Singh Anand Kumar, Ruiz David, Rasheed Mohd Sami Ur, Avery Thomas D, Turner Dion J L, Abell Andrew D, Grace Peter M
Laboratories of Neuroimmunology, Department of Symptom Research, and the MD Anderson Pain Research Consortium, University of Texas MD Anderson Cancer Center, Houston, USA.
ARC Centre of Excellence for Nanoscale BioPhotonics (CNBP), Institute for Photonics and Advanced Sensing (IPAS), Department of Chemistry, The University of Adelaide, Adelaide, Australia.
bioRxiv. 2024 Jun 10:2024.06.10.598291. doi: 10.1101/2024.06.10.598291.
While cancer survivorship has increased due to advances in treatments, chemotherapy often carries long-lived neurotoxic side effects which reduce quality of life. Commonly affected domains include memory, executive function, attention, processing speed and sensorimotor function, colloquially known as chemotherapy-induced cognitive impairment (CICI) or "chemobrain". Oxidative stress and neuroimmune signaling in the brain have been mechanistically linked to the deleterious effects of chemotherapy on cognition and sensorimotor function. With this in mind, we tested if activation of the master regulator of antioxidant response nuclear factor E2-related factor 2 (Nrf2) alleviates cognitive and sensorimotor impairments induced by doxorubicin. The FDA-approved systemic Nrf2 activator, diroximel fumarate (DRF) was used, along with our recently developed prodrug which has the advantage of specifically releasing monomethyl fumarate at sites of oxidative stress. DRF and both reversed doxorubicin-induced deficits in executive function, spatial and working memory, as well as decrements in fine motor coordination and grip strength, across both male and female mice. Both treatments reversed doxorubicin-induced loss of synaptic proteins and microglia phenotypic transition in the hippocampus. Doxorubicin-induced myelin damage in the corpus callosum was reversed by both Nrf2 activators. These results demonstrate the therapeutic potential of Nrf2 activators to reverse doxorubicin-induced cognitive impairments, motor incoordination, and associated structural and phenotypic changes in the brain. The localized release of monomethyl fumarate by has the potential to diminish unwanted effects of fumarates while retaining efficacy.
尽管由于治疗方法的进步，癌症幸存者数量有所增加，但化疗常常会带来长期的神经毒性副作用，从而降低生活质量。常见的受影响领域包括记忆、执行功能、注意力、处理速度和感觉运动功能，通俗地称为化疗引起的认知障碍（CICI）或“化疗脑”。大脑中的氧化应激和神经免疫信号在机制上与化疗对认知和感觉运动功能的有害影响相关联。考虑到这一点，我们测试了抗氧化反应主调节因子核因子E2相关因子2（Nrf2）的激活是否能减轻阿霉素诱导的认知和感觉运动障碍。使用了美国食品药品监督管理局（FDA）批准的全身性Nrf2激活剂二氧肟酸富马酸酯（DRF），以及我们最近开发的前药，其优点是在氧化应激部位特异性释放单甲基富马酸酯。DRF和该前药均能逆转阿霉素诱导的雄性和雌性小鼠执行功能、空间和工作记忆方面的缺陷，以及精细运动协调和握力的下降。两种治疗方法都能逆转阿霉素诱导的海马体中突触蛋白的丢失和小胶质细胞表型转变。两种Nrf2激活剂都能逆转阿霉素诱导的胼胝体髓鞘损伤。这些结果证明了Nrf2激活剂在逆转阿霉素诱导的认知障碍、运动不协调以及大脑相关结构和表型变化方面的治疗潜力。前药对单甲基富马酸酯的局部释放有可能减少富马酸酯的不良影响，同时保持疗效。
