Department of Functional Histology, Ehime University Graduate School of Medicine, Ehime, Japan.
J Cereb Blood Flow Metab. 2012 Oct;32(10):1897-908. doi: 10.1038/jcbfm.2012.92. Epub 2012 Jun 27.
The organic cation transporters OCT1, 2, and 3 (SLC22A1-3) have been implicated in the elimination of biogenic amines such as histamine. Among them, OCT3 was identified as an uptake-2 transporter, responsible for clearance of histamine. Because increasing evidence suggests the involvement of histamine in cerebral ischemia, we investigated the effects of targeted disruption of organic cation transporter-3 (Oct3) on the severity of ischemic brain damage. Transient focal ischemia for 1 hour was induced by occlusion of the middle cerebral artery (MCA) of homozygous Oct3-deficient mice and their wild-type (Wt) littermates. Although targeted disruption of Oct3 did not affect physiological parameters after MCA occlusion, this disruption significantly increased histamine content in the ischemic cortex and significantly reduced the infarct volume after cerebral ischemia. Furthermore, targeted disruption of Oct3 prevented the reduction of regulatory T-cell proportion after cerebral ischemia while this disruption did not affect Th1 and Th2 cells proportions after ischemia. Since repeated administration of L-histidine (a precursor of histamine) to Wt mice also showed the same effects, our observations suggested that OCT3 is the molecule responsible for clearance of ischemia-induced histamine in the brain and targeted disruption of Oct3 ameliorated ischemic brain damage through an increase in regulatory T cells.
有机阳离子转运体 OCT1、2 和 3（SLC22A1-3）已被认为参与了生物胺如组胺的消除。其中，OCT3 被鉴定为摄取 2 转运体，负责清除组胺。由于越来越多的证据表明组胺参与脑缺血，我们研究了靶向敲除有机阳离子转运体 3（Oct3）对缺血性脑损伤严重程度的影响。通过阻断大脑中动脉（MCA）诱导 1 小时的短暂局灶性缺血，在同源性 Oct3 缺陷型小鼠及其野生型（Wt）同窝仔鼠中。虽然靶向敲除 Oct3 不影响 MCA 闭塞后的生理参数，但这种敲除显著增加了缺血皮质中的组胺含量，并显著减少了脑缺血后的梗死体积。此外，靶向敲除 Oct3 可防止脑缺血后调节性 T 细胞比例的降低，而这种敲除并不影响脑缺血后 Th1 和 Th2 细胞的比例。由于向 Wt 小鼠反复给予 L-组氨酸（组胺的前体）也显示出相同的效果，我们的观察结果表明，OCT3 是负责清除脑内缺血诱导的组胺的分子，靶向敲除 Oct3 通过增加调节性 T 细胞来改善缺血性脑损伤。
