This study aimed to determine whether nordihydroguaiaretic acid (NDGA) can reduce NLRP3 inflammasome activation in microglial cells exposed to amyloid-β (Aβ) and α-synuclein (α-syn) oligomers.

Activation of the NLRP3 inflammasome drives neuroinflammation in Alzheimer’s and Parkinson’s disease. Misfolded protein aggregates, such as Aβ and α-syn oligomers, activate this pathway. This activation triggers caspase-1 and the release of pro-inflammatory cytokines that contribute to neuronal damage. NDGA, a plant-derived polyphenol with known antioxidant and anti-inflammatory effects, has not been well studied in this context.

IMG and BV2 microglial cells were pretreated with NDGA (5–10 μM) for two hours, then exposed to Aβ1-42 or α-syn oligomers. Cell viability was measured with MTT assay. Nitric oxide (NO) levels were measured using Griess assay. Protein expression of NLRP3 and caspase-1 was assessed by Western blot. IL-1β secretion was measured with ELISA.

NDGA preserved microglial viability and significantly reduced oligomer-induced NO production in a dose-dependent manner. It also suppressed NLRP3 expression, decreased caspase-1 cleavage, and inhibited IL-1β secretion after Aβ or α-syn exposure. These results suggest that NDGA dampens inflammasome activation, possibly by mitigating mitochondrial oxidative stress.

While NDGA has previously been shown to suppress NLRP3 activity in ischemic models, our findings are the first to extend this effect to neurodegenerative contexts, showing that NDGA suppresses inflammasome activation triggered by both Aβ and α-syn oligomers in microglia. NDGA reduces NLRP3 inflammasome activation and downstream inflammatory responses in oligomer-stimulated microglia. These outcomes support its potential capacity as a natural therapeutic approach to limit neuroinflammation in protein aggregation–related neurodegenerative diseases.