Asiaticoside Attenuates Cell Growth Inhibition and Apoptosis Induced by Aβ1-42 via Inhibiting the TLR4/NF-κB Signaling Pathway in Human Brain Microvascular Endothelial Cells

Abstract

Alzheimer’s disease (AD) is a very common progressive neurodegenerative disorder with the highest incidence in the world. Dysfunction of the blood–brain barrier (BBB) may be responsible for the pathogenesis and pathology of AD for abnormally transporting amyloid-β (Aβ, the main component of the senile plaques) from the sera into the central nervous system. Aβ peptides induce apoptosis in human brain microvascular endothelial cells (hBMECs), the main component of BBB. Apoptosis in neuronal cells plays a critical role in the pathogenesis of AD. Asiaticoside, a natural glycoside extracted from Centella asiatica (L.) Urban, has an anti-apoptotic effect on hBMECs but the molecule mechanism remains unclear. Therefore, we investigate the protective effect of asiaticoside on Aβ1-42-induced cytotoxicity and apoptosis as well as associated mechanism in hBMECs with commonly used in vitro methods for clinical development of asiaticoside as a novel anti-AD agent. In the present study, we investigated the effects of asiaticoside on cytotoxicity by Cell Counting Kit-8 assay, mitochondrial membrane potential by JC-1 fluorescence analysis, anti-apoptosis by Hoechst 33258 staining and Annexin V-FITC (fluorescein isothiocyanate) and propidium iodide (PI) analyses, the expressions of TNF-α and IL-6 by enzyme-linked immunosorbent assay (ELISA) and TLR4, MyD88, TRAF6, p-NF-κB p65, and total NF-κB p65 by Western blotting, and nuclear translocation of NF-κB p65 by immunofluorescence analysis in hBMECs. The results showed that pretreatment of asiaticoside (25, 50, and 100 μM) for 12 h significantly attenuated cell growth inhibition and apoptosis, and restored declined mitochondrial membrane potential induced by Aβ1-42 (50 μM) in hBMECs. Asiaticoside also significantly downregulated the elevated expressions of TNF-α, IL-6, TLR4, MyD88, TRAF6, and p-NF-κB p65, as well as inhibited NF-κB p65 translocation from cytoplasm to nucleus induced by Aβ1-42 in hBMECs in a concentration-dependent manner. The possible underlying molecular mechanism of asiaticoside may be through inhibiting the TLR4/NF-κB signaling pathway. Therefore, asiaticoside may be developed as a novel agent for the prevention and/or treatment of AD clinically.

Protective effect of asiaticoside on radiation-induced proliferation inhibition and DNA damage of fibroblasts and mice death

“…It is known that antioxidants have an effective role in ameliorating radiation-induced oxidative injuries [15]. AC has been cells [6,23]. In our study, we found that AC significantly restored the level of serum T-AOC caused by radiation, and mitigated radiation-induced DNA damage, indicating that AC might act as a radio-protectant for the treatment of side effects produced by radiation therapy.…”

Effects of Betaine on LPS-Stimulated Activation of Microglial M1/M2 Phenotypes by Suppressing TLR4/NF-κB Pathways in N9 Cells

“…Once microglia are activated, IκB-α is separated and transferred from the cytoplasm to the nucleus, resulting in transcription and expression of inflammatory factors [49]. NF-κB is expressed in nearly all cells and plays an important role in the activation of the M1 microglial phenotype [50]. Our results further showed that betaine interacted with the IKK complex and specifically targeted its IKK-β subunit, thereby protecting the IκB subunit from LPS-mediated inflammatory stimulus-induced phosphorylation and subsequent proteasomal degradation.…”

Therapeutic Potential of Centella asiatica and Its Triterpenes: A Review

“…It dissolves in methanol, ethanol, and water. Relevant literature on the nervous system demonstrated that C. asiatica and its triterpenes could be used to relieve a variety of neurological diseases, but the most researched are improve Alzheimer's disease (AD) (Song et al, 2018) and Parkinson's disease (Nataraj et al, 2017b) (Table 2). The pathogenesis of AD and Parkinson's disease involve neuroinflammatory activities (Gelders et al, 2018), oxidative stress (Jiang et al, 2016), mitochondrial dysfunction (Morais and De Strooper, 2010), and dysfunction in brain-derived neurotrophic factor (Mohammadi et al, 2018).…”