Feinberg Konstantin, Kolaj Adelaida, Wu Chen, Grinshtein Natalie, Krieger Jonathan R, Moran Michael F, Rubin Lee L, Miller Freda D, Kaplan David R
Program in Neurosciences and Mental Health, Hospital for Sick Children, Toronto, ON, Canada.
Department of Physiology, University of Toronto, Toronto, ON, Canada.
J Cell Biol. 2017 Nov 6;216(11):3655-3675. doi: 10.1083/jcb.201705085. Epub 2017 Sep 6.
Axon degeneration is an early event and pathological in neurodegenerative conditions and nerve injuries. To discover agents that suppress neuronal death and axonal degeneration, we performed drug screens on primary rodent neurons and identified the pan-kinase inhibitor foretinib, which potently rescued sympathetic, sensory, and motor and SOD1 mutant neurons from trophic factor withdrawal-induced degeneration. By using primary sympathetic neurons grown in mass cultures and Campenot chambers, we show that foretinib protected neurons by suppressing both known degenerative pathways and a new pathway involving unliganded TrkA and transcriptional regulation of the proapoptotic BH3 family members BimEL, Harakiri,and Puma, culminating in preservation of mitochondria in the degenerative setting. Foretinib delayed chemotherapy-induced and Wallerian axonal degeneration in culture by preventing axotomy-induced local energy deficit and preserving mitochondria, and peripheral Wallerian degeneration in vivo. These findings identify a new axon degeneration pathway and a potentially clinically useful therapeutic drug.
轴突退化是神经退行性疾病和神经损伤中的早期事件且具有病理性。为了发现能够抑制神经元死亡和轴突退化的药物，我们对原代啮齿动物神经元进行了药物筛选，并鉴定出泛激酶抑制剂福瑞替尼，它能有效挽救交感神经元、感觉神经元和运动神经元以及超氧化物歧化酶1（SOD1）突变神经元，使其免受营养因子剥夺诱导的退化。通过使用在大规模培养物中生长的原代交感神经元和坎佩诺特小室，我们发现福瑞替尼通过抑制已知的退化途径以及一条涉及未结合的酪氨酸激酶受体A（TrkA）和促凋亡BH3家族成员BimEL、Harakiri和Puma转录调控的新途径来保护神经元，最终在退化环境中维持线粒体功能。福瑞替尼通过防止轴突切断诱导的局部能量不足并维持线粒体功能，延缓了培养物中化疗诱导的和华勒氏轴突退化，以及体内的外周华勒氏退化。这些发现确定了一条新的轴突退化途径和一种可能具有临床应用价值的治疗药物。
