Lin Renbao, Luo Rui, Yu Xinyue, Zou Junjie, Huang Xiaowei, Guo Yanwu
The National Key Clinic Specialty, The Engineering Technology Research Center of Education Ministry of China, Guangdong Provincial Key Laboratory On Brain Function Repair and Regeneration, Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, Guangzhou, 510000, China.
Dermatology Hospital, Southern Medical University, Guangzhou, 510000, China.
J Transl Med. 2024 Dec 2;22(1):1094. doi: 10.1186/s12967-024-05912-2.
Status epilepticus (SE) is a common severe neurological emergency. Cerebral edema caused by SE is unavoidable and may exacerbate epilepsy. Recent studies have identified cerebrospinal fluid (CSF) as a crucial fluid source of initial cerebral edema following ischemic stroke and cardiac arrest. Moreover, synchronized neuronal firings drive CSF influx into interstitial fluid (ISF). Parenchymal border macrophages (PBMs) have been found to play a role in regulating CSF flow dynamics. However, the involvement of CSF and PBMs in cerebral edema during SE remains unclear. Here, we investigated the fluid source of cerebral edema in the initial phase of SE with the role of PBMs involved.
Lithium chloride-pilocarpine was used to induce SE in C57BL/6 J mice. Electroencephalogram (EEG) was acquired to assess changes in relative EEG power pre- and post-seizure onset. Apparent diffusion coefficient (ADC) maps reconstructed from diffusion-weighted imaging (DWI) were utilized to evaluate cytotoxic edema. Blood-brain barrier (BBB) permeability was examined using sodium fluorescein (NaFl). CSF tracer influx into the brain was assessed by transcranial imaging and brain slices. PBMs were depleted using clodronate liposomes. Immunohistochemistry was used to evaluate PBM depletion, severity of vasogenic edema, inflammation, and neuronal damage.
During the initial stage of SE, relative EEG power sharply increased and ADC values significantly decreased. Concurrently, CSF tracer influx into the cortex significantly elevated, though NaFl leakage from blood to brain parenchyma did not evidently alter. Following depletion of PBM, CSF influx declined but AQP4 expression and polarization remained unaffected. Post-PBM depletion, there was no significant alteration in relative EEG power, yet CSF influx decreased substantially during the initial stage of SE. The degree of ADC decline lessened, IgG extravasation after SE decreased, activated microglia and proliferating astrocytes count fell, and neuronal damage post-SE alleviated.
CSF appeared to contribute to cerebral edema in SE. Depletion of PBM alleviated cytotoxic edema in the initial phase of SE, and subsequent vasogenic edema, inflammatory response and neurological damage were reduced. These findings may provide potential novel strategies for treating cerebral edema following SE.
癫痫持续状态（SE）是一种常见的严重神经系统急症。SE所致的脑水肿不可避免，且可能会加重癫痫发作。最近的研究已确定脑脊液（CSF）是缺血性卒中和心脏骤停后最初脑水肿的关键液体来源。此外，同步神经元放电驱动脑脊液流入细胞间液（ISF）。已发现实质边界巨噬细胞（PBM）在调节脑脊液流动动力学中发挥作用。然而，脑脊液和PBM在SE期间脑水肿中的作用仍不清楚。在此，我们研究了SE初始阶段脑水肿的液体来源以及PBM所起的作用。
采用氯化锂-匹罗卡品诱导C57BL/6 J小鼠发生SE。采集脑电图（EEG）以评估癫痫发作前后相对EEG功率的变化。利用从扩散加权成像（DWI）重建的表观扩散系数（ADC）图评估细胞毒性水肿。使用荧光素钠（NaFl）检测血脑屏障（BBB）通透性。通过经颅成像和脑切片评估脑脊液示踪剂向脑内的流入。使用氯膦酸盐脂质体清除PBM。采用免疫组织化学法评估PBM清除情况、血管源性水肿的严重程度、炎症反应和神经元损伤。
在SE的初始阶段，相对EEG功率急剧增加，ADC值显著降低。同时，脑脊液示踪剂向皮质的流入显著增加，尽管NaFl从血液向脑实质的渗漏没有明显改变。PBM清除后，脑脊液流入减少，但水通道蛋白4（AQP4）的表达和极化未受影响。PBM清除后，相对EEG功率无显著变化，但在SE初始阶段脑脊液流入大幅减少。ADC下降程度减轻，SE后IgG外渗减少，活化小胶质细胞和增殖星形胶质细胞数量减少，SE后神经元损伤减轻。
脑脊液似乎在SE所致脑水肿中起作用。PBM清除减轻了SE初始阶段的细胞毒性水肿，随后的血管源性水肿、炎症反应和神经损伤均减少。这些发现可能为治疗SE后的脑水肿提供潜在的新策略。
