Rosmarinic acid modulates microglial Nrf2/HO-1 and NF-κB-NLRP3 signaling in vascular dementia: Multi-omics and experimental evidence.
TL;DR
RA ameliorated cognitive dysfunction in BCAS mice by suppressing microglial oxidative stress and neuroinflammation and attenuating BBB-related disruption and the data suggest that RA provide a pharmacological strategy for BCAS-associated cognitive impairment.
Abstract
Background
Chronic cerebral hypoperfusion contributes to cognitive decline through interacting vascular, inflammatory, and redox abnormalities. Whether rosmarinic acid (RA) modifies these processes through microglial Nrf2/HO-1 and NF-κB-NLRP3 signaling has not been adequately defined.
Methods
RA was evaluated in bilateral common carotid artery stenosis (BCAS) mice and OGD-exposed microglial models using a framework that combined behavioral and imaging assessments, histopathology, transcriptomic profiling, computational prediction, cellular thermal shift assays (CETSA), and genetic or pharmacological pathway intervention.
Results
RA attenuated cognitive and anxiety-like behavioral abnormalities, neuronal injury, corpus callosum demyelination, brain microstructural alterations, and mitochondrial ultrastructural damage in BCAS mice. Multi-omics analyses identified microglia as a prominent disease-responsive cell population and highlighted oxidative stress, neuroinflammation, and BBB disruption as major pathological processes. Molecular docking and dynamics simulations predicted interactions of RA with Nrf2, P65, and NLRP3, whereas CETSA supported cellular target engagement with Nrf2 and P65. In BV2 cells and primary microglia, RA promoted Nrf2 nuclear translocation and HO-1 expression while reducing ROS accumulation, P65 nuclear translocation, phospho-P65, NLRP3, N-GSDMD, Caspase-1 p20, IL-1β, and IL-18. Nrf2 knockdown and ML385 attenuated these effects. Conditioned-medium experiments further indicated that RA-mediated regulation of microglia reduced neuronal and synaptic injury. In vivo, RA improved redox homeostasis, reduced MMP-2 and MMP-9, and restored ZO-1 and Occludin expression.
Conclusion
RA ameliorated cognitive dysfunction in BCAS mice by suppressing microglial oxidative stress and neuroinflammation and attenuating BBB-related disruption. Collectively, the data suggest that RA provide a pharmacological strategy for BCAS-associated cognitive impairment.