Department of Radiation Oncology, University of California Irvine, Medical Sciences I, Room B-146B, Irvine, CA, 92697-2695, USA.
Department of Anatomy and Neurobiology, University of California, Irvine, CA, USA.
Sci Rep. 2024 May 28;14(1):12274. doi: 10.1038/s41598-024-62691-y.
Cranial irradiation used to control brain malignancies invariably leads to progressive and debilitating declines in cognition. Clinical efforts implementing hippocampal avoidance and NMDAR antagonism, have sought to minimize dose to radiosensitive neurogenic regions while normalizing excitatory/inhibitory (E/I) tone. Results of these trials have yielded only marginal benefits to cognition, prompting current studies to evaluate the potential of systemic extracellular vesicle (EV) therapy to restore neurocognitive functionality in the irradiated brain. Here we tested the hypothesis that EVs derived from inhibitory but not excitatory neuronal cultures would prove beneficial to cognition and associated pathology. Rats subjected to a clinically relevant, fractionated cranial irradiation paradigm were given multiple injections of either GABAergic- or glutamatergic-derived EV and subjected to behavioral testing. Rats treated with GABAergic but not glutamatergic EVs showed significant improvements on hippocampal- and cortical-dependent behavioral tasks. While each treatment enhanced levels of the neurotrophic factors BDNF and GDNF, only GABAergic EVs preserved granule cell neuron dendritic spine density. Additional studies conducted with GABAergic EVs, confirmed significant benefits on amygdala-dependent behavior and modest changes in synaptic plasticity as measured by long-term potentiation. These data point to a potentially more efficacious approach for resolving radiation-induced neurological deficits, possibly through a mechanism able to restore homeostatic E/I balance.
颅部放疗用于控制脑部恶性肿瘤，往往会导致认知能力逐渐下降和衰弱。临床努力实施海马回避和 NMDAR 拮抗作用，试图将放射敏感的神经发生区域的剂量降至最低，同时使兴奋性/抑制性（E/I）平衡正常化。这些试验的结果仅对认知产生了微不足道的益处，促使当前的研究评估系统细胞外囊泡（EV）治疗在放射性脑内恢复神经认知功能的潜力。在这里，我们测试了这样一个假设，即源自抑制性而非兴奋性神经元培养物的 EV 将对认知和相关病理学有益。接受临床相关的分次颅照射范例的大鼠接受了多次 GABA 能或谷氨酸能衍生的 EV 注射，并进行了行为测试。用 GABA 能但不是谷氨酸能 EV 治疗的大鼠在海马和皮质依赖的行为任务中表现出显著的改善。虽然每种治疗都增强了神经营养因子 BDNF 和 GDNF 的水平，但只有 GABA 能 EV 保留了颗粒细胞神经元树突棘密度。用 GABA 能 EV 进行的进一步研究证实了对杏仁核依赖行为的显著益处，以及通过长时程增强作用测量的突触可塑性的适度变化。这些数据表明，通过一种能够恢复内稳态 E/I 平衡的机制，解决辐射诱导的神经功能缺损可能是一种更有效的方法。
