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

Kirsten M Wright, Melissa Bollen, Jason David, Alex B Speers, Mikah S Brandes, Nora E Gray, Armando Alcázar Magaña, Christine McClure, Jan F Stevens, Claudia S Maier, Joseph F Quinn, Amala Soumyanath, Kirsten M Wright, Melissa Bollen, Jason David, Alex B Speers, Mikah S Brandes, Nora E Gray, Armando Alcázar Magaña, Christine McClure, Jan F Stevens, Claudia S Maier, Joseph F Quinn, Amala Soumyanath

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.

Keywords: Alzheimer’s disease; Centella asiatica; NRF2; antioxidant; pharmacodynamics; pharmacokinetics; tolerability.

Conflict of interest statement

A.S. is an ad hoc consultant for Oregon’s Wild Harvest. Services for clinical trial product manufacture provided by Ashland Laboratories and Oregon’s Wild Harvest were financed by the NIH grant R61AT009628 awarded to Oregon Health & Science University. The CAP products described in this study were made for research purposes only and not for commercial use.

Figures

Figure 1
Figure 1
Structures of the triterpenoid saponins, aglycones, monocaffeoylquinic acids, and dicaffeoylquinic acids identified in Centella asiatica water extract.
Figure 2
Figure 2
Total ion chromatogram (TIC) of Centella asiatica water extract product (CAP) showing peaks corresponding to the triterpene and caffeoylquinic acid components of interest. The total ion chromatogram in negative ion mode corresponds to 2 g (blue) and 4 g (pink) of the Centella asiatica water extract present in each sachet (~20 g). The major compounds are indicated in the chromatogram. Extracted ion chromatograms (XIC) are shown for the monocaffeoylquinic acids (mono-CQAs; m/z 353.08, [M-H]−), the dicaffeoylquinic acids (Di-CQA, m/z 515.12, [M-H]−), madecassic acid (m/z 503.3, [M-H]−), and asiatic acid (m/z 487.3, [M-H]−).
Figure 3
Figure 3
Consort flow diagram.
Figure 4
Figure 4
Mean plasma concentration-time profiles of the triterpene aglycones derived from Centella asiatica water extract product (CAP); (a) asiatic acid; (b) madecassic acid, after single oral administration of 2 g or 4 g doses in cognitively impaired older adults on cholinesterase inhibitor therapy. Data are presented as mean ± SEM (n = 4).
Figure 5
Figure 5
Mean plasma concentration-time profiles of the caffeoylquinic acids (CQAs) and related compounds from Centella asiatica water extract product (CAP) after a single oral administration of 2 g or 4 g doses in cognitively impaired older adults on cholinesterase inhibitor therapy. (a) Caffeic acid; (b) dicaffeoylquinic acids; (c) dihydrocaffeic acid; (d) dihydroferulic acid; (e) ferulic acid; (f) 3-(3-hydroxyphenyl)propionic acid; (g) isoferulic acid; (h) monocaffeoylquinic acids. Data are presented as means ± SEM (n = 4).
Figure 6
Figure 6
Mean urinary excretion (over 10 h) of free (unconjugated) and total (unconjugated and conjugated) forms of compounds from Centella asiatica water extract product (CAP) after a single oral administration of a 2 g or 4 g dose in cognitively impaired older adults on cholinesterase inhibitor therapy. AA = asiatic acid; DHCA = dihydrocaffeic acid; DHFA = dihydroferulic acid; FA = ferulic acid; HPP = 3-(3-hydroxyphenyl)propionic acid; IFA = isoferulic acid; MA = madecassic acid; Monos = monocaffeoylquinic acids; MS = madecassoside. Data are presented as means (n = 4).
Figure 7
Figure 7
Temporal profile of induction of NRF2 gene expression in peripheral blood mononuclear cells following oral administration of 2 g and 4 g of Centella asiatica water extract product (CAP) in two cognitively impaired older adults on cholinesterase inhibitor therapy. Cells were isolated using a BD Vacutainer™ CPT™ Mononuclear Cell Preparation Tube and RNA was reverse transcribed with the Superscript III First Strand Synthesis kit to generate cDNA. Relative mRNA expression was determined using TaqMan Gene Expression Master Mix and commercially available TaqMan primers for NRF2 (NFE2L2) and GAPDH. Quantitative PCR was performed on a QuantStudio3 Machine and analyzed using the delta-delta Ct method normalizing to GAPDH expression.

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Source: PubMed

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