Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal University, Manipal, Karnataka, 576104, India.
Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal University, Manipal, Karnataka, 576104, India; Discovery Biology, Suven Life Sciences Limited, Hyderabad, Telangana, 502307, India.
Biomed Pharmacother. 2017 Dec;96:736-741. doi: 10.1016/j.biopha.2017.09.150. Epub 2017 Nov 6.
Increasing number of scientific reports have highlighted the role of histone acetylation/deacetylation in neurodegenerative conditions, including chemotherapy-induced cognitive dysfunction (also known as chemobrain). Multiple sources state that increased activity of histone deacetylases (HDACs) play a detrimental role in chemobrain. In the present study, sodium valproate, a well-known HDAC inhibitor, was explored for its neuroprotective potential against chemobrain development.
Doxorubicin (DOX), a chemotherapeutic agent, was used to induce chemobrain in experimental animals while treating with sodium valproate simultaneously. The animals were subjected to novel object recognition test (NORT) in order to assess their cognitive status and further, brain antioxidant levels were estimated. The animal body weights and survival were noted throughout the period of the study. Blood parameters such as red blood cell count, white blood cell count and haemoglobin levels were also measured.
Our findings are in contradiction to the known neuroprotective properties of valproic acid. We observed that sodium valproate failed to prevent chemobrain development in DOX treated animals. In fact, treatment with sodium valproate dose dependently worsened cognitive status in DOX treated animals including their brain antioxidant status, possibly leading to neuronal damage through free radical induced toxicity.
The present study highlights the caution that needs to be exercised in projecting HDAC inhibitors as in vivo neuroprotective agents, due to the complexity of existing neurological pathways and the diverse roles of histone deacetylases.
越来越多的科学报告强调了组蛋白乙酰化/去乙酰化在神经退行性疾病中的作用，包括化疗引起的认知功能障碍（也称为化疗脑）。多个来源表明，组蛋白去乙酰化酶（HDACs）的活性增加在化疗脑中起着有害的作用。在本研究中，探索了丙戊酸钠（一种已知的 HDAC 抑制剂）对化疗脑发展的神经保护潜力。
阿霉素（DOX）是一种化疗药物，用于在同时用丙戊酸钠治疗的情况下诱导实验动物的化疗脑。通过新物体识别测试（NORT）评估动物的认知状态，并进一步估计大脑抗氧化水平。在研究期间，记录动物的体重和存活率。还测量了血液参数，如红细胞计数、白细胞计数和血红蛋白水平。
我们的发现与丙戊酸的已知神经保护特性相矛盾。我们观察到丙戊酸钠未能预防 DOX 处理动物的化疗脑发展。事实上，丙戊酸钠治疗剂量依赖性地恶化了 DOX 处理动物的认知状态，包括其大脑抗氧化状态，可能通过自由基诱导的毒性导致神经元损伤。
本研究强调了由于现有神经通路的复杂性和组蛋白去乙酰化酶的多种作用，在将 HDAC 抑制剂作为体内神经保护剂进行预测时需要谨慎。
