Anti-stress effect of milk-derived iron binding proteins

乳铁蛋白（LF）是一种铁结合糖蛋白，特别是在牛奶中。我们已经证明，牛LF（bLF）的肠道内给药，从肠道吸收，并通过受体介导的系统进入血液循环。我们发现bLF最终被转运到脑脊液中。然而，它在中枢神经系统（CNS）的生理作用还不清楚，在这个项目中，bLF对心理困扰的抑制作用在新生和成年大鼠进行了研究。腹腔注射bLF（100毫克/公斤）减少行为反应的压力，在母鼠分离的幼崽或在一个条件性恐惧诱导的冻结测试和高架十字迷宫测试在成年大鼠。有趣的是，bLF抑制心理困扰不仅在幼鼠，而且在成年大鼠。bLF的这种抑制作用可通过预先给予阿片受体拮抗剂纳洛酮（1 mg/kg，ip）逆转。一氧化氮合酶（NOS）抑制剂N^ω-硝基-L-精氨酸甲酯（L-NAME）也可阻断bLF的抑制作用。此外，联合应用低剂量的bLF（30 mg/kg，ip）和L-精氨酸（30和100 mg/kg，ip）潜在地抑制了对心理应激的行为反应。这些结果表明，bLF对心理困扰有抑制作用，尤其是在中等应激条件下。此外，bLF可能通过一氧化氮合酶激活增强内源性阿片系统。

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.