Leibowitz Akiva, Boyko Matthew, Shapira Yoram, Zlotnik Alexander
Department of Anesthesiology and Critical Care, Soroka Medical Center, Ben-Gurion University, Beer Sheva 84894, Israel.
Int J Mol Sci. 2012;13(8):10041-10066. doi: 10.3390/ijms130810041. Epub 2012 Aug 13.
Brain insults are characterized by a multitude of complex processes, of which glutamate release plays a major role. Deleterious excess of glutamate in the brain's extracellular fluids stimulates glutamate receptors, which in turn lead to cell swelling, apoptosis, and neuronal death. These exacerbate neurological outcome. Approaches aimed at antagonizing the astrocytic and glial glutamate receptors have failed to demonstrate clinical benefit. Alternatively, eliminating excess glutamate from brain interstitial fluids by making use of the naturally occurring brain-to-blood glutamate efflux has been shown to be effective in various animal studies. This is facilitated by gradient driven transport across brain capillary endothelial glutamate transporters. Blood glutamate scavengers enhance this naturally occurring mechanism by reducing the blood glutamate concentration, thus increasing the rate at which excess glutamate is cleared. Blood glutamate scavenging is achieved by several mechanisms including: catalyzation of the enzymatic process involved in glutamate metabolism, redistribution of glutamate into tissue, and acute stress response. Regardless of the mechanism involved, decreased blood glutamate concentration is associated with improved neurological outcome. This review focuses on the physiological, mechanistic and clinical roles of blood glutamate scavenging, particularly in the context of acute and chronic CNS injury. We discuss the details of brain-to-blood glutamate efflux, auto-regulation mechanisms of blood glutamate, natural and exogenous blood glutamate scavenging systems, and redistribution of glutamate. We then propose different applied methodologies to reduce blood and brain glutamate concentrations and discuss the neuroprotective role of blood glutamate scavenging.
脑损伤具有多种复杂过程，其中谷氨酸释放起主要作用。脑细胞外液中谷氨酸的有害过量会刺激谷氨酸受体，进而导致细胞肿胀、凋亡和神经元死亡。这些会加剧神经功能结局。旨在拮抗星形胶质细胞和神经胶质谷氨酸受体的方法未能显示出临床益处。相反，在各种动物研究中，利用自然存在的脑-血谷氨酸外流从脑间质液中清除过量谷氨酸已被证明是有效的。这通过跨脑毛细血管内皮谷氨酸转运体的梯度驱动转运来实现。血谷氨酸清除剂通过降低血谷氨酸浓度来增强这种自然机制，从而提高清除过量谷氨酸的速率。血谷氨酸清除通过多种机制实现，包括：催化谷氨酸代谢中涉及的酶促过程、将谷氨酸重新分布到组织中以及急性应激反应。无论涉及何种机制，血谷氨酸浓度降低都与改善的神经功能结局相关。本综述重点关注血谷氨酸清除的生理、机制和临床作用，特别是在急性和慢性中枢神经系统损伤的背景下。我们讨论了脑-血谷氨酸外流的细节、血谷氨酸的自动调节机制、天然和外源性血谷氨酸清除系统以及谷氨酸的重新分布。然后，我们提出了不同的应用方法来降低血和脑谷氨酸浓度，并讨论了血谷氨酸清除的神经保护作用。
