Vitamin C and vitamin E double-deficiency increased neuroinflammation and impaired conditioned fear memory

• Published in: Archives of biochemistry and biophysics 2019-03, Vol.663, p.120-128
• Main Authors: Takahashi, Keita, Yanai, Shuichi, Takisawa, Shoko, Kono, Nozomu, Arai, Hiroyuki, Nishida, Yoichiro, Yokota, Takanori, Endo, Shogo, Ishigami, Akihito
• Format: Article
• Language: English
• Subjects: Animals; Ascorbic Acid - blood; Ascorbic Acid Deficiency - complications; Behavioral experiments; Brain - pathology; Brain - physiopathology; Calcium-Binding Proteins - genetics; Carrier Proteins - genetics; Conditioning, Classical; Fear; Inflammation - complications; Intracellular Signaling Peptides and Proteins - genetics; Maze Learning; Memory; Mice; Mice, Knockout; Neuroinflammation; SMP30; Vitamin C; Vitamin E; Vitamin E - blood; Vitamin E Deficiency - complications; αTTP
• ISSN: 0003-9861; 1096-0384
• DOI: 10.1016/j.abb.2019.01.003

Vitamin C (l-ascorbic acid, VC) and vitamin E (α-tocopherol, VE) play important physiological roles as endogenous antioxidants in many tissues and organs. However, their roles in the brain remain entirely elusive. We established senescence marker protein 30 (SMP30)/α-tocopherol transfer protein (αTTP) double knockout (DKO) mice as a novel VC and VE double-deficiency model and examined the effect of VC and VE double-deficiency on brain functions. DKO and wild-type (WT) mice were divided into the following two groups: mice in the CE (+) group were supplied with sufficient amounts of VC and VE and mice in the CE (−) group were deficient in both VC and VE. After 8 weeks of CE (+) or CE (−) treatments, a battery of behavioral experiments was conducted to analyze cognitive functions, including memory, through the Morris water maze and Pavlovian fear conditioning tasks. The plasma VC and VE levels in DKO-CE (−) mice and VE level in WT-CE (−) mice were almost completely depleted after 8 weeks of the deficient treatment. The behavioral study revealed that the general behaviors, including locomotor activity and anxiety level, were not influenced by the CE (−) treatment in DKO and WT mice. However, in the Pavlovian fear conditioning task, DKO-CE (−) mice showed impaired conditioned fear memory compared with that of DKO-CE (+) mice. Furthermore, increased mRNA expression was observed in inflammatory-related genes, such as IL-6, TNFα, F4/80, and Mcp-1, in the hippocampus of DKO-CE (−) mice. The findings of this study provide evidence that VC and VE deficiency led to impaired conditioned fear memory possibly caused by neuroinflammation in the brain.