Elliott-Hunt Caroline R, Marsh Barnaby, Bacon Andrea, Pope Robert, Vanderplank Penny, Wynick David
Laboratories for Integrative Neuroscience and Endocrinology, Bristol University, Whitson Street, Bristol BS1 3NY, United Kingdom.
Proc Natl Acad Sci U S A. 2004 Apr 6;101(14):5105-10. doi: 10.1073/pnas.0304823101. Epub 2004 Mar 23.
The expression of the neuropeptide galanin is markedly up-regulated in many areas of the central and peripheral nervous system after injury. We have recently demonstrated that peripheral sensory neurons depend on galanin for neurite extension after injury, mediated by activation of the second galanin receptor subtype (GALR2). We therefore hypothesized that galanin might also act in a similar manner in the CNS, reducing cell death in hippocampal models of excitotoxicity. Here we report that galanin acts an endogenous neuroprotective factor to the hippocampus in a number of in vivo and in vitro models of injury. Kainate-induced hippocampal cell death was greater in both the CA1 and CA3 regions of galanin knockout animals than in WT controls. Similarly, exposure to glutamate or staurosporine induced significantly more neuronal cell death in galanin knockout organotypic and dispersed primary hippocampal cultures than in WT controls. Conversely, less cell death was observed in the hippocampus of galanin overexpressing transgenic animals after kainate injection and in organotypic cultures after exposure to staurosporine. Further, exogenous galanin or the previously described high-affinity GALR2 agonist, both reduced cell death when coadministered with glutamate or staurosporine in WT cultures. These results demonstrate that galanin acts an endogenous neuroprotective factor to the hippocampus and imply that a galanin agonist might have therapeutic uses in some forms of brain injury.
神经肽甘丙肽的表达在损伤后的中枢和外周神经系统的许多区域显著上调。我们最近证明，外周感觉神经元在损伤后轴突延伸依赖甘丙肽，这是由第二种甘丙肽受体亚型（GALR2）的激活介导的。因此，我们推测甘丙肽在中枢神经系统中可能也以类似方式起作用，减少兴奋性毒性海马模型中的细胞死亡。在此我们报告，在一些体内和体外损伤模型中，甘丙肽对海马起内源性神经保护因子作用。在甘丙肽基因敲除动物的CA1和CA3区域，海人酸诱导的海马细胞死亡比野生型对照更严重。同样，在甘丙肽基因敲除的器官型和分散的原代海马培养物中，暴露于谷氨酸或星形孢菌素诱导的神经元细胞死亡明显多于野生型对照。相反，在注射海人酸后的甘丙肽过表达转基因动物海马以及暴露于星形孢菌素后的器官型培养物中，观察到的细胞死亡较少。此外，在野生型培养物中，外源性甘丙肽或先前描述的高亲和力GALR2激动剂与谷氨酸或星形孢菌素共同给药时，均能减少细胞死亡。这些结果表明甘丙肽对海马起内源性神经保护因子作用，并暗示甘丙肽激动剂在某些形式的脑损伤中可能具有治疗用途。
