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Malignant astrocyte swelling and impaired glutamate clearance drive the expansion of injurious spreading depolarization foci
Journal of Cerebral Blood Flow & Metabolism ( IF 4.9 ) Pub Date : 2021-08-24 , DOI: 10.1177/0271678x211040056
Ákos Menyhárt 1 , Rita Frank 1 , Attila E Farkas 2 , Zoltán Süle 3 , Viktória É Varga 1 , Ádám Nyúl-Tóth 2, 4 , Anne Meiller 5 , Orsolya Ivánkovits-Kiss 1 , Coline L Lemale 6, 7 , Írisz Szabó 1 , Réka Tóth 1 , Dániel Zölei-Szénási 1 , Johannes Woitzik 8 , Stephane Marinesco 5 , István A Krizbai 2, 9 , Ferenc Bari 1 , Jens P Dreier 6, 7, 10, 11, 12 , Eszter Farkas 13, 14
Affiliation  

Spreading depolarizations (SDs) indicate injury progression and predict worse clinical outcome in acute brain injury. We demonstrate in rodents that acute brain swelling upon cerebral ischemia impairs astroglial glutamate clearance and increases the tissue area invaded by SD. The cytotoxic extracellular glutamate accumulation (>15 µM) predisposes an extensive bulk of tissue (4–5 mm2) for a yet undescribed simultaneous depolarization (SiD). We confirm in rat brain slices exposed to osmotic stress that SiD is the pathological expansion of prior punctual SD foci (0.5–1 mm2), is associated with astrocyte swelling, and triggers oncotic neuron death. The blockade of astrocytic aquaporin-4 channels and Na+/K+/Cl co-transporters, or volume-regulated anion channels mitigated slice edema, extracellular glutamate accumulation (<10 µM) and SiD occurrence. Reversal of slice swelling by hyperosmotic mannitol counteracted glutamate accumulation and prevented SiD. In contrast, inhibition of glial metabolism or inhibition of astrocyte glutamate transporters reproduced the SiD phenotype. Finally, we show in the rodent water intoxication model of cytotoxic edema that astrocyte swelling and altered astrocyte calcium waves are central in the evolution of SiD. We discuss our results in the light of evidence for SiD in the human cortex. Our results emphasize the need of preventive osmotherapy in acute brain injury.



中文翻译:

恶性星形胶质细胞肿胀和谷氨酸清除受损导致有害扩散去极化病灶的扩大

扩散去极化 (SDs) 表明损伤进展并预测急性脑损伤的临床结果更差。我们在啮齿动物身上证明,脑缺血引起的急性脑肿胀会损害星形神经胶质细胞的谷氨酸清除率,并增加 SD 侵入的组织面积。细胞毒性细胞外谷氨酸积累 (>15 µM) 使大量组织 (4–5 mm 2 ) 易发生尚未描述的同时去极化 (SiD)。我们在暴露于渗透压的大鼠脑切片中证实,SiD 是先前准时 SD 病灶 (0.5–1 mm 2 ) 的病理性扩张,与星形胶质细胞肿胀相关,并引发渗透性神经元死亡。星形胶质细胞水通道蛋白 4 通道和 Na + /K + /Cl −的阻断协同转运蛋白或体积调节阴离子通道减轻切片水肿、细胞外谷氨酸积累 (<10 µM) 和 SiD 发生。高渗甘露醇逆转切片肿胀可抵消谷氨酸积累并防止 SiD。相反,抑制神经胶质代谢或抑制星形胶质细胞谷氨酸转运蛋白可再现 SiD 表型。最后,我们在细胞毒性水肿的啮齿动物水中毒模型中表明,星形胶质细胞肿胀和改变的星形胶质细胞钙波是 SiD 演变的核心。我们根据人类皮层中 SiD 的证据讨论我们的结果。我们的结果强调了预防性渗透疗法在急性脑损伤中的必要性。

更新日期:2021-08-24
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