Pharmacological inhibition of HDAC6 reverses cognitive impairment and tau pathology as a result of cisplatin treatment.
Pharmacological inhibition of HDAC6 reverses cognitive impairment and tau pathology as a result of cisplatin treatment.
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DOI：
10.1186/s40478-018-0604-3
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发表时间：
2018-10-01
影响因子：
7.1
通讯作者：
Heijnen CJ
中科院分区：
文献类型：
--
作者：
Ma J;Huo X;Jarpe MB;Kavelaars A;Heijnen CJ
化疗诱导的认知障碍（CICI）是化疗常见的神经毒性副作用，发生在高达75%的癌症患者中。CICI表现为工作记忆、执行功能、注意力和处理速度的下降，极大地干扰了患者的日常表现和生活质量。目前，美国食品和药物管理局尚未批准CICI的治疗。我们在这里表明，治疗与脑穿透组蛋白去乙酰化酶6（HDAC 6）抑制剂两周足以完全逆转顺铂诱导的认知障碍的雄性小鼠，如在Y-迷宫测试的自发交替，新的物体/地点识别测试，和拼图盒测试。认知障碍的正常化与顺铂诱导的突触体线粒体缺陷的逆转和突触完整性的恢复相关。从机制上讲，顺铂诱导微管蛋白α-微管蛋白脱乙酰化和微管相关蛋白tau过度磷酸化。这些顺铂诱导的变化被HDAC 6抑制逆转。我们的数据表明，HDAC 6的抑制恢复微管稳定性和逆转tau磷酸化，导致突触体线粒体功能和突触完整性的正常化，从而逆转CICI。值得注意的是，我们的研究结果表明，HDAC 6抑制剂的短期每日治疗足以实现顺铂诱导的既定行为，结构和功能缺陷的长期逆转。由于HDAC 6抑制剂作为癌症治疗的添加剂的有益作用已在临床试验中得到证实，因此用脑穿透抑制剂选择性靶向HDAC 6似乎是一种有希望的治疗方法，用于逆转化疗诱导的神经毒性，同时增强肿瘤控制。本文的在线版本（10.1186/s40478-018-0604-3）包含补充材料，可供授权用户使用。
Chemotherapy-induced cognitive impairment (CICI) is a commonly reported neurotoxic side effect of chemotherapy, occurring in up to 75% cancer patients. CICI manifests as decrements in working memory, executive functioning, attention, and processing speed, and greatly interferes with patients’ daily performance and quality of life. Currently no treatment for CICI has been approved by the US Food and Drug Administration. We show here that treatment with a brain-penetrating histone deacetylase 6 (HDAC6) inhibitor for two weeks was sufficient to fully reverse cisplatin-induced cognitive impairments in male mice, as demonstrated in the Y-maze test of spontaneous alternation, the novel object/place recognition test, and the puzzle box test. Normalization of cognitive impairment was associated with reversal of cisplatin-induced synaptosomal mitochondrial deficits and restoration of synaptic integrity. Mechanistically, cisplatin induced deacetylation of the microtubule protein α-tubulin and hyperphosphorylation of the microtubule-associated protein tau. These cisplatin-induced changes were reversed by HDAC6 inhibition. Our data suggest that inhibition of HDAC6 restores microtubule stability and reverses tau phosphorylation, leading to normalization of synaptosomal mitochondrial function and synaptic integrity and thereby to reversal of CICI. Remarkably, our results indicate that short-term daily treatment with the HDAC6 inhibitor was sufficient to achieve prolonged reversal of established behavioral, structural and functional deficits induced by cisplatin. Because the beneficial effects of HDAC6 inhibitors as add-ons to cancer treatment have been demonstrated in clinical trials, selective targeting of HDAC6 with brain-penetrating inhibitors appears a promising therapeutic approach for reversing chemotherapy-induced neurotoxicity while enhancing tumor control. The online version of this article (10.1186/s40478-018-0604-3) contains supplementary material, which is available to authorized users.
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影响因子：
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作者：
Aldana-Masangkay GI;Sakamoto KM
通讯作者：
Sakamoto KM
影响因子：
64.8
作者：
Hubbert, C;Guardiola, A;Yao, TP
通讯作者：
Yao, TP
DOI：
10.15585/mmwr.mm6603a1
发表时间：
2017-01-27
期刊：
MMWR. Morbidity and mortality weekly report
影响因子：
--
作者：
Henley SJ;Singh SD;King J;Wilson RJ;O'Neil ME;Ryerson AB
通讯作者：
Ryerson AB
蒽环类药物与非人性差的化学疗法对乳腺癌幸存者认知的神经毒性作用。
影响因子：
28.4
作者：
Kesler SR;Blayney DW
通讯作者：
Blayney DW
影响因子：
64.8
作者：
通讯作者：
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