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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 (Cmax range: 5.6–8410 ng/mL), while withaferin A, withanolide A, 12-deoxywithastramonolide, and withanoside IV pharmacokinetic parameters have been described in humans (Cmax range: 0.1–49.5 ng/mL). [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Centella asiatica is a medicinal plant traditionally used for promoting brain health and improving cognition. Our lab has shown that a water extract of Centella asiatica (CAW), can enhance mitochondrial function, promote antioxidant response, and improve cognitive deficits in mouse models of aging and Alzheimer's disease (AD). Because neuroinflammation is also prevalent in the AD brain and there is growing evidence that the interplay between oxidative stress, mitochondrial dysfunction, and neuroinflammation play a central role in the progression of AD, here we explore the effects of oral CAW treatment on neuroinflammation in the 5xFAD mouse model of beta‐amyloid accumulation. Methods: Eight to nine month old male and female 5xFAD mice were treated with 0 or 1000 mg/kg/day of CAW administered in their drinking water or integrated into their diet (AIN‐93M rodent diet) for a total of 5 weeks, after which brain samples were collected. Microglial and astrocytic activation as well as beta‐amyloid pathology is currently being assessed by immunohistochemistry (IHC). Expression of pro‐ and anti‐inflammatory cytokines is also being determined by qPCR in brain samples from these treated animals. Results: Preliminary IHC results suggest that CAW administered in the diet reduces the heightened microglial activation found in 5xFAD mice. Our ongoing analysis will determine if there are also effects on astrocytic activation and beta‐amyloid pathology, and whether these effects vary if the CAW is administered in the drinking water rather than the diet. Additionally, gene expression assessments are currently underway on these samples to evaluate the effects of CAW on the expression of pro‐ and anti‐inflammatory cytokines. Conclusion: Initial data suggests an anti‐inflammatory effect of the CAW extract. Results will continue to be collected over the next few months, further clarifying our preliminary results as well as generating data for the potential mechanisms or cell types that may mediate the effect of CAW on neuroinflammation. Moreover, we will learn whether the mode of administration, in the diet versus the drinking water, has an effect on the response to CAW, which would have important implications for future experimental design as well as the development of CAW for clinical use. [ABSTRACT FROM AUTHOR]