Molecular pharmacological aspects of the neuropeptide PACAP in brain and pancreas

PACAP是一种多效神经肽，具有神经递质和神经营养因子的功能。本研究旨在通过药理学和遗传学方法探讨PACAP在脑和胰腺中的病理生理作用，包括神经心理功能障碍和糖尿病的基因工程小鼠模型，以及临床遗传学研究。总结结果及其意义如下：1)我们最近开发的pacap基因敲除小鼠（PACAP-KO）表现出显著的表型，包括昼夜节律的不对称光反应，海马LTP受损，炎症性和神经性疼痛消失，乙醇敏感性降低。这些结果进一步揭示了内源性PACAP在中枢神经系统中的一些意想不到的作用。2) PACAP-KO的行为学和药理学研究表明，5 -羟色胺1A受体介导的通路可能是关键的，更多地参与精神兴奋剂引起的矛盾的抗多动作用，为多动症等多动障碍的病理生理学提供了新的见解。此外，研究表明，PACAP对缺血性神经元死亡的保护作用主要是通过IL-6诱导介导的，这为这种病理状况提供了一种新的潜在治疗方法。3)在链脲霉素诱导的（1型）糖尿病和2型糖尿病遗传模型KKA^y小鼠胰腺b细胞中转基因过表达PACAP的研究表明，PACAP在b细胞增殖和病理性胰岛增生的控制中起重要作用。我们目前已经确定了胰岛基因可能参与控制b细胞增殖使用激光捕获显微解剖结合DNA微阵列分析。4)比利时一个研究小组对两名相关的18p部分三体患者进行了研究，发现PACAP基因有三个拷贝，血浆PACAP浓度升高。在与这个小组的合作中，我们提出PACAP可能是血小板活化的生理抑制剂。少

PACAP is a pleiotropic neuropeptide functioning as a neurotransmitter and neurotrophic factor. The current study was aimed to investigate the (patho)physiological roles of PACAP in brain and pancreas by a pharmacological and genetic approaches, including genetically engineered mouse models of neuropsychological dysfunctions and diabetes, as well as clinical genetic investigation. The summarized results and their respective significance are as follows :1)Our recently developed PACAP-knockout mice (PACAP-KO) exhibited remarkable phenotypes including asymmetric photic response of circadian rhythm, impaired hippocampal LTP, disappearance of inflammatory and neuropathic pain, and reduced ethanol sensitivity. These results have led to a better understanding of the physiological roles and revealed some unexpected roles of endogenous PACAP in the central nervous system.2)Behavioral and pharmacological studies on PACAP-KO proposed that the serotonin 1A receptor-mediated pathways may be critical … More ly involved in the psychostimulant-elicited paradoxical anti-hyperkinetic effects, providing insights into the pathophysiology of hyperkinetic disorder such as ADHD. In addition, it was demonstrated that protective effects exerted by PACAP on ischemic neuronal death are mainly mediated by IL-6 induction, proposing a novel and potential therapeutic approach for such pathological conditions.3)Studies in transgenic overexpression of PACAP in pancreatic b-cells under streptozotocin-induced (type 1) diabetes and in KKA^y mice (a genetic model for type 2 diabetes) suggested that PACAP plays important roles in the proliferation of b-cells and the control of pathological islet hyperplasia. We have currently identified islet genes possibly involved in the control of b-cell proliferation using laser capture microdissection coupled with DNA microarray analysis.4)A Belgian group has conducted studies in two related patients with a partial trisomy 18p and revealed three copies of the PACAP gene and elevated plasma PACAP concentrations. In collaboration with this group, we proposed that PACAP might be a physiological inhibitor of platelet activation. Less