Cognitive impairments following cranial irradiation can be mitigated by treatment with a tropomyosin receptor kinase B agonist.
Cognitive impairments following cranial irradiation can be mitigated by treatment with a tropomyosin receptor kinase B agonist.
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DOI：
10.1016/j.expneurol.2016.02.021
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发表时间：
2016-05
影响因子：
5.3
通讯作者：
Huang TT
中科院分区：
文献类型：
--
作者：
Yang P;Leu D;Ye K;Srinivasan C;Fike JR;Huang TT
脑放射治疗经常成功地用于治疗脑肿瘤。然而，放射治疗通常与短期和长期记忆、学习能力和语言流畅性的下降有关。我们以前确定了一个下调脑源性神经营养因子（BDNF）后，颅照射实验动物。在本研究中，我们调查是否针对BDNF高亲和力受体，原溶素受体激酶B（Trk B），可以减轻辐射诱导的认知功能障碍。照射后，用小分子TrkB激动剂7，8-二羟基黄酮（DHF）在小鼠中进行慢性治疗导致TrkB及其下游靶点ERK和AKT的活化增强，这两个靶点都是神经元发育中的重要因素。DHF治疗显著恢复了空间，背景和工作记忆，并且在治疗完成后至少持续3个月。与认知功能的保存一致，慢性DHF治疗减轻了辐射诱导的海马神经发生抑制。脊髓密度和兴奋性突触的主要成分，包括谷氨酸受体和突触后密度蛋白95（PSD-95），也保持在正常水平的DHF治疗照射后。综上所述，我们的研究结果表明，长期治疗与DHF照射后显着减轻辐射引起的认知缺陷。这很可能是通过海马神经发生和突触可塑性的保存来实现的。
Brain radiotherapy is frequently used successfully to treat brain tumors. However, radiotherapy is often associated with declines in short-term and long-term memory, learning ability, and verbal fluency. We previously identified a downregulation of the brain-derived neurotrophic factor (BDNF) following cranial irradiation in experimental animals. In the present study, we investigated whether targeting the BDNF high affinity receptor, tropomysin receptor kinase B (TrkB), could mitigate radiation-induced cognitive deficits. After irradiation, chronic treatment with a small molecule TrkB agonist, 7,8-dihydroxyflavone (DHF) in mice led to enhanced activation of TrkB and its downstream targets ERK and AKT, both important factors in neuronal development. DHF treatment significantly restored spatial, contextual, and working memory, and the positive effects persisted for at least 3 months after completion of the treatment. Consistent with preservation of cognitive functions, chronic DHF treatment mitigated radiation-induced suppression of hippocampal neurogenesis. Spine density and major components of the excitatory synapses, including glutamate receptors and postsynaptic density protein 95 (PSD-95), were also maintained at normal levels by DHF treatment after irradiation. Taken together, our results show that chronic treatment with DHF after irradiation significantly mitigates radiation-induced cognitive defects. This is achieved most likely by preservation of hippocampal neurogenesis and synaptic plasticity.