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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.

Introduction: Dichloroacetic acid (DCA), a by‐product of disinfection in drinking water, is a multiple organ carcinogen in humans and animals. Still, little research on its neurotoxicity and its underlying mechanism has not been elucidated. Methods: Sprague Dawley rats were intragastrically treated with DCA at 10, 30, 90 mg/kg body weight from pregnancy till delivery. At eight weeks of age of pups, we assessed cognitive performance using the standard behavioral tests. And the hippocampus structure and ultrastructure were evaluated using light and electron microscope. The oxidative stress indicators and neuroinflammation factors were measured with the corresponding kits. The mRNA and protein of synaptic factors were detected using RT‐PCR and Western blot. Results: The results indicated that maternal weight gain and offspring birthweight were not significantly affected by DCA. However, behavioral tests, including morris water maze and step down, showed varying degrees of changes in DCA‐treated pups. Additionally, we found significant differences in hippocampal neurons by histomorphological observation. Biochemical analysis results indicated superoxide dismutase (SOD) and catalase (CAT) activities, as well as reactive oxygen species (ROS), nitric oxide (NO), and reduced glutathione (GSH) levels, were affected by DCA accompanying with DNA damage. Moreover, the results showed that the neuroinflammation factors (TNF‐α, IL‐6, IL‐1β) in DCA treatment groups increased significantly compared with the control pups. And we also found that DCA treatment caused a differential modulation of proteins (BDNF, cAMP‐response element‐binding protein1 (CREB1), p‐CREB1, postsynaptic density‐95 (PSD‐95), synapsin I, p‐synapsin I), and mRNA (BDNF, PSD‐95). Conclusions: Taken together, these results above showed that oxidative stress, neuroinflammation response, and weakened synaptic plasticity in pups hippocampus induced by fetal exposure to DCA could damage the function of memory and cognition in the adulthood. [ABSTRACT FROM AUTHOR]