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.

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Background Centella asiatica (CA) is a botanical from Eastern medicine reputed to enhance cognition. Preclinical studies on CA and its bioactive components (triterpenoids and caffeoylquinic acids) strongly support its potential as a phytotherapeutic agent for aging, cognitive decline, and Alzheimer’s disease (AD) through influences on antioxidant response, mitochondrial activity, tau phosphorylation, and synaptic density. Translation from preclinical models to humans, and developing an optimized, reproducible product for use in aging and AD clinical trials, present particular challenges for phytotherapeutic agents compared to single chemical entities. Method To perform translational studies, a comprehensive scientific approach was developed including: identifying an optimal dose range for clinical evaluation, analysis and characterization of phytochemical variability, assessment for contamination and adulteration of raw material, formulation and manufacture of a stable botanical intervention and matching placebo, and application to a human pharmacokinetic trial (NCT03929250). Two doses of a custom made CA water extract product (2g and 4g) were administered orally to eight healthy elders (n=4 female, n=4 male) on two separate days. Plasma was collected over 12 hours to determine bioavailability and analyzed using reversed phase liquid chromatography‐tandem mass spectrometry. Result The maximum plasma concentration (Cmax) of the bioactive triterpenoids (1‐1.6µM) occurred at two hours (Tmax) after oral administration. Conclusion A robust scientific approach is necessary to address the complexity and variability of raw botanicals and botanical extracts for AD. Triterpenoids from CA water extract are orally bioavailable in humans.

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