Age-Dependent Cellular and Behavioral Deficits Induced by Molecularly Targeted Drugs Are Reversible.
Age-Dependent Cellular and Behavioral Deficits Induced by Molecularly Targeted Drugs Are Reversible.
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DOI：
10.1158/0008-5472.can-17-2254
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发表时间：
2018-04-15
期刊：
影响因子：
11.2
通讯作者：
Gallo V
中科院分区：
文献类型：
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作者：
Scafidi J;Ritter J;Talbot BM;Edwards J;Chew LJ;Gallo V
新开发的靶向抗癌药物可抑制成人和儿科癌症中常见的信号通路改变。然而，由于这些途径对正常的大脑发育也是必不可少的，因此人们担心它们在儿科癌症中的应用会导致神经系统后遗症。这些药物诱导的体内效应的神经底物和年龄依赖性尚不清楚，其长期行为后果尚未表征。这项研究定义了这些药物对正常发育的大脑的年龄依赖性细胞和行为影响，并确定了药物干预后的可逆性。不同出生后年龄的小鼠接受短期的分子靶向药物治疗方案类似于临床治疗。对感觉运动和认知功能重要的快速发育的脑结构的分析表明，虽然成人给药没有效果，但新生儿早期给予靶向治疗比后期给药更深刻地减弱了白色少突胶质细胞和海马神经元的发育，导致长期的行为缺陷。这种功能障碍通过身体和认知丰富的康复来逆转。我们的研究结果证明了这些药物对大脑发育的年龄依赖性，可逆性影响，这是儿科癌症治疗选择扩大的重要考虑因素。
Newly developed targeted anti-cancer drugs inhibit signaling pathways commonly altered in adult and pediatric cancers. However, as these pathways are also essential for normal brain development, concerns have emerged of neurological sequelae resulting specifically from their application in pediatric cancers. The neural substrates and age dependency of these drug-induced effects in vivo are unknown, and their long-term behavioral consequences have not been characterized. This study defines the age-dependent cellular and behavioral effects of these drugs on normally developing brains and determines their reversibility with post-drug-intervention. Mice at different postnatal ages received short courses of molecularly targeted drugs in regimens analagous to clinical treatment. Analysis of rapidly developing brain structures important for sensorimotor and cognitive function showed that, while adult administration was without effect, earlier neonatal administration of targeted therapies attenuated white matter oligodendroglia and hippocampal neuronal development more profoundly than later administration, leading to long-lasting behavioral deficits. This functional impairment was reversed by rehabilitation with physical and cognitive enrichment. Our findings demonstrate age-dependent, reversible effects of these drugs on brain development, which are important considerations as treatment options expand for pediatric cancers.