Banks W A, Kastin A J, Akerstrom V, Jaspan J B
Veterans Affairs Medical Center, New Orleans, Louisiana.
Am J Physiol. 1993 May;264(5 Pt 1):E723-9. doi: 10.1152/ajpendo.1993.264.5.E723.
Cyclo(His-Pro) (cHP) is a peptide widely distributed in the central nervous system (CNS) and peripheral tissues that can affect brain function after either peripheral or CNS administration. This suggests that cHP may be a neuromodulator capable of crossing the blood-brain barrier (BBB). We, therefore, studied the ability of radioactively labeled cHP (I-cHP) to cross the BBB. We found that I-cHP can cross the BBB in either the direction of blood to brain or brain to blood by nonsaturable mechanisms. The rate of entry of I-cHP into the CNS was low in comparison with other peptides, especially considering its relatively low molecular weight and high lipid solubility. However, this slow entry was offset by a long half-life in blood and extreme enzymatic resistance, allowing cHP to accumulate in the CNS. This accumulation was sufficient to allow intravenous cHP to reverse ethanol-induced narcosis, an effect mediated through the CNS. The rate of entry of I-cHP was resistant to conditions that alter the passage of some other substances across the BBB or that have been shown to affect cHP metabolism such as aging, diabetes, and pretreatment with aluminum. Entry of cHP into the brain was not retarded by binding to serum proteins. Significant amounts of I-cHP entered the serum, brain, and other tissues after intraperitoneal administration, the route used in many studies of cHP. Taken together, these results show that cHP is a highly stable peptide that, after intravenous injection, slowly enters the brain by a nonsaturable mechanism in amounts large enough to affect such aspects of the CNS as ethanol-induced narcosis.
环（组氨酸 - 脯氨酸）（cHP）是一种广泛分布于中枢神经系统（CNS）和外周组织的肽，在外周或中枢神经系统给药后均可影响脑功能。这表明cHP可能是一种能够穿越血脑屏障（BBB）的神经调节剂。因此，我们研究了放射性标记的cHP（I - cHP）穿越血脑屏障的能力。我们发现I - cHP可以通过非饱和机制在血脑或脑血两个方向穿越血脑屏障。与其他肽相比，I - cHP进入中枢神经系统的速率较低，尤其是考虑到其相对较低的分子量和高脂溶性。然而，这种缓慢的进入被血液中的长半衰期和极强的酶抗性所抵消，使得cHP能够在中枢神经系统中积累。这种积累足以使静脉注射的cHP逆转乙醇诱导的麻醉，这是一种通过中枢神经系统介导的效应。I - cHP的进入速率不受改变其他一些物质穿越血脑屏障的条件或已被证明影响cHP代谢的条件（如衰老、糖尿病和铝预处理）的影响。cHP进入大脑不会因与血清蛋白结合而受阻。在许多cHP研究中使用的腹腔注射后，大量的I - cHP进入血清、大脑和其他组织。综上所述，这些结果表明cHP是一种高度稳定的肽，静脉注射后，通过非饱和机制缓慢进入大脑，其进入量足以影响中枢神经系统的诸如乙醇诱导的麻醉等方面。
