Frank Rita, Szarvas Péter Archibald, Pesti István, Zsigmond Anna, Berkecz Róbert, Menyhárt Ákos, Bari Ferenc, Farkas Eszter
Hungarian Centre of Excellence for Molecular Medicine - University of Szeged Cerebral Blood Flow and Metabolism Research Group, Szeged, Hungary; Department of Cell Biology and Molecular Medicine, Albert Szent-Györgyi Medical School and Faculty of Science and Informatics, University of Szeged, Szeged, Hungary.
Hungarian Centre of Excellence for Molecular Medicine - University of Szeged Cerebral Blood Flow and Metabolism Research Group, Szeged, Hungary; Department of Cell Biology and Molecular Medicine, Albert Szent-Györgyi Medical School and Faculty of Science and Informatics, University of Szeged, Szeged, Hungary.
Eur J Pharmacol. 2024 Aug 15;977:176718. doi: 10.1016/j.ejphar.2024.176718. Epub 2024 Jun 6.
Nimodipine is used to prevent delayed ischemic deficit in patients with aneurysmal subarachnoid hemorrhage (aSAH). Spreading depolarization (SD) is recognized as a factor in the pathomechanism of aSAH and other acute brain injuries. Although nimodipine is primarily known as a cerebral vasodilator, it may have a more complex mechanism of action due to the expression of its target, the L-type voltage-gated calcium channels (LVGCCs) in various cells in neural tissue. This study was designed to investigate the direct effect of nimodipine on SD, ischemic tissue injury, and neuroinflammation. SD in control or nimodipine-treated live mouse brain slices was induced under physiological conditions using electrical stimulation, or by subjecting the slices to hypo-osmotic stress or mild oxygen-glucose deprivation (mOGD). SD was recorded applying local field potential recording or intrinsic optical signal imaging. Histological analysis was used to estimate tissue injury, the number of reactive astrocytes, and the degree of microglia activation. Nimodipine did not prevent SD occurrence in mOGD, but it did reduce the rate of SD propagation and the cortical area affected by SD. In contrast, nimodipine blocked SD occurrence in hypo-osmotic stress, but had no effect on SD propagation. Furthermore, nimodipine prevented ischemic injury associated with SD in mOGD. Nimodipine also exhibited anti-inflammatory effects in mOGD by reducing reactive astrogliosis and microglial activation. The results demonstrate that nimodipine directly inhibits SD, independent of nimodipine's vascular effects. Therefore, the use of nimodipine may be extended to treat acute brain injuries where SD plays a central role in injury progression.
尼莫地平用于预防动脉瘤性蛛网膜下腔出血（aSAH）患者的迟发性缺血性神经功能缺损。扩散性去极化（SD）被认为是aSAH和其他急性脑损伤发病机制中的一个因素。尽管尼莫地平主要被认为是一种脑血管扩张剂，但由于其靶点L型电压门控钙通道（LVGCCs）在神经组织中的各种细胞中表达，其作用机制可能更为复杂。本研究旨在探讨尼莫地平对SD、缺血性组织损伤和神经炎症的直接影响。在生理条件下，通过电刺激、使脑片处于低渗应激或轻度氧糖剥夺（mOGD），在对照或尼莫地平处理的活小鼠脑片中诱导SD。应用局部场电位记录或内在光学信号成像记录SD。组织学分析用于评估组织损伤、反应性星形胶质细胞数量和小胶质细胞活化程度。尼莫地平不能预防mOGD中SD的发生，但它确实降低了SD的传播速度和受SD影响的皮质面积。相比之下，尼莫地平在低渗应激中阻断了SD的发生，但对SD的传播没有影响。此外，尼莫地平预防了mOGD中与SD相关的缺血性损伤。尼莫地平还通过减轻反应性星形胶质细胞增生和小胶质细胞活化，在mOGD中表现出抗炎作用。结果表明，尼莫地平直接抑制SD，与尼莫地平的血管效应无关。因此，尼莫地平的应用可能会扩展到治疗SD在损伤进展中起核心作用的急性脑损伤。
