The comparative ameliorating effects of an amorphous formula of curcumin and α-glycosyl isoquercitrin on hippocampal dysfunction in a rat gulf war illness model.

Brain dysfunction is a primary symptom of Gulf War illness (GWI). The present study investigated the effects of an amorphous formula of curcumin (CUR) and α-glycosyl isoquercitrin (AGIQ) on neurobehaviors and adult neurogenesis and following synaptic plasticity of produced neurons in the hippocampal dentate gyrus (DG) in a rat GWI model. Ten-week-old rats received GWI-related chemicals and restraint stress for 28 days; thereafter, animals were fed either a diet without supplement or mixed with 0.1% CUR or 0.5% AGIQ for 126 days. GWI treatment adversely affected behavioral endpoints, including novel object recognition, sucrose preference, novelty-suppressed feeding, and contextual fear conditioning. CUR ameliorated all these effects, while AGIQ caused anxiety-like behavior and improved fear extinction learning. GWI treatment downregulated NRF2-KEAP1 pathway-related genes in the DG; both phytochemicals reversed most of these changes. GWI treatment increased CD68+ and CD163+ microglia populations in the DG hilus; both phytochemicals reversed the increase of CD68+ microglia. In the neurogenic niche, GWI treatment decreased GFAP+ neural stem cells but increased DCX+ and PCNA+ cells, decreased hilar SST+ and GAD67+ GABAergic interneurons, and downregulated Pvalb. CUR reversed decreases in GFAP+ cell and SST+ interneuron numbers. Both phytochemicals increased VGLUT1 immunoreactivity, restored the VGLUT1/VGAT ratio, and upregulated Bdnf, Gria1, Gria2, Gria3, Slc17a7, Ptgs2, and Mapk1. AGIQ further increased COX2+ cell numbers and upregulated Grin2a, Grin2b, and Mapk3. In summary, both phytochemicals may have exerted antioxidant effects and modulated excitatory/inhibitory balance via glutamatergic signaling in GWI animals; CUR was superior to AGIQ at normalizing aberrant neurobehaviors and neurogenesis.