Antonawich F J, Azmitia E C, Kramer H K, Strand F L
Department of Biology, New York University, New York 10003.
Ann N Y Acad Sci. 1994 Oct 31;739:60-73. doi: 10.1111/j.1749-6632.1994.tb19807.x.
The results of the present study demonstrate that administration of the ACTH-(4-9) analogue Org 2766 acutely enhances behavioral, morphological, and biochemical recovery after nigrostriatal destruction. Animals treated with Org 2766 (10 micrograms/kg every 24 hr) demonstrated an acceleration of denervation supersensitivity and a significantly decreased ipsilateral rotational response, as compared to their saline counterparts. Upon evaluation of the mesolimbic DA system using open field behavior, peptide-treated rats demonstrated a compensatory response in their rearing behavior. Furthermore, tyrosine hydroxylase immunocytochemical analysis indicated an enhanced staining in the Org 2766-treated groups. This evaluation was confirmed and quantified using specific high-affinity dopamine uptake. The brains of animals treated with Org 2766 maintained higher uptake levels, suggesting a greater fiber density than the saline-treated animals. Although recovery via reinnervation is very unlikely in this short period of time, improved recovery may be the result of a protective effect of Org 2766 after administration of 6-OHDA into the substantia nigra. Thus, it appears that Org 2766 provides the rapid effects in this system, by both accelerating some compensatory mechanisms necessary for functional recovery and promoting cell survival by providing neuronal protection. However, it does not appear that this protection is due to NMDA receptor manipulation. Org 2766 neither mimicked the NMDA antagonist MK-801 behaviorally nor biochemically in binding displacement studies. Interestingly, other studies have suggested that only the full ACTH molecule, and fragments larger than ACTH-(1-17), demonstrated binding activity at micromolar concentrations, whereas the shorter, noncorticotropic fragments were either less active or inactive (Table 2). As for ACTH-(4-10) immunoreactivity, it appears that this neurotrophic fragment of ACTH reappears in adults following injury to the nigrostriatal system. In addition, the systemically administered ACTH-(4-9) analogue, Org 2766, seems to be gaining access to the CNS, but is only effective in the injured system. Therefore, based on the immunocytochemical localization of the ACTH-(4-10) fragment in neonatal brains and in the injured adult rat CNS, the interesting possibility may be raised that endogenous ACTH peptides appear during both ontogeny and regeneration. These studies demonstrate once again that biological responses to the family of ACTH/MSH peptides depend on the specific peptide fragment administered, its dosage, and the timing of the administration. Consequently, since early intervention is of vital importance in CNS recovery processes, synergistic administration of ACTH fragments and other neurotrophic agents may offer a viable approach with which to combat degeneration in the CNS.
本研究结果表明，急性给予促肾上腺皮质激素（ACTH）-(4 - 9)类似物Org 2766可增强黑质纹状体破坏后的行为、形态和生化恢复。与注射生理盐水的动物相比，用Org 2766（每24小时10微克/千克）治疗的动物去神经超敏反应加速，同侧旋转反应显著降低。在用旷场行为评估中脑边缘多巴胺（DA）系统时，经肽处理的大鼠在其竖毛行为中表现出代偿反应。此外，酪氨酸羟化酶免疫细胞化学分析表明，Org 2766治疗组的染色增强。使用特异性高亲和力多巴胺摄取对该评估进行了确认和量化。用Org 2766治疗的动物大脑保持较高的摄取水平，表明其纤维密度高于注射生理盐水的动物。虽然在如此短的时间内通过神经再支配恢复的可能性很小，但恢复改善可能是在黑质注射6 - 羟基多巴胺（6 - OHDA）后Org 2766具有保护作用的结果。因此，似乎Org 2766通过加速功能恢复所需的一些代偿机制以及通过提供神经元保护促进细胞存活，在该系统中产生快速作用。然而，这种保护似乎并非由于NMDA受体的调控。在结合置换研究中，Org 2766在行为学和生物化学方面既没有模拟NMDA拮抗剂MK - 801。有趣的是，其他研究表明，只有完整的ACTH分子以及大于ACTH-(1 - 17)的片段在微摩尔浓度下表现出结合活性，而较短的、非促肾上腺皮质激素片段要么活性较低要么无活性（表2）。至于ACTH-(4 - 10)免疫反应性，似乎这种ACTH的神经营养片段在黑质纹状体系统损伤后的成年动物中重新出现。此外，全身给药的ACTH-(4 - 9)类似物Org 2766似乎能够进入中枢神经系统（CNS），但仅在受损系统中有效。因此，基于ACTH-(4 - 10)片段在新生动物大脑和成年大鼠受损CNS中的免疫细胞化学定位，可能会引发一个有趣的可能性，即内源性ACTH肽在个体发育和再生过程中都会出现。这些研究再次证明，对ACTH/MSH肽家族的生物学反应取决于所给予的特定肽片段、其剂量以及给药时间。因此，由于早期干预在CNS恢复过程中至关重要，ACTH片段与其他神经营养剂的协同给药可能为对抗CNS退变提供一种可行的方法。
