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.

Withania somnifera (common name: ashwagandha; WS) is an Ayurvedic botanical that has become popular for its reputed effects on stress and insomnia. Research into the bioactive compounds responsible for the biological effects of WS has largely focused on withanolides, a group of steroidal lactones commonly found in the Solanaceae family. Until recently, however, it was unclear which, if any, withanolides were present in the plasma after the ingestion of WS products. The aim of this review is to summarize current knowledge regarding the plasma pharmacokinetics of withanolides found in WS and the analytical methods developed to detect them in plasma. Twenty studies (sixteen animal, four human) were identified in which isolated withanolides or withanolide-containing products were administered to animals or humans and quantified in plasma. Withanolides were commonly analyzed using reversed-phase liquid chromatography coupled to mass spectrometry. Plasma concentrations of withanolides varied significantly depending on the substance administered, withanolide dose, and route of administration. Plasma pharmacokinetics of withaferin A, withanolide A, withanolide B, withanoside IV, 12-deoxywithastramonolide, and withanone have been reported in rodents (C_max range: 5.6–8410 ng/mL), while withaferin A, withanolide A, 12-deoxywithastramonolide, and withanoside IV pharmacokinetic parameters have been described in humans (C_max range: 0.1–49.5 ng/mL).

Introduction: A water extract of Centella asiatica (L.) Urban [Apiaceae] (CAW) has demonstrated cognitive-enhancing effects in mouse models of Alzheimer’s disease and aging, the magnitude of which is influenced by whether CAW is delivered in the drinking water or the diet. These cognitive benefits are accompanied by improvements in oxidative stress and mitochondrial function in the brain, two pathways related to the neuroinflammatory response. The effect of CAW on neuroinflammation, however, has not been directly studied. Here, we investigated the effect of CAW on neuroinflammation in 5xFAD mice and compared plasma levels of CAW’s active compounds following two modes of CAW administration.Methods: Eight-to-nine-month-old male and female 5xFAD mice and their wild-type littermates were administered CAW in their diet or drinking water (0 or 1,000 mg/kg/day) for five weeks. Immunohistochemistry was performed for β-amyloid (Aβ), glial fibrillary acidic protein (GFAP), and Griffonia simplicifolia lectin I (GSL I) in the cortex and hippocampus. Gene expression of inflammatory mediators (IL-6, TNFα, IL-1β, TREM2, AIF1, CX3CR1, CX3CL1, CD36, C3AR1, RAGE, CCR6, CD3E) was measured in the deep grey matter.Results: CAW decreased cortical Aβ plaque burden in female 5xFAD mice administered CAW in the drinking water but had no effect on Aβ plaques in other treatment groups. CAW did not impact elevated levels of GFAP or GSL I in 5xFAD mice, regardless of sex, brain region, or mode of CAW administration. In the deep grey matter, CAW increased C3AR1 expression in 5xFAD females administered CAW in the drinking water and decreased IL-1β expression in 5xFAD males administered CAW in the diet. CAW had no effect, however, on gene expression levels of any other inflammatory mediator in the deep grey, for either sex or mode of CAW administration. Mice administered CAW in the drinking water versus the diet had significantly higher plasma levels of CAW compounds.Discussion: CAW had little impact on the neuroinflammatory markers selected for evaluation in the present study, suggesting that the cognitive benefits of CAW may not be mediated by an anti-inflammatory effect or that additional molecular markers are needed to fully characterize the effect of CAW on neuroinflammation.

/SUMMARY: INTRODUCTION: Behavioral intervention studies for family care partners for those with dementia need to be both feasible and acceptable in order implement and complete the investigative work. Our study, Tele-STELLA (Support via Technology: Living and Learning with Advancing dementia), was as single arm clinical trial completed in 2025. While 188 care partners enrolled, the attrition rate was high (44%). Here we describe the feasibility, acceptability, fidelity processes and preliminary efficacy of Tele-STELLA. METHODS: Quantitative measures were used to assess care partner burden, study participation, feasibility and acceptability. Our weekly survey assessed the prevalence of adverse events. Qualitative methods paralleled our quantitative findings, in that care partners generally found the study acceptable, but dementia progression and life demands made participation difficult for some. RESULTS: The total attrition rate was 44% but was attenuated by increasing the sample size. This adequately-powered study found that the intervention significantly reduced burden. Overall, care partners found the study feasible, but care demands made participation difficult for 28 of the care partners resulting in their withdrawal. In addition, 21 care recipients died, and thus their care partners had to be removed from the study. Protocol deviations and losing care partner contact also added to the attrition rate. DISCUSSION: Our findings reveal that, even in the later stages of dementia, care partners are willing to participate in intervention research. However, care demands and death can affect the sample size. Our data and recommendations for future studies will inform caregiving scientists in designing behavioral interventions in late-stage dementia.

Ashwagandha (Withania somnifera (L.) Dunal; WS) is an adaptogenic herb, widely used in botanical dietary supplements. Plasma pharmacokinetics of selected withanolides, an important group of bioactive phytochemicals found in WS, have been described but no previous reports were found on their urinary excretion following WS ingestion. Healthy, older adults were administered oral doses of 240 or 480 mg of Shoden^®, a commercial extract of WS roots and leaves, and urine was collected over the subsequent 12 h. Using validated methods employing liquid chromatography coupled to multiple reaction monitoring mass spectrometry (LC-MRM-MS), we analyzed Shoden^® and participant urine samples for the presence of 11 withanolides for which standards were available. Only withaferin A (0.09 µmol/mg Shoden^®), withanoside IV (0.03 µmol/mg Shoden^®), and a mixture of 2,3-didehydrosomnifericin and 3R-viscosalactone B (0.19 µmol/mg Shoden^®) were present in Shoden^® powder in amounts greater than 0.01 µmol/mg Shoden^®. We detected four withanolides in participant urine: withaferin A; sominone, the aglycone of withanoside IV; 3R-viscosalactone B; and an abundant unidentified metabolite (WFNX), isomeric with 4-oxo withaferin A, and not detected in Shoden^®. Urinary recovery of the other 3 detected compounds was generally low (<3% of the amount in Shoden^®). These results provide new insights into the oral absorption, metabolism, and urinary excretion of withanolides found in WS and highlight additional withanolides to consider in future human pharmacokinetic and bioactivity studies of WS products.