单胺氧化酶-B抑制剂PF9601N在兴奋性毒性体内模型中的神经保护作用。
Neuroprotective effects of the MAO-B inhibitor, PF9601N, in an in vivo model of excitotoxicity.
作者信息
Bolea Irene, Colivicchi Maria Alessandra, Ballini Chiara, Marco-Contelles José, Tipton Keith Francis, Unzeta Mercedes, Della Corte Laura
机构信息
Departament de Bioquimica i Biologia Molecular, Facultat de Medicina, Institut de Neurociències, Universitat Autònoma de Barcelona, Bellaterra, Barcelona, Spain; Dipartimento di Neuroscienze, Psicologia Area del Farmaco e Salute del Bambino (NEUROFARBA), Università degli Studi di Firenze, Firenze, Italy.
出版信息
CNS Neurosci Ther. 2014 Jul;20(7):641-50. doi: 10.1111/cns.12271. Epub 2014 Apr 28.
BACKGROUND
PF9601N [N-(2-propynyl)-2-(5-benzyloxy-indolyl) methylamine] is an inhibitor of monoamine oxidase B (MAO-B), which has shown to possess neuroprotective properties in several in vitro and in vivo models of Parkinson's disease (PD). As there is evidence that excitotoxicity may be implicated in the pathophysiology of several neurodegenerative diseases, the aim of the present work was to investigate the effects of PF9601N in an acute in vivo model of excitotoxicity induced by the local administration of kainic acid during striatal microdialysis in adult rats.
METHODS
The basal and evoked release of neurotransmitters was monitored by HPLC analysis of microdialysate samples and tissue damage was evaluated histologically "ex vivo."
RESULTS
PF9601N (40 mg/kg, single i.p. administration) reduced the kainate-evoked release of glutamate and aspartate and increased taurine release, but it had no effect on the release of dopamine, DOPAC, and HVA. PF9601N pretreatment also resulted in a significant reduction in the kainate-induced astrocytosis, microgliosis, and apoptosis.
CONCLUSIONS
The results suggest PF9601N to be a good candidate for the treatment of neurodegenerative diseases mediated by excitotoxicity.
背景
PF9601N [N-(2-丙炔基)-2-(5-苄氧基-吲哚基)甲胺] 是一种单胺氧化酶B（MAO-B）抑制剂，在帕金森病（PD）的多种体外和体内模型中已显示出具有神经保护特性。由于有证据表明兴奋性毒性可能与几种神经退行性疾病的病理生理学有关，本研究的目的是在成年大鼠纹状体微透析期间，通过局部注射海藻酸诱导的急性兴奋性毒性体内模型中，研究PF9601N的作用。
方法
通过对微透析样品进行高效液相色谱分析监测神经递质的基础释放和诱发释放，并通过“离体”组织学评估组织损伤。
结果
PF9601N（40mg/kg，单次腹腔注射）减少了海藻酸盐诱发的谷氨酸和天冬氨酸释放，并增加了牛磺酸释放，但对多巴胺、二羟基苯乙酸（DOPAC）和高香草酸（HVA）的释放没有影响。PF9601N预处理还导致海藻酸盐诱导的星形细胞增生、小胶质细胞增生和细胞凋亡显著减少。
结论
结果表明PF9601N是治疗由兴奋性毒性介导的神经退行性疾病的良好候选药物。
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