High dietary fat induces NADPH oxidase-associated oxidative stress and inflammation in rat cerebral cortex

Epidemiological and experimental studies have suggested that high dietary intake of fats is associated with cognitive decline and a significantly increased risk of dementia. Since oxidative stress and inflammation have been speculated to be critical mechanisms underlying neurodegenerative diseases, we hypothesized that a high fat (HF) diet might induce cerebral oxidative stress or neural inflammation and subsequently contribute to the high risk of dementia. To test this hypothesis, male rats were placed on either a HF diet or a low fat (LF) diet starting at 1 month of age and lasting for 5 months. Intracellular reactive oxidative species (ROS) generation in the cerebral cortex was measured by the oxidant-sensitive dye 5-(6)-chloromethyl-2′,7′-dichlorodihydrofluorescein diacetate (CM-H2DCFDA). Cortical tissue concentration of prostaglandin E2 (PGE2) was determined using an enzymatic immunoassay. Expression of NADPH oxidase subunits, cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2), nuclear transcription factor NFkappa-B (NF-κB) p65 subunit, Ikappa B(IκB), and phospho-Ikappa B(phospho-IκB) was evaluated by Western blot analysis. The HF diet significantly increased ROS generation and expression of gp91phox, p22phox, p47phox, and p67phox NADPH oxidase subunits in cerebral cortex. Elevated PGE2 levels and markedly increased COX-2 expression suggested a neural inflammatory response in response to excessive fat intake. These findings were further supported by significantly increased phospho-IκB and nuclear NF-κB expression that suggested a role of IκB phosphorylation in HF diet-induced NF-κB translocation. The present study revealed that HF diet induced neural oxidative stress, inflammation, and NF-κB activation in rat cerebral cortex, and provided novel evidence regarding the link between high dietary fat and increased risk of dementia.