Forslin Aronsson Asa, Spulber Stefan, Oprica Mircea, Winblad Bengt, Post Claes, Schultzberg Marianne
Division of Neurodegeneration and Neuroinflammation, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, SE-141 86 Stockholm, Sweden.
J Mol Neurosci. 2007;33(3):239-51. doi: 10.1007/s12031-007-0019-2. Epub 2007 Apr 17.
This study investigates the effects of alpha-melanocyte-stimulating hormone (alpha-MSH), on neurodegeneration, gliosis and changes in the neurotrophic protein brain-derived neurotrophic factor (BDNF) and in pro-inflammatory cytokines, following kainic acid (KA)-induced excitotoxic damage in the rat. Male Sprague-Dawley rats were treated with alpha-MSH (intraperitoneally, i.p.) at 20 min, and 24 and 48 h following administration of 10 mg/kg KA (i.p.). The animals were sacrificed at 30 min, 4 h, 24 h and 72 h after KA-administration and the levels of interleukin-1beta (IL-1beta), interleukin-6 (IL-6) and tumour necrosis factor-alpha (TNF-alpha) were analysed in samples of hippocampus and hypothalamus. Levels of BDNF were analysed in the hippocampus. Stereological quantification showed a markedly reduced number of viable neurons in the CA1 pyramidal cell layer upon KA-administration as compared to animals injected with vehicle (p < 0.05, 79,587 +/- 25,554 vs. 145,254 +/- 27,871). The number of viable neurons upon administration of alpha-MSH was significantly higher than upon KA alone (p < 0.05, 119,776 +/- 33,158, KA+alpha-MSH vs. 79,587 +/- 27,554, KA + Saline). Astrocyte activation due to the KA-induced excitotoxicity was reduced, and the KA-induced increase in IL-1beta levels was delayed by the treatment with alpha-MSH. In conclusion, the degree of reduction in cell viability in the hippocampus CA1 pyramidal cell layer upon KA-induced excitotoxicity was similar to that seen previously upon global cerebral ischaemia. Furthermore, the administration of alpha-MSH resulted in a similar increase in cell viability, supporting the hypothesis that administration of alpha-MSH has rescuing effects on neurons subjected to excitotoxic insults.
本研究调查了α-黑素细胞刺激素（α-MSH）对大鼠经海人酸（KA）诱导的兴奋性毒性损伤后神经退行性变、胶质细胞增生以及神经营养蛋白脑源性神经营养因子（BDNF）和促炎细胞因子变化的影响。雄性Sprague-Dawley大鼠在腹腔注射10mg/kg KA后20分钟、24小时和48小时接受α-MSH腹腔注射。在注射KA后30分钟、4小时、24小时和72小时处死动物，分析海马和下丘脑样本中白细胞介素-1β（IL-1β）、白细胞介素-6（IL-6）和肿瘤坏死因子-α（TNF-α）的水平。分析海马中BDNF的水平。立体定量分析显示，与注射溶剂的动物相比，注射KA后CA1锥体细胞层中存活神经元的数量明显减少（p<0.05，79,587±25,554对145,254±27,871）。给予α-MSH后存活神经元的数量显著高于单独给予KA时（p<0.05，119,776±33,158，KA+α-MSH对79,587±27,554，KA+生理盐水）。α-MSH治疗可减轻KA诱导的兴奋性毒性所致的星形胶质细胞活化，并延迟KA诱导的IL-1β水平升高。总之，KA诱导的兴奋性毒性导致海马CA1锥体细胞层细胞活力降低的程度与之前全脑缺血时观察到的相似。此外，给予α-MSH可使细胞活力有类似的增加，支持了给予α-MSH对遭受兴奋性毒性损伤的神经元具有挽救作用的假说。
