Dietary n-3 PUFA Deficiency Increases Vulnerability to Scopolamine-Induced Cognitive Impairment in Male C57BL/6 Mice

Background: DHA (22:6n-3), a long-chain n-3 PUFA, is essential for normal brain development and function. Our previous study demonstrated that DHA significantly improves scopolamine-induced dementia. However, there are no reports on the relation between n-3 PUFA deficiency and scopolamine-induced cognitive impairment. Objectives: The aim of this study was to evaluate whether n-3 PUFA deficiency increases vulnerability to scopolamine-induced cognitive impairment. Methods: Male and female C57BL/6 mice were mated and fed an n-3 PUFA-adequate [containing 2.88% ce-linolenic acid (ALA; 18:3n-3)] or-deficient (containing 0.09% ALA) diet for 2 consecutive generations. The corresponding second-generation male offspring were kept on the same diet as their mothers after weaning, and were randomly assigned to 2 subgroups at 7 wk of age, in which they were intraperitoneally injected with saline [fed n-3 PUFA-adequate (Con) or -deficient (Def) diet] or scopolamine [5 mg/kg body weight; fed n-3 PUFA-adequate (Sco) or -deficient (Def + Sco) diet] once per day for 7 d before killing. Behavioral performance was analyzed using the Morris Water Maze test. Fatty acid composition, protein expression, and indicators of cholinergic and oxidative stress in the brain were measured. Results: The Def group showed lower brain DHA (-63.7%, P <= 0.01) and higher n-6 PUFA (+65.5%, P <= 0.05) concentrations than the Con group. The Def + Sco group and the Sco group showed poorer spatial learning and memory (escape latency on the sixth day: +60.3% and +36.8%; platform crossings: -43.9% and -28.2%, respectively) and more obvious cholinergic dysfunction (acetylcholine: -476% and -27.7%, respectively), oxidative stress (glutathione peroxidase: -64.2% and -32.5%, respectively), apoptosis (B-cell lymphoma 2 (BCL2)-associated X protein/BCL2: +230.8% and +153.8%; phosphorylated P38/P38: +232% and +130%, phosphorylated c-Jun N-terminal kinase (JNKI/JNK: +104.5% and +58.8%, respectively], neuroinflammation (IL-1 beta: +317.6% and +95%, respectively), and neurodevelopmental delay (brain-derived neurotrophic factor: -54.4% and -725%, respectively) than their corresponding saline-treated controls. Conclusions: Dietary n-3 PUFA deficiency significantly decreases brain DHA concentrations and increases vulnerability to scopolamine-induced cognitive impairment in C57BL/6 male mice.