Jiang Zhi-Gang, Winocur Gordon, Wojtowicz J Martin, Shevtsova Olga, Fuller Steven, Ghanbari Hossein A
Panacea Pharmaceuticals, Inc., Gaithersburg, Maryland, United States of America.
Department of Psychology, Trent University, Peterborough, Ontario, Canada.
PLoS One. 2018 Jan 25;13(1):e0191866. doi: 10.1371/journal.pone.0191866. eCollection 2018.
Chemotherapy-induced cognitive impairment (CICI) occurs in a substantial proportion of treated cancer patients, with no drug currently available for its therapy. This study investigated whether PAN-811, a ribonucleotide reductase inhibitor, can reduce cognitive impairment and related suppression of neurogenesis following chemotherapy in an animal model. Young adult rats in Chemo and Chemo+PAN-811 groups received 3 intraperitoneal (i.p.) injections of methotrexate (MTX) and 5-fluorouracil (5-FU), and those in Saline and Saline+PAN-811 groups received equal volumes of physiological saline at 10-day intervals. PAN-811 in saline was delivered through i.p. injection, 10 min following each saline (Saline+PAN-811 group) or MTX/5-FU (Chemo+PAN-811 group) treatment, while equal volumes of saline were delivered to Saline and Chemo groups. Over Days 31-66, rats were administered tests of spatial memory, nonmatching-to-sample rule learning, and discrimination learning, which are sensitive to dysfunction in hippocampus, frontal lobe and striatum, respectively. On Day 97, neurogenesis was immnunohistochemically evaluated by counting doublecortin-positive (DCX+) cells in the dentate gyrus (DG). The results demonstrated that the Chemo group was impaired on the three cognitive tasks, but co-administration of PAN-811 significantly reduced all MTX/5-FU-induced cognitive impairments. In addition, MTX/5-FU reduced DCX+ cells to 67% of that in Saline control rats, an effect that was completely blocked by PAN-811 co-administration. Overall, we present the first evidence that PAN-811 protects cognitive functions and preserves neurogenesis from deleterious effects of MTX/5-FU. The current findings provide a basis for rapid clinical translation to determine the effect of PAN-811 on CICI in human.
化疗引起的认知障碍（CICI）在接受治疗的癌症患者中相当常见，目前尚无药物可用于治疗。本研究调查了核糖核苷酸还原酶抑制剂PAN - 811是否能在动物模型中减轻化疗后出现的认知障碍以及相关的神经发生抑制。化疗组和化疗 + PAN - 811组的成年大鼠每隔10天接受3次腹腔注射甲氨蝶呤（MTX）和5 - 氟尿嘧啶（5 - FU），生理盐水组和生理盐水 + PAN - 811组则接受等量的生理盐水。生理盐水 + PAN - 811组和化疗 + PAN - 811组在每次生理盐水或MTX/5 - FU治疗后10分钟通过腹腔注射给予溶于生理盐水的PAN - 811，生理盐水组和化疗组则给予等量的生理盐水。在第31至66天，对大鼠进行空间记忆测试、非匹配样本规则学习测试和辨别学习测试，这些测试分别对海马体、额叶和纹状体功能障碍敏感。在第97天，通过计数齿状回（DG）中双皮质素阳性（DCX +）细胞，对神经发生进行免疫组织化学评估。结果表明，化疗组在三项认知任务中均受损，但联合使用PAN - 811显著减轻了所有MTX/5 - FU诱导的认知障碍。此外，MTX/5 - FU使DCX +细胞减少至生理盐水对照大鼠的67%，而联合使用PAN - 811完全阻断了这一效应。总体而言，我们首次证明PAN - 811可保护认知功能，并使神经发生免受MTX/5 - FU的有害影响。目前的研究结果为快速临床转化提供了依据，以确定PAN - 811对人类CICI的影响。
