Molecular pharmacological aspects of the neuropeptide PACAP in brain and pancreas

PACAP是一种多效性神经肽，具有神经递质和神经营养因子的功能。本研究旨在从药理学和遗传学的角度探讨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。1)我们新近建立的PACAP基因敲除小鼠(PACAP-KO)表现出显著的表型，包括昼夜节律的光反应不对称，海马LTP受损，炎性和神经病理性疼痛消失，酒精敏感性降低。这些结果使人们对PACAP的生理作用有了更好的理解，并揭示了内源性PACAP在中枢神经系统中的一些意想不到的作用。2)对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…更多地参与了精神刺激剂引起的矛盾的抗多动效应，为多动障碍(如ADHD)的病理生理学提供了见解。此外，PACAP对缺血性神经元死亡的保护作用主要是通过诱导IL-6介导的，为此类病理状态的治疗提供了新的潜在的治疗途径。3)在链脲佐菌素诱导的1型糖尿病胰腺b细胞和Kka^y小鼠(2型糖尿病的遗传模型)中PACAP转基因过表达的研究表明，PACAP在b细胞的增殖和病理性胰岛增生的控制中起重要作用。我们目前已经利用激光捕获显微切割结合DNA微阵列分析确定了可能参与控制b细胞增殖的胰岛基因。4)比利时的一个小组对两名部分三体18P的相关患者进行了研究，发现了三个PACAP基因副本和血浆PACAP浓度升高。在与该小组的合作中，我们提出PACAP可能是一种血小板激活的生理性抑制物。较少

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