Skoglösa Y, Lewén A, Takei N, Hillered L, Lindholm D
Department of Neurosciences, Developmental Neurobiology, Biomedical Center, Uppsala, Sweden.
Neuroscience. 1999 Apr;90(1):235-47. doi: 10.1016/s0306-4522(98)00414-x.
Neurotrophic factors are known to promote neuronal survival during development and after acute brain injury. Recent data suggest that some neuropeptides also exhibit neurotrophic activities, as shown for the pituitary adenylate cyclase activating polypeptide, which increases the survival of various neuronal populations in culture. Employing in situ hybridization techniques, we have studied the regulation of messenger RNA for pituitary adenylate cyclase activating polypeptide and its receptor type 1 after a moderate traumatic brain injury to rat brain cortex. We have further compared their messenger RNA expression to that of brain-derived neurotrophic factor and to the amount of cell death occurring in the brain at various times after the brain injury. Levels of brain-derived neurotrophic factor messenger RNA increased rapidly within 2 h after trauma in cortex and hippocampus, and returned to control levels thereafter. The levels of messenger RNA for pituitary adenylate cyclase activating polypeptide also increased with time in the injured brains and reached maximal expression at 72 h, i.e. the end of the observation period. The alterations in pituitary adenylate cyclase activating polypeptide messenger RNA levels were particularly pronounced in the perifocal region and in the ipsilateral dentate gyrus of the brain injury. In contrast, the messenger RNA levels encoding pituitary adenylate cyclase activating polypeptide receptor type 1 first decreased after trauma and were then normalized in the dentate gyrus. There was a large increase in the number of cells labelled for DNA breaks at 12 h post-trauma, indicative of enhanced cell death. The number of labelled cells, however, decreased at later stages concomitant with an increase in the expression of pituitary adenylate cyclase activating polypeptide messenger RNA. Pituitary adenylate cyclase activating polypeptide rescued cortical neurons in cultures against ionomycin-induced cell death, supporting the concept of a neuroprotective effect for the peptide. These results demonstrate a differential regulation of messenger RNA for brain-derived neurotrophic factor and the pituitary adenylate cyclase activating polypeptide and its receptor after brain trauma. The data also suggest that pituitary adenylate cyclase activating polypeptide might have a beneficial effect in brain injury by counteracting neuronal cell death.
已知神经营养因子在发育过程中和急性脑损伤后可促进神经元存活。最近的数据表明，一些神经肽也表现出神经营养活性，如垂体腺苷酸环化酶激活多肽，它可增加培养的各种神经元群体的存活率。利用原位杂交技术，我们研究了大鼠脑皮质中度创伤性脑损伤后垂体腺苷酸环化酶激活多肽及其1型受体的信使核糖核酸的调节情况。我们进一步将它们的信使核糖核酸表达与脑源性神经营养因子的表达以及脑损伤后不同时间大脑中发生的细胞死亡数量进行了比较。脑源性神经营养因子信使核糖核酸水平在创伤后2小时内于皮质和海马中迅速升高，此后恢复到对照水平。垂体腺苷酸环化酶激活多肽的信使核糖核酸水平在受伤大脑中也随时间增加，并在72小时（即观察期结束时）达到最大表达。垂体腺苷酸环化酶激活多肽信使核糖核酸水平的变化在脑损伤的灶周区域和同侧齿状回中尤为明显。相比之下，编码垂体腺苷酸环化酶激活多肽1型受体的信使核糖核酸水平在创伤后首先下降，然后在齿状回中恢复正常。创伤后12小时，标记有DNA断裂的细胞数量大幅增加，表明细胞死亡增强。然而，标记细胞的数量在后期减少，同时垂体腺苷酸环化酶激活多肽信使核糖核酸的表达增加。垂体腺苷酸环化酶激活多肽可挽救培养中的皮质神经元免受离子霉素诱导的细胞死亡，支持了该肽具有神经保护作用的概念。这些结果表明，脑创伤后脑源性神经营养因子、垂体腺苷酸环化酶激活多肽及其受体的信使核糖核酸存在差异调节。数据还表明，垂体腺苷酸环化酶激活多肽可能通过抵消神经元细胞死亡对脑损伤具有有益作用。
