Bridging neuroinflammation, oxidative stress, and neurogenesis: aromatic turmerone as a multifunctional modulator via NF-κB and Nrf2 pathways.

Neuroinflammation and oxidative stress are central mechanisms driving neurodegenerative diseases, while impaired neurogenesis limits regeneration. Aromatic-turmerone (ar-turmerone), a bioactive sesquiterpenoid from Curcuma longa, has emerged as a multifunctional neuroprotective agent capable of modulating inflammatory and regenerative processes simultaneously. Evidence from in vitro and in vivo models demonstrates that ar-turmerone suppresses Toll-like receptor 4 (TLR4)-dependent NF-κB and MAPK signaling, thereby reducing microglial activation, nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and proinflammatory cytokines (TNF-α, IL-1β, IL-6). Concurrently, it activates the Nrf2/HO-1 antioxidant pathway and enhances cAMP/PKA-CREB signaling, restoring redox homeostasis and promoting neuronal survival. Importantly, ar-turmerone drives microglial polarization toward the M2 anti-inflammatory phenotype and stimulates neural stem cell (NSC) proliferation and neuronal differentiation in the subventricular zone and hippocampus. These dual anti-inflammatory and neurogenic actions position ar-turmerone as a unique bridge between neuroinflammation suppression and neuroregeneration enhancement. Recent structure-activity relationship studies further reveal that N-substituted amide and naphthyl derivatives exhibit superior inhibition of NO and TNF-α release and improved neuroprotective potency in Alzheimer's and Parkinson's disease models. Collectively, ar-turmerone represents a promising multi-target natural scaffold for developing therapeutics that counteract neurodegeneration by simultaneously modulating microglial activation, oxidative stress, and endogenous neurogenesis.