Institute of Medical Science, University of Toronto, Toronto, ON, Canada.
Terrence Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON, Canada.
Cell Rep Med. 2021 Apr 6;2(4):100231. doi: 10.1016/j.xcrm.2021.100231. eCollection 2021 Apr 20.
Cranial irradiation (IR) is an effective adjuvant therapy in the treatment of childhood brain tumors but results in long-lasting cognitive deficits associated with impaired neurogenesis, as evidenced in rodent models. Metformin has been shown to expand the endogenous neural stem cell (NSC) pool and promote neurogenesis under physiological conditions and in response to neonatal brain injury, suggesting a potential role in neurorepair. Here, we assess whether metformin pretreatment, a clinically feasible treatment for children receiving cranial IR, promotes neurorepair in a mouse cranial IR model. Using immunofluorescence and the neurosphere assay, we show that NSCs are depleted by cranial IR but spontaneously recover, although deficits to proliferative neuroblasts persist. Metformin pretreatment enhances the recovery of neurogenesis, attenuates the microglial response, and promotes recovery of long-term olfactory memory. These findings indicate that metformin is a promising candidate for further preclinical and clinical investigations of neurorepair in childhood brain injuries.
颅部照射（IR）是治疗儿童脑肿瘤的有效辅助治疗方法，但会导致与神经发生受损相关的长期认知缺陷，这在啮齿动物模型中得到了证实。二甲双胍已被证明可在生理条件下和对新生脑损伤的反应中扩大内源性神经干细胞（NSC）池并促进神经发生，这表明其在神经修复中具有潜在作用。在这里，我们评估了颅部 IR 治疗的儿童的临床可行的二甲双胍预处理是否能促进小鼠颅部 IR 模型中的神经修复。通过免疫荧光和神经球测定，我们发现颅部 IR 会耗尽 NSCs，但会自发恢复，尽管增殖性神经母细胞的缺陷持续存在。二甲双胍预处理可增强神经发生的恢复，减轻小胶质细胞反应，并促进长期嗅觉记忆的恢复。这些发现表明，二甲双胍是进一步研究儿童脑损伤神经修复的有前途的候选药物。
