间歇性θ爆发刺激在缺血性卒中中的应用：连接小胶质细胞重编程与神经元存活的线粒体中心框架

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中文摘要

缺血性卒中触发线粒体代谢危机，并通过神经免疫和神经元内在机制传播继发性损伤。在数分钟内，氧化磷酸化（OXPHOS）崩溃驱动琥珀酸积累；再灌注时，琥珀酸快速再氧化通过反向电子传递产生线粒体活性氧（ROS）爆发，触发神经炎症、血脑屏障破坏和调节性神经元死亡。间歇性θ爆发刺激（iTBS）是一种省时的重复经颅磁刺激方案，在系统水平上靶向这一危机。临床前证据表明，iTBS可恢复神经血管完整性，通过抑制琥珀酸/缺氧诱导因子-1α（HIF-1α）驱动的Toll样受体4（TLR4）/核因子-κB（NF-κB）/NLR家族含pyrin结构域3（NLRP3）炎症小体级联反应来重编程小胶质细胞活化，并促进修复性免疫微环境。我们进一步提出，恢复小胶质细胞OXPHOS可能将炎症消退与脑源性神经营养因子（BDNF）和胰岛素样生长因子-1（IGF-1）合成的增强耦合起来，形成免疫消退与神经元存活之间的代谢桥梁——这一联系由独立支持的组件组装而成，但尚未在iTBS背景下作为整合通路进行测试。在神经元内在水平，iTBS通过miR-34c-5p/p53/Bax信号抑制凋亡，通过恢复铁稳态和抗氧化能力减轻铁死亡，并通过转录因子EB（TFEB）介导的自噬增强线粒体质量控制。我们提出一个以线粒体为中心的框架，其中线粒体稳态作为连接小胶质细胞免疫代谢重编程与神经元内在存活程序的核心整合枢纽。该框架旨在作为产生假说的综合，而非对已确立因果通路的总结；其若干核心联系，包括小胶质细胞琥珀酸-衣康酸轴和OXPHOS-营养桥，仍有待在iTBS处理的组织中直接测试。初步临床研究报告了运动、认知、语言和吞咽领域的功能改善，尽管样本量有限且方案异质。我们讨论了转化挑战，包括参数异质性，并指出外周标志物如血浆琥珀酸和无细胞线粒体DNA值得探索作为候选药效学指标，而非作为经过验证的反应指导面板。

英文摘要

Ischemic stroke triggers a mitochondrial metabolic crisis that propagates secondary injury through neuroimmune and neuron-intrinsic mechanisms. Within minutes, collapse of oxidative phosphorylation (OXPHOS) drives succinate accumulation; upon reperfusion, rapid succinate re-oxidation generates a burst of mitochondrial reactive oxygen species (ROS) via reverse electron transport, triggering neuroinflammation, blood-brain barrier disruption, and regulated neuronal death. Intermittent theta burst stimulation (iTBS), a time-efficient repetitive transcranial magnetic stimulation protocol, targets this crisis at a systems level. Preclinical evidence indicates that iTBS restores neurovascular integrity, reprograms microglial activation by suppressing the succinate/hypoxia-inducible factor-1α (HIF-1α)-driven Toll-like receptor 4 (TLR4)/nuclear factor-κB (NF-κB)/ NLR family pyrin domain-containing 3 (NLRP3) inflammasome cascade, and promotes a reparative immune microenvironment. We further propose that restoration of microglial OXPHOS may couple inflammatory resolution to enhanced synthesis of brain-derived neurotrophic factor (BDNF) and insulin-like growth factor-1 (IGF-1), forming a metabolic bridge between immune resolution and neuronal survival-a connection assembled from independently supported components but not yet tested as an integrated pathway in the iTBS context. At the neuron-intrinsic level, iTBS suppresses apoptosis via miR-34c-5p/p53/Bax signaling, attenuates ferroptosis by restoring iron homeostasis and antioxidant capacity, and reinforces mitochondrial quality control through transcription factor EB (TFEB)-mediated autophagy. We propose a mitochondria-centered framework wherein mitochondrial homeostasis serves as the central integrative hub linking microglial immunometabolic reprogramming to neuron-intrinsic survival programs. This framework is intended as a hypothesis-generating synthesis rather than a summary of established causal pathways; several of its central links, including the microglial succinate-itaconate axis and the OXPHOS-trophic bridge, remain to be tested directly in iTBS-treated tissue. Preliminary clinical studies report functional improvements across motor, cognitive, language, and swallowing domains, although sample sizes are limited and protocols heterogeneous. We discuss translational challenges including parameter heterogeneity, and note that peripheral markers such as plasma succinate and cell-free mitochondrial DNA warrant exploration as candidate pharmacodynamic indices rather than as a validated response-guided panel.