In vitro and in silico evaluation of the anti-amyloid and anti-inflammatory properties of curcumin and a V (IV) – curcumin complex in LPS-stimulated primary rat neurons-microglia mixed cultures

Abstract

Abstract Lipopolysaccharides (LPS) of Gram-negative bacteria are mediators of neuroinflammation and neurodegeneration that have been detected in close association with aggregations of brain amyloid beta (Aβ) and microtubule-associated protein tau (MAPT). LPS induce the release of cytokines by microglia, the residing immune cells of the brain, and mediate the upregulation of inducible nitric oxide synthase (iNOS) – a mechanism associated with amyloidosis and MAPT destabilization. Curcumin is a natural product possessing several medicinal effects; however, its pharmaceutical exploitation is hindered by low bioavailability. V-Cur, a novel hemocompatible Vanadium (IV)-curcumin complex with higher solubility and pharmaceutical activity than curcumin, has been employed in the present study. Mixed cultures of primary rat brain neurons and microglia stimulated LPS presented increased levels of amyloid precursor protein (APP), an effect inhibited by either curcumin or V-Cur. V-Cur was also proved a more potent inhibitor of amyloid aggregation than curcumin, by both insulin aggregation assay and in silico studies. Cell stimulation with LPS increased full-length, inactivated, and total iNOS levels, and the inflammation markers IL-1β and TNF-α. Both curcumin and V-Cur alleviated these effects, with V-Cur reducing iNOS levels more than curcumin, whereas curcumin and V-Cur increased the MAPT levels in LPS-stimulated cells. Complementary insights into possible bioactivity mechanisms of both curcumin and V-Cur were provided by in silico molecular docking calculations on iNOS, TNF-α, IL-1β, Aβ1−42, APP and Aβ fibrils. This study renders curcumin-based compounds a promising anti-inflammatory intervention that may be proven a strong tool in the effort to mitigate neurodegenerative disease pathology and neuroinflammatory conditions.