Umebayashi Daisuke, Natsume Atsushi, Takeuchi Hideyuki, Hara Masahito, Nishimura Yusuke, Fukuyama Ryuichi, Sumiyoshi Naoyuki, Wakabayashi Toshihiko
1 Department of Neurosurgery, Nagoya University School of Medicine , Nagoya, Japan .
J Neurotrauma. 2014 Dec 15;31(24):1967-74. doi: 10.1089/neu.2013.3223. Epub 2014 Sep 23.
We previously demonstrated that activated microglia release excessive glutamate through gap junction hemichannels and identified a novel gap junction hemichannel blocker, INI-0602, that was proven to penetrate the blood-brain barrier and be an effective treatment in mouse models of amyotrophic lateral sclerosis and Alzheimer disease. Spinal cord injury causes tissue damage in two successive waves. The initial injury is mechanical and directly causes primary tissue damage, which induces subsequent ischemia, inflammation, and neurotoxic factor release resulting in the secondary tissue damage. These lead to activation of glial cells. Activated glial cells such as microglia and astrocytes are common pathological observations in the damaged lesion. Activated microglia release glutamate, the major neurotoxic factor released into the extracellular space after neural injury, which causes neuronal death at high concentration. In the present study, we demonstrate that reduction of glutamate-mediated exitotoxicity via intraperitoneal administration of INI-0602 in the microenvironment of the injured spinal cord elicited neurobehavioral recovery and extensive suppression of glial scar formation by reducing secondary tissue damage. Further, this intervention stimulated anti-inflammatory cytokines, and subsequently elevated brain-derived neurotrophic factor. Thus, preventing microglial activation by a gap junction hemichannel blocker, INI-0602, may be a promising therapeutic strategy in spinal cord injury.
我们之前证明，活化的小胶质细胞通过间隙连接半通道释放过量谷氨酸，并鉴定出一种新型间隙连接半通道阻滞剂INI-0602，该阻滞剂已被证明可穿透血脑屏障，在肌萎缩侧索硬化症和阿尔茨海默病小鼠模型中是一种有效的治疗方法。脊髓损伤在两个连续阶段导致组织损伤。初始损伤是机械性的，直接导致原发性组织损伤，进而引发后续的缺血、炎症和神经毒性因子释放，导致继发性组织损伤。这些会导致胶质细胞活化。活化的胶质细胞，如小胶质细胞和星形胶质细胞，是受损病变中常见的病理表现。活化的小胶质细胞释放谷氨酸，这是神经损伤后释放到细胞外空间的主要神经毒性因子，高浓度时会导致神经元死亡。在本研究中，我们证明，通过在受损脊髓的微环境中腹腔注射INI-0602来降低谷氨酸介导的兴奋性毒性，可通过减少继发性组织损伤引发神经行为恢复并广泛抑制胶质瘢痕形成。此外，这种干预刺激了抗炎细胞因子，随后提高了脑源性神经营养因子水平。因此，用间隙连接半通道阻滞剂INI-0602预防小胶质细胞活化可能是脊髓损伤中一种有前景的治疗策略。
