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The present study was designed to evaluate the role of cAMP-PKA-CREB signaling in mediating the neuroprotective effects of curcumin against DCAA-induced oxidative stress, inflammation and impaired synaptic plasticity in rats. Sixty Sprague-Dawley rats were randomly divided into five groups, and we assessed the histomorphological, behavioral and biochemical characteristics to investigate the beneficial effects of different concentrations of curcumin against DCAA-induced neurotoxicity in rat hippocampus. The results indicated that animal weight gain and food consumption were not significantly affected by DCAA. However, behavioral tests, including morris water maze and shuttle box, showed varying degrees of alterations. Additionally, we found significant changes in hippocampal neurons by histomorphological observation. DCAA exposure could increase lipid peroxidation, reactive oxygen species (ROS), inflammation factors while reducing superoxide dismutase (SOD) activity and glutathione (GSH) level accompanied by DNA damage in the hippocampus. Furthermore, we found that DCAA exposure could cause a differential modulation of mRNA and proteins (cyclic adenosine monophosphate (cAMP), protein kinase A (PKA), cAMP-response element-binding protein (CREB), p-CREB, brain-derived neurotrophic factor (BDNF), postsynaptic density-95 (PSD-95), synaptophysin (SYP)). Conversely, various doses of curcumin attenuated DCAA-induced oxidative stress, inflammation response and impaired synaptic plasticity, while elevating cAMP, PKA, p-CREB, BDNF, PSD-95, SYP levels. Thus, curcumin could activate the cAMP-PKA-CREB signaling pathway, conferring neuroprotection against DCAA-induced neurotoxicity. [ABSTRACT FROM AUTHOR]