INRS - Institut Armand-Frappier, Institut National de la Recherche Scientifique, 531 boul. des Prairies, Ville de Laval, Québec, Canada H7V 1B7.
Curr Med Chem. 2009;16(33):4462-80. doi: 10.2174/092986709789712899.
Pituitary adenylate cyclase-activating polypeptide (PACAP) is a 38-amino acid peptide that was initially isolated from hypothalamus extracts on the basis of its ability to stimulate the production of cAMP in cultured pituitary cells. Recent studies have shown that PACAP exerts potent neuroprotective effects not only in vitro but also in in vivo models of Parkinson's disease, Huntington's disease, traumatic brain injury and stroke. The protective effects of PACAP are based on its capacity to prevent neuronal apoptosis by acting directly on neurons or indirectly through the release of neuroprotective factors by astrocytes. These biological activities are mainly mediated through activation of the PAC1 receptor which is currently considered as a potential target for the treatment of neurodegenerative diseases. However, the use of native PACAP, the endogenous ligand of PAC1, as an efficient neuroprotective drug is actually limited by its rapid degradation. Moreover, injection of PACAP to human induces peripheral side effects which are mainly mediated through VPAC1 and VPAC2 receptors. Strategies to overcome these compromising conditions include the development of metabolically stable analogs of PACAP acting as selective agonists of the PAC1 receptor. This review presents an overview of the structure-activity relationships of PACAP and summarizes the molecular and conformational requirements for activation of PAC1 receptor. The applicability of PACAP analogs as therapeutic agents for treatment of neurodegenerative diseases is also discussed.
垂体腺苷酸环化酶激活肽（PACAP）是一种 38 个氨基酸的肽，最初是根据其在体外培养的垂体细胞中刺激 cAMP 产生的能力从下丘脑提取物中分离出来的。最近的研究表明，PACAP 不仅在体外，而且在帕金森病、亨廷顿病、创伤性脑损伤和中风的体内模型中都具有强大的神经保护作用。PACAP 的保护作用基于其通过直接作用于神经元或通过星形胶质细胞释放神经营养因子而间接防止神经元凋亡的能力。这些生物学活性主要通过激活 PAC1 受体介导，该受体目前被认为是治疗神经退行性疾病的潜在靶点。然而，内源性 PAC1 配体天然 PACAP 作为一种有效的神经保护药物的实际应用受到其快速降解的限制。此外，PACAP 注射到人体中会引起外周副作用，这些副作用主要通过 VPAC1 和 VPAC2 受体介导。克服这些不利条件的策略包括开发代谢稳定的 PACAP 类似物作为 PAC1 受体的选择性激动剂。本文综述了 PACAP 的结构-活性关系，并总结了激活 PAC1 受体的分子和构象要求。还讨论了 PACAP 类似物作为治疗神经退行性疾病的治疗剂的适用性。
