The Neuroprotective Effects and Therapeutic Potential of the Chalcone Cardamonin for Alzheimer's Disease

Neurodegenerative diseases (NDs) such as Alzheimer’s disease (AD) and Parkinson’s disease are increasing with aging populations. Despite symptomatic treatments, disease-modifying therapies remain limited. Oxidative stress (OS) and neuroinflammation are central to AD pathogenesis, driven by excess reactive oxygen/nitrogen species, mitochondrial dysfunction, and glial activation. The transcription factor Nrf2 regulates antioxidant and cytoprotective responses via ARE-driven gene expression, while NF-κB and MAPKs drive inflammatory signaling. With aging, Nrf2 activity and adaptive antioxidant responses decline in a region- and cell-type–dependent manner, contributing to vulnerability. This review focuses on the potential of the natural chalcone cardamonin (CD) to confer neuroprotection in AD by activating Nrf2-dependent antioxidant defenses, suppressing NF-κB–mediated inflammation, and modulating related pathways (e.g., autophagy, microRNAs), thereby addressing key mechanisms underlying AD progression.

The review synthesizes evidence on AD pathogenesis (amyloid-β accumulation, tau hyperphosphorylation, synaptic loss, mitochondrial dysfunction, OS), risk factors, and biomarkers (CSF Aβ42, total tau, phospho-tau; emerging neuroinflammatory markers such as TREM2, IL-1β, MCP-1, IL-6, TNF-α receptor complexes, TGF-β, YKL-40; neuroinflammation PET ligands). It details the role of neuroinflammation—particularly microglia and astrocytes—in AD; microglial receptors for Aβ (CD14, TLR2/4/6/9, CD36, integrins), impaired Aβ clearance, and cytokine networks (TNF-α, IL-1β, IL-6, IL-10). Intracellular signaling pathways implicated include MAPKs (ERK, JNK, p38) and NF-κB (canonical and noncanonical), with crosstalk between NF-κB and Nrf2. Current FDA-approved AD drugs (AChE inhibitors and memantine) provide symptomatic benefit with side effects, motivating exploration of natural compounds. The review catalogs natural products with antioxidant/neuroprotective properties and centers on cardamonin’s reported actions: inhibition of NF-κB and inflammatory mediators, activation of Nrf2/ARE-driven antioxidant genes, modulation of autophagy and mTORC1, attenuation of inflammasome activation (NLRP3), microglial deactivation, and miRNA regulation, integrating in vitro and in vivo findings across models relevant to neuroinflammation and OS.

Narrative review. PubMed was searched for publications since 1995 using keywords including cardamonin, neurodegeneration, neuroprotection, neuroinflammation, cytokines, anti-inflammatory, antioxidant, Alzheimer’s disease (AD), Parkinson’s disease (PD), Nrf2, microglia, MAPK and NF-κB signaling, autophagy, and microRNA. The conclusion was based on screening of data from identified papers.

- Cardamonin (CD) exhibits broad bioactivities pertinent to AD: antioxidant, anti-inflammatory, neuroprotective, and cytoprotective. - Nrf2 activation: CD is a potent small-molecule activator of Nrf2, inducing phase II/ARE-driven enzymes (e.g., HO-1, NQO1, GCL, SOD, CAT, GPx, GR, GST). In PC12 cells, CD protected against H2O2- and 6-OHDA-induced cell death; protection was lost upon Nrf2 silencing, indicating Nrf2 dependence. - NF-κB and inflammatory mediators: CD inhibits NF-κB activation (prevents IκB degradation/phosphorylation, IKK activation, nuclear translocation) and reduces LPS/TNF-α–induced NF-κB reporter activity in RAW264.7 cells; decreases TNF-α and NO production and iNOS/COX-2 expression; reduces LPS-induced mortality and circulating TNF-α in C57BL/6 mice. - Microglia deactivation: In BV-2 microglia, CD suppressed release of NO, PGE2, TNF-α, IL-1β, and IL-6 at mRNA and protein levels and reduced NF-κB DNA-binding; also downregulated CD14 surface expression. - Inflammasome: CD is a broad-spectrum inhibitor of the NLRP3 inflammasome (but not NLRC4/AIM2), improving survival in NLRP3-dependent LPS-induced endotoxic shock in mice. - Autophagy/mTOR: CD induces autophagy and exerts antiproliferative effects via JNK activation in HCT116 cells; inhibits mTORC1 and induces autophagy in SKOV3 ovarian cancer cells (distinct from rapamycin’s FKBP12-dependent mechanism), supporting a role in proteostasis relevant to ND. - Pathway breadth: CD modulates transcription factors (Nrf2, NF-κB, STAT3), cytokines (TNF-α, IL-1, IL-6), enzymes (COX-2, MMP-9, ALDH1), and proteins/genes (Bcl-2, XIAP, cyclin D1); it also affects miRNA expression patterns in cancer/colon models, suggesting potential for miRNA modulation in neuroinflammation. - Nrf2–NF-κB crosstalk: Evidence supports reciprocal regulation; Nrf2 activation attenuates inflammatory gene expression, aligning with CD’s dual antioxidant/anti-inflammatory profile. - Relevance to AD: By enhancing antioxidant defenses, dampening cytokine-driven neuroinflammation, improving mitochondrial function, and supporting proteostasis/autophagy, CD targets convergent AD mechanisms (OS, microglial activation, cytokine signaling, NF-κB/MAPK pathways).

The collected evidence indicates that cardamonin targets key upstream and downstream mechanisms implicated in AD pathogenesis. Through Nrf2 activation, CD enhances endogenous antioxidant capacity and mitigates ROS/RNS-driven damage and mitochondrial dysfunction. Concurrently, by inhibiting NF-κB and MAPK signaling, CD reduces production of neurotoxic mediators (TNF-α, IL-1β, IL-6, NO, PGE2), restrains microglial overactivation, and dampens NLRP3 inflammasome activity—processes that exacerbate Aβ- and tau-related neurotoxicity. CD’s effects on autophagy/mTOR and reported modulation of miRNAs further support maintenance of protein homeostasis and regulation of inflammatory gene networks, both relevant to amyloid/tau handling and synaptic integrity. While most mechanistic data derive from cellular and animal models of oxidative or inflammatory injury (with some non-neurologic models validating pathway actions), the convergence on Nrf2–NF-κB crosstalk and microglial pathways underscores CD’s potential as a multi-target candidate to modify disease-relevant processes in AD. These findings support advancing CD for further preclinical AD models and translational studies to evaluate pharmacokinetics, brain penetration, efficacy, and safety in the AD context.

Dietary/natural-product strategies are of growing interest to prevent or delay neurodegenerative diseases. Cardamonin appears to exert neuroprotective, antioxidant, anti-inflammatory, and cytoprotective effects primarily via activation of the Keap1–Nrf2–ARE pathway and inhibition of proinflammatory signaling (e.g., NF-κB, STAT3). CD modulates multiple signaling molecules (transcription factors, cytokines, enzymes, apoptosis/survival regulators) and engages additional protective mechanisms (inflammasome suppression, autophagy modulation, miRNA regulation). Given its multitarget profile and preclinical evidence, CD is a promising compound with potential utility in AD-preventive or disease-modifying therapy. Future research should include rigorous in vivo AD models, pharmacological optimization, dosing and safety studies, and ultimately clinical evaluation to determine efficacy in humans.