Preclinical neuropharmacological effects of Centella asiatica-derived asiaticoside and madecassoside in Alzheimer's disease

Abstract

Alzheimer's disease (AD), a progressive neurodegenerative disorder, is characterized by amyloid-beta (Aβ) plaque accumulation, chronic neuroinflammation, oxidative stress, and neuronal apoptosis, leading to cognitive decline. Recent preclinical studies have highlighted the neuroprotective effects of Asiaticoside (AS) and Madecassoside (MS), two primary triterpenoid saponins derived from C. asiatica. These compounds show promise in addressing multiple pathological pathways associated with AD. AS and MS exhibit potent anti-amyloidogenic properties, effectively inhibiting Aβ aggregation and reducing plaque formation, primarily through direct binding to amyloid peptides and disruption of fibrillogenesis. In vitro studies demonstrated that AS prevents the early stages of Aβ aggregation, while in vivo research confirms its role in reducing plaque deposition in critical brain regions like the hippocampus, enhancing cognitive function. MS similarly disrupts Aβ aggregation, as shown through molecular docking studies, and has demonstrated efficacy in reducing amyloid burden and improving synaptic health in AD models. Both compounds also modulate neuroinflammation by downregulating key inflammatory pathways, such as NF-κB and MAPK. AS reduces pro-inflammatory cytokines (TNF-α and IL-6) by inhibiting NF-κB activation, while MS downregulates iNOS and COX-2, thereby alleviating neuroinflammatory damage. Notably, both saponins activate the Nrf2 antioxidant pathway, contributing to an enhanced cellular antioxidant response, reducing oxidative stress, and stabilizing mitochondrial function. These anti-inflammatory and antioxidant mechanisms further protect against cognitive decline associated with neuroinflammation and oxidative stress. Additionally, AS and MS prevent neuronal apoptosis by modulating apoptotic signaling pathways, such as caspase-3 inhibition and upregulation of anti-apoptotic proteins like Bcl-2. In vivo studies indicate that these compounds support cognitive function and synaptic integrity, as demonstrated by improved memory and learning outcomes in AD animal models, likely via enhanced synaptic plasticity and cholinergic support. In conclusion, the triterpenoids AS and MS show multifaceted neuroprotective effects in preclinical models of AD. Their abilities to inhibit Aβ aggregation, modulate neuroinflammation, enhance mitochondrial function, and prevent neuronal apoptosis highlight their therapeutic potential. These findings warrant further exploration in clinical studies to assess their viability as treatments for AD.