INRS - Centre Armand-Frappier, Laboratoire d'études moléculaires et pharmacologiques des peptides, 531 boul. des Prairies, Ville de Laval, QC H7V 1B7, Canada; INSERM-U982, Laboratory of Neuronal and Neuroendocrine Differentiation and Communication, IRIB, Université de Rouen, 76821 Mont-Saint-Aignan, France.
INRS - Centre Armand-Frappier, Laboratoire d'études moléculaires et pharmacologiques des peptides, 531 boul. des Prairies, Ville de Laval, QC H7V 1B7, Canada; INRS - Centre Armand-Frappier, Groupe de Recherche en Ingénierie des Peptides et en Pharmacothérapie (GRIPP), 531 boul. des Prairies, Ville de Laval, QC H7V 1B7, Canada.
Biochim Biophys Acta Gen Subj. 2019 Nov;1863(11):129410. doi: 10.1016/j.bbagen.2019.08.003. Epub 2019 Aug 8.
Neurodegenerative disorders, such as Parkinson's disease (PD), are characterized by neuronal death involving, among other events, mitochondrial dysfunction and excitotoxicity. Along these lines, several attempts have been made to slow this pathology but none have been yet discovered. Based on its capacity to cross the blood-brain barrier and provide neuronal protection in vitro and in vivo, the pituitary adenylate cyclase-activating polypeptide (PACAP) represents a promising lead molecule. Pharmacological studies showed that PACAP interacts with three different G protein-coupled receptors, i.e. PAC1, VPAC1 and VPAC2. However, only PAC1 is associated with neuronal anti-apoptotic actions, whilst VPAC activation might cause adverse effects. In the context of the development of PAC1-selective agonists, PACAP(1-23) (PACAP23) appears as the shortest known PACAP bioactive fragment.
Hence, the capacity of this peptide to bind PACAP receptors and protect neuroblastoma cells was evaluated under conditions of mitochondrial dysfunction and glutamate excitotoxicity. In addition, its ability to activate downstream signaling events involving G proteins (Gα and Gα), EPAC, and calcium was also assessed.
Compared to the endogenous peptide, PACAP23 showed a reduced affinity towards PAC1, although this fragment exerted potent neuroprotection. However, surprisingly, some disparities were observed for PACAP23 signaling compared to full length PACAP, suggesting that downstream signaling related to neuroprotection is distinctly regulated following subtle differences in their PAC1 interactions.
Altogether, this study demonstrates the potent neuroprotective action of amidated PACAP23.
PACAP23 represents an attractive template for development of shorter PACAP-derived neuroprotective molecules.
神经退行性疾病，如帕金森病（PD），其特征是神经元死亡，涉及线粒体功能障碍和兴奋性毒性等事件。沿着这些思路，已经有几种尝试来减缓这种病理学，但尚未发现。基于其穿过血脑屏障并在体外和体内提供神经元保护的能力，垂体腺苷酸环化酶激活肽（PACAP）代表了一种有前途的先导分子。药理学研究表明，PACAP 与三种不同的 G 蛋白偶联受体相互作用，即 PAC1、VPAC1 和 VPAC2。然而，只有 PAC1 与神经元抗凋亡作用相关，而 VPAC 激活可能会引起不良反应。在开发 PAC1 选择性激动剂的背景下，PACAP(1-23)（PACAP23）似乎是已知最短的 PACAP 生物活性片段。
因此，在线粒体功能障碍和谷氨酸兴奋性毒性条件下，评估了该肽结合 PACAP 受体和保护神经母细胞瘤细胞的能力。此外，还评估了其激活涉及 G 蛋白（Gα 和 Gα）、EPAC 和钙的下游信号事件的能力。
与内源性肽相比，PACAP23 对 PAC1 的亲和力降低，尽管该片段具有强大的神经保护作用。然而，令人惊讶的是，与全长 PACAP 相比，PACAP23 的信号传递存在一些差异，这表明下游信号传递与神经保护的关系在其与 PAC1 的相互作用存在细微差异时被明显调节。
总之，这项研究证明了酰胺化 PACAP23 的强大神经保护作用。
PACAP23 代表了开发更短的 PACAP 衍生神经保护分子的有吸引力的模板。
