Hsieh Yih-Shou, Yang Shun-Fa, Chu Shu-Chen, Kuo Dong-Yih
Institute of Biochemistry, Chung Shan Medical University, Taichung City, Taiwan.
J Neurochem. 2008 Jan;104(1):50-61. doi: 10.1111/j.1471-4159.2007.04919.x. Epub 2007 Sep 11.
The mechanism for phenylpropanolamine (PPA)-induced anorexia has been attributed to its inhibitory action on hypothalamic neuropeptide Y (NPY), an orexigenic agent abundant in the brain. However, molecular mechanisms behind this effect are not well known. In this study, we investigated whether activator protein-1 (AP-1) signaling was involved. Rats were daily treated with PPA for 4 days. Changes in hypothalamic NPY, c-fos, c-jun, superoxide dismutase (SOD)-1, and SOD-2 mRNA contents were measured and compared. Results showed that c-fos and c-jun mRNA levels were increased following PPA treatment, which were relevant to a reduction in NPY mRNA level. To further determine if c-fos/c-jun genes were involved in PPA anorexia, infusions of antisense oligonucleotide into cerebroventricle were performed before daily PPA treatment in freely moving rats. Results showed that either c-fos or c-jun knock down could block PPA anorexia and restore NPY mRNA content to normal level. It is suggested that AP-1 signaling may participate in the central regulation of PPA-mediated appetite suppression via the modulation of NPY gene expression. Moreover, this modulation might be partly because of the neuroprotective effect of AP-1 since SOD gene was activated during PPA treatment.
苯丙醇胺（PPA）所致厌食的机制被认为是其对下丘脑神经肽Y（NPY）具有抑制作用，NPY是一种在大脑中大量存在的促食欲因子。然而，这种作用背后的分子机制尚不清楚。在本研究中，我们调查了活化蛋白-1（AP-1）信号通路是否参与其中。大鼠每日接受PPA治疗，持续4天。测量并比较下丘脑NPY、c-fos、c-jun、超氧化物歧化酶（SOD）-1和SOD-2 mRNA含量的变化。结果显示，PPA治疗后c-fos和c-jun mRNA水平升高，这与NPY mRNA水平降低相关。为进一步确定c-fos/c-jun基因是否参与PPA所致厌食，在自由活动的大鼠每日接受PPA治疗前，向脑室注射反义寡核苷酸。结果显示，敲低c-fos或c-jun均可阻断PPA所致厌食，并使NPY mRNA含量恢复至正常水平。提示AP-1信号通路可能通过调节NPY基因表达参与PPA介导的食欲抑制的中枢调节。此外，这种调节可能部分归因于AP-1的神经保护作用，因为在PPA治疗期间SOD基因被激活。
