Chen Yun, Samal Babru, Hamelink Carol R, Xiang Charlie C, Chen Yong, Chen Mei, Vaudry David, Brownstein Michael J, Hallenbeck John M, Eiden Lee E
Section on Molecular Neuroscience, Laboratory of Cellular and Molecular Regulation, NIH, Bethesda, MD 20892, USA.
Regul Pept. 2006 Nov 15;137(1-2):4-19. doi: 10.1016/j.regpep.2006.06.016. Epub 2006 Oct 4.
We investigated the effects of PACAP treatment, and endogenous PACAP deficiency, on infarct volume, neurological function, and the cerebrocortical transcriptional response in a mouse model of stroke, middle cerebral artery occlusion (MCAO). PACAP-38 administered i.v. or i.c.v. 1 h after MCAO significantly reduced infarct volume, and ameliorated functional motor deficits measured 24 h later in wild-type mice. Infarct volumes and neurological deficits (walking faults) were both greater in PACAP-deficient than in wild-type mice, but treatment with PACAP reduced lesion volume and neurological deficits in PACAP-deficient mice to the same level of improvement as in wild-type mice. A 35,546-clone mouse cDNA microarray was used to investigate cortical transcriptional changes associated with cerebral ischemia in wild-type and PACAP-deficient mice, and with PACAP treatment after MCAO in wild-type mice. 229 known (named) transcripts were increased (228) or decreased (1) in abundance at least 50% following cerebral ischemia in wild-type mice. 49 transcripts were significantly up-regulated only at 1 h post-MCAO (acute response transcripts), 142 were up-regulated only at 24 h post-MCAO (delayed response transcripts) and 37 transcripts were up-regulated at both times (sustained response transcripts). More than half of these are transcripts not previously reported to be altered in ischemia. A larger percentage of genes up-regulated at 24 hr than at 1 hr required endogenous PACAP, suggesting a more prominent role for PACAP in later response to injury than in the initial response. This is consistent with a neuroprotective role for PACAP in late response to injury, i.e., even when administered 1 hr or more after MCAO. Putative injury effector transcripts regulated by PACAP include beta-actin, midline 2, and metallothionein 1. Potential neuroprotective transcripts include several demonstrated to be PACAP-regulated in other contexts. Prominent among these were transcripts encoding the PACAP-regulated gene Ier3, and the neuropeptides enkephalin, substance P (tachykinin 1), and neurotensin.
我们在大脑中动脉闭塞（MCAO）的小鼠脑卒中模型中，研究了垂体腺苷酸环化酶激活肽（PACAP）治疗以及内源性PACAP缺乏对梗死体积、神经功能和大脑皮质转录反应的影响。在MCAO后1小时静脉内或脑室内给予PACAP-38可显著减小野生型小鼠的梗死体积，并改善24小时后测量的功能性运动缺陷。PACAP缺陷型小鼠的梗死体积和神经功能缺损（行走障碍）均大于野生型小鼠，但用PACAP治疗可将PACAP缺陷型小鼠的损伤体积和神经功能缺损改善至与野生型小鼠相同的水平。使用一个包含35,546个克隆的小鼠cDNA微阵列来研究野生型和PACAP缺陷型小鼠中与脑缺血相关的皮质转录变化，以及野生型小鼠MCAO后用PACAP治疗后的转录变化。野生型小鼠脑缺血后，229个已知（命名）转录本的丰度增加（228个）或减少（1个）至少50%。49个转录本仅在MCAO后1小时显著上调（急性反应转录本），142个仅在MCAO后24小时上调（延迟反应转录本），37个转录本在两个时间点均上调（持续反应转录本）。其中超过一半是先前未报道在缺血中发生改变的转录本。在24小时上调的基因中，需要内源性PACAP的基因比例高于1小时上调的基因，这表明PACAP在损伤后期反应中比在初始反应中发挥更突出的作用。这与PACAP在损伤后期反应中的神经保护作用一致，即即使在MCAO后1小时或更长时间给药。由PACAP调节的假定损伤效应转录本包括β-肌动蛋白、中线2和金属硫蛋白1。潜在的神经保护转录本包括在其他情况下已被证明受PACAP调节的几个转录本。其中突出的是编码PACAP调节基因Ier3以及神经肽脑啡肽、P物质（速激肽1）和神经降压素的转录本。
