Anti-stress effect of milk-derived iron binding proteins

乳铁蛋白（LF）是一种结合铁的糖蛋白，特别存在于牛奶中。我们已经证明，十二指肠内给药的牛- lf （bLF）从肠道吸收并通过受体介导系统进入血液循环。我们发现bLF最终被输送到脑脊液中。然而，其在中枢神经系统（CNS）中的生理作用尚不清楚。本项目研究了bLF对新生大鼠和成年大鼠心理困扰的抑制作用。腹腔注射bLF （100 mg/kg）降低了母鼠分离幼鼠、条件恐惧诱导的冷冻实验和成年大鼠升高的迷宫实验对应激的行为反应。有趣的是，bLF不仅抑制了幼鼠的心理困扰，也抑制了成年大鼠的心理困扰。bLF的这种抑制作用可通过以1mg /kg （ip）剂量的阿片受体拮抗剂纳洛酮进行预处理而逆转。一氧化氮合酶（NOS）抑制剂N^ω-硝基- l -精氨酸甲酯（L-NAME）也阻断了bLF的抑制作用。此外，低剂量bLF （30 mg/kg, ip）和l -精氨酸（30和100 mg/kg， ip）联合应用可能抑制心理应激的行为反应。这些结果表明，体力劳动对心理困扰有一定的抑制作用，尤其是在中等应激条件下。此外，bLF可能通过激活一氧化氮合酶增强内源性阿片能系统。

Lactoferrin(LF) is known as an iron-binding glycoprotein, specially contained in milk. We have shown that intra-duodenally administered bovine-LF(bLF) was absorbed from intestine and transported into blood circulation via receptor mediated system. We found that the bLF was finally transported into cerebrospinal fluid. However, its physiological effects in the central nervous system(CNS) are still unclear.In this project, suppressive effects of bLF on psychological distress were investigated in neonatal and adult rats. Intraperitonealy injected bLF (100 mg/kg) reduced behavioral responses to the stress in maternally separated pups or in a conditioned-fear-induced freezing test and an elevated plus-maze test in adult rats. Interestingly, bLF suppressed psychological distress not only in pups but also in adult rats. This suppressive effect of bLF was reversed by pre-treatment with naloxone, an opioid receptor antagonist, at a dose of 1 mg/kg (ip). N^ω-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase(NOS) inhibitor, also blocked the suppressive effect of bLF. Additionally, combined application of a low dose of bLF (30 mg/kg, ip) and L-arginine (30 and 100 mg/kg, ip) potentiatively suppressed behavioral responses to the psychological stress. These results suggest that bLF has suppressive effects on the psychological distress, especially under the condition of moderate stress. Furthermore, bLF possibly enhances an endogenous opioidergic system via nitric oxide synthase activation.