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

Abstract

ABSTRACT 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% α-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: −47.6% 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 (JNK)/JNK: +104.5% and +58.8%, respectively], neuroinflammation (IL-1β: +317.6% and +95%, respectively), and neurodevelopmental delay (brain-derived neurotrophic factor: −54.4% and −7.25%, 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.