Zisiadis Georgios Alkis, Alevyzaki Androniki, Nicola Elene, Rodrigues Carlos F D, Blomgren Klas, Osman Ahmed M
Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.
Pediatric Oncology, Karolinska University Hospital, Stockholm, Sweden.
Front Oncol. 2023 Oct 4;13:1202200. doi: 10.3389/fonc.2023.1202200. eCollection 2023.
Cranial irradiation (IR) negatively regulates hippocampal neurogenesis and causes cognitive dysfunctions in cancer survivors, especially in pediatric patients. IR decreases proliferation of neural stem/progenitor cells (NSPC) and consequently diminishes production of new hippocampal neurons. Memantine, an NMDA receptor antagonist, used clinically to improve cognition in patients suffering from Alzheimer's disease and dementia. In animal models, memantine acts as a potent enhancer of hippocampal neurogenesis. Memantine was recently proposed as an intervention to improve cognitive impairments occurring after radiotherapy and is currently under investigation in a number of clinical trials, including pediatric patients. To date, preclinical studies investigating the mechanisms underpinning how memantine improves cognition after IR remain limited, especially in the young, developing brain. Here, we investigated whether memantine could restore proliferation in the subgranular zone (SGZ) or rescue the reduction in the number of hippocampal young neurons after IR in the juvenile mouse brain.
Mice were whole-brain irradiated with 6 Gy on postnatal day 20 (P20) and subjected to acute or long-term treatment with memantine. Proliferation in the SGZ and the number of young neurons were further evaluated after the treatment. We also measured the levels of neurotrophins associated with memantine improved neural plasticity, brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF).
We show that acute intraperitoneal treatment with a high, non-clinically used, dose of memantine (50 mg/kg) increased the number of proliferating cells in the intact brain by 72% and prevented 23% of IR-induced decrease in proliferation. Long-term treatment with 10 mg/kg/day of memantine, equivalent to the clinically used dose, did not impact proliferation, neither in the intact brain, nor after IR, but significantly increased the number of young neurons (doublecortin expressing cells) with radial dendrites (29% in sham controls and 156% after IR) and enhanced their dendritic arborization. Finally, we found that long-term treatment with 10 mg/kg/day memantine did not affect the levels of BDNF, but significantly reduced the levels of NGF by 40%.
These data suggest that the enhanced dendritic complexity of the hippocampal young neurons after treatment with memantine may contribute to the observed improved cognition in patients treated with cranial radiotherapy.
颅脑照射（IR）对海马神经发生具有负向调节作用，并导致癌症幸存者，尤其是儿科患者出现认知功能障碍。IR会降低神经干细胞/祖细胞（NSPC）的增殖，从而减少新的海马神经元的产生。美金刚是一种NMDA受体拮抗剂，临床上用于改善阿尔茨海默病和痴呆患者的认知功能。在动物模型中，美金刚是海马神经发生的有效增强剂。最近有人提出美金刚作为一种干预措施来改善放疗后出现的认知障碍，目前正在包括儿科患者在内的多项临床试验中进行研究。迄今为止，关于美金刚改善IR后认知功能的潜在机制的临床前研究仍然有限，尤其是在发育中的幼龄大脑中。在此，我们研究了美金刚是否可以恢复幼龄小鼠大脑IR后颗粒下区（SGZ）的增殖或挽救海马幼龄神经元数量的减少。
在出生后第20天（P20）对小鼠进行6 Gy的全脑照射，并给予美金刚急性或长期治疗。治疗后进一步评估SGZ的增殖情况和幼龄神经元的数量。我们还测量了与美金刚改善神经可塑性相关的神经营养因子水平，即脑源性神经营养因子（BDNF）和神经生长因子（NGF）。
我们发现，用高剂量、非临床使用剂量的美金刚（50 mg/kg）进行急性腹腔注射治疗可使完整大脑中增殖细胞的数量增加72%，并防止IR诱导的增殖减少23%。用相当于临床使用剂量的10 mg/kg/天的美金刚进行长期治疗，无论是在完整大脑中还是在IR后，均不影响增殖，但显著增加了具有放射状树突的幼龄神经元（双皮质素表达细胞）的数量（假手术对照组中增加29%，IR后增加156%），并增强了它们的树突分支。最后，我们发现用10 mg/kg/天的美金刚进行长期治疗不影响BDNF的水平，但显著降低NGF水平40%。
这些数据表明，美金刚治疗后海马幼龄神经元树突复杂性的增强可能有助于改善接受颅脑放疗患者的认知功能。
