase Inhibitor by UF-UHPLC-MS and Its In Vivo Antischistosomal Activity

“…In this regard, it is also reported that after oral administration of asiaticoside, it may undergo biotransformation into asiatic acid, the aglycone of asiaticoside that was also annotated as apyrase ligand in our ultrafiltration screening. Then, the hypothesis that asiatic acid may also have antischistosomal activity [ 55 ] should be further explored in the future. Thus, the precise in vivo antischistosomal mechanisms of asiaticoside must be further investigated.…”

Asiatic Acid Ameliorates Cognitive Impairment in Diabetic Rats

“…DACD is described as learning and memory impairments, which are closely related to hyperglycemia. The AA with anti-oxidation, anti-inflammation and anti-apoptosis could protect against both diabetes and cognitive defect 11,12 . Previous studies showed that AA prevented organs against hyperglycemia-related injuries, such as diabetic nephropathy and diabetic cardiopathy 13 .…”