Department of Pediatrics, Goryeb Children's Hospital-Atlantic Health, Morristown, NJ, 07960, USA; Division of Pediatric Hematology/Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA.
Rutgers Graduate Program in Cellular and Molecular Pharmacology, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, New Brunswick, NJ, USA; Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, NJ, USA.
Neuropharmacology. 2022 Mar 15;206:108939. doi: 10.1016/j.neuropharm.2021.108939. Epub 2022 Jan 2.
Methotrexate (MTX) is widely employed for children with cancer, but is also associated with persistent cognitive deficits among survivors. The present study investigated the mechanisms behind long-term cognitive dysfunction after juvenile animals are treated with MTX. Male and female Long-Evans rats were treated with a combination of 6 systemic doses (0.5 mg/kg/dose intraperitoneally) and 4 intrathecal doses (1 mg/kg) beginning at post-natal age 3 weeks, a schedule designed to mimic repeated exposure given to children with leukemia. Behavioral testing was conducted at 60-61 weeks of age, followed by analysis of brain histolopathology. This MTX regimen had no acute toxicity and no effect on growth. The spatial memory and visual memory deficits observed at 13 and 17 weeks of age persisted 1 year after MTX exposure in both females and males. Significantly decreased cell proliferation and increased hippocampal microglial activation were observed in MTX-treated females when compared to the controls, with a similar trend in the male groups. In addition, MTX treatment significantly increased the number of TUNEL positive cells in the periventricular area. Our study demonstrates that a clinically relevant regimen of systemic and intrathecal MTX induces persistent deficits in cognition, lasting approximately 1 year after the last injection. The mechanisms behind MTX-induced deficits are likely multifactorial, including suppression of neurogenesis, microglial activation, and increased brain cell apoptosis. Our study suggests female and male animals differ in susceptibility to MTX-induced neurotoxicity and provides insights for developing therapeutic approaches to prevent treatment related cognitive impairment among children with ALL.
甲氨蝶呤（MTX）广泛用于治疗癌症儿童，但也与幸存者持续存在认知缺陷有关。本研究探讨了幼年动物接受 MTX 治疗后长期认知功能障碍的背后机制。雄性和雌性长耳大仓鼠从出生后 3 周开始接受 6 次全身剂量（0.5mg/kg/腹腔内）和 4 次鞘内剂量（1mg/kg）的联合治疗，这一方案旨在模拟儿童白血病的重复暴露。在 60-61 周龄时进行行为测试，然后分析大脑组织病理学。这种 MTX 方案没有急性毒性，也不影响生长。在 13 和 17 周龄时观察到的空间记忆和视觉记忆缺陷在 MTX 暴露 1 年后在雌性和雄性中均持续存在。与对照组相比，MTX 治疗的雌性鼠的细胞增殖明显减少，海马微胶质细胞激活增加，雄性鼠也有类似的趋势。此外，MTX 治疗显著增加了脑室周围区域 TUNEL 阳性细胞的数量。我们的研究表明，一种临床相关的全身和鞘内 MTX 方案会导致认知功能持续缺陷，在最后一次注射后大约持续 1 年。MTX 诱导缺陷的机制可能是多因素的，包括神经发生抑制、小胶质细胞激活和脑细胞凋亡增加。我们的研究表明，雌性和雄性动物对 MTX 诱导的神经毒性的敏感性不同，并为开发预防 ALL 儿童治疗相关认知障碍的治疗方法提供了思路。
