Effects Of Tyrosine Oxidation Products On Learning And Memory In Rats And Mice

Objectives: Oxidation of food protein leads to a decrease of food quality and has some bad effects on human health. Studies showed that long-term intake of tyrosine oxidation products(TOP,including dityrosine and 3-nitrotyrosine) induce oxidative damage to rat heart,liver and kidney and lead to accumulation of dityrosine and AOPP in tissues. However,it is unclear whether dietary tyrosine oxidation products will accumulate in brain tissue. This topic is designed to explore the effects of tyrosine oxidation products on neurobehavioral functions such as learning and memory, locomotor activity and anxiety and its possible mechanisms.Methods: 1. TOP feeding experiment: 40 four-week old SD rats were divided into four groups: Control group(normal diet),Tyr group(0.44%Tyr),TOP1 group(0.22%TOP),TOP2 group(0.44%TOP). After 24-week feeding experiments,Morris water maze was used to test the spatial learning and memory of rats; hippocampal oxidation products were detected; hippocampal antioxidation and inflammation related genes were detected using real-time fluorescent quantitative PCR. 2. Dityrosine intragastric administration experiment: 30 fourweek old C57BL/6 mice were divided into three groups. They were daily administrated with either 0.9% saline(Saline group),320 μg/kg?bw Dityr(Dityr1 group) or 960 μg/kg?bw Dityr(Dityr2 group) for consecutive eight weeks. One week after intragastric administration finishing, locomotor activity and anxiety-like behavior were assessed in open field and elevated plus maze paradigms,respectively. Non-spatial and spatial memory performance were tested in novel object recognition and Morris water maze paradigms, respectively. Sociability and social recognition were examined in a three-chamber social interaction paradigm. Hippocampal oxidation products and inflammatory cytokines were detected. Furthermore, hippocampal antioxidation genes, inflammation related genes, thyroid hormone receptor and its downstream genes,and learning and memory related genes were detected using real-time fluorescent quantitative PCR.Results:1. After 24-week TOP feeding: In Morris water maze, the time spent and distance traveled in platform quadrant of TOP1 and TOP2 group rats were significantly lesser than Control and Tyr group rats. Compared to Control and Tyr group,hippocampal MDA,4-HNE,Dityr,3-NT and Aβ40 of TOP1 and TOP2 group were significantly increased(p<0.05); gene expressions of Nrf2,Nf-κb and Inos were significantly up-regulated(p<0.05). 2. After 8-week intragastric administration:(1) In novel object recognition test,Saline group mice spent significantly more time exploring novel object compared to familiar object(p<0.05). However,Dityr1 and Dityr2 group mice showed no significant difference between the time spent exploring the two objects(p>0.05).(2) In open field test,elevated plus maze,social interaction test and Morris water maze,Dityr1 and Dityr2 group mice showed no significantly differences in all parameters compared to Saline group(p > 0.05).(3) Hippocampal MDA, 4-HNE of Dityr1 and Dityr2 group were significantly increased compared to Saline group(p<0.05). Hippocampal Dityr,3-NT,Aβ40 and IL-6,TNF-α were increased in some extent(p>0.05).(4) Gene expressions of Nrf2,Prdx-1,Nf-κb,Ap-1, Il-6, Tnf-α and p38 of Dityr1 and Dityr2 group were significantly up-regulated compared to Saline group(p < 0.05).(5) Gene expression of hippocampal Thrα; its downstream genes Rc3,Gap-43; learning and memory related genes Nr1,Nr2 a,Nr2b; Bdnf, Trkb; Creb, Egr-1 of Dityr1 and Dityr2 group mice were significantly downregulated compared to Saline group mice(p<0.05).Conclusions: Long-term intake of tyrosine oxidation products induced redox imbalance and accumulation of protein and lipid oxidation products in rat hippocampus; destroyed spatial learning and memory of rats. Dityrosine caused mild redox imbalance, impaired memory in novel object recognition test with decreased expressions of learning and memory related genes.The underlined mechanism of impacts of tyrosine oxidaiton products on animal learning and memory needs further studies.