Watanabe Akihiro, Sasaki Tsutomu, Yukami Toshiro, Kanki Hideaki, Sakaguchi Manabu, Takemori Hiroshi, Kitagawa Kazuo, Mochizuki Hideki
Department of Neurology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
Department of Neurology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
Neuroscience. 2016 Dec 17;339:139-149. doi: 10.1016/j.neuroscience.2016.09.036. Epub 2016 Sep 28.
There are no effective neuroprotectant drugs for acute cerebral ischemia. Serine racemase (SR) synthesizes d-serine, which is involved in N-methyl-d-aspartate (NMDA) receptor-induced neurotoxicity. Recently, SR deletion was reported to protect against focal cerebral ischemia. However, regulatory mechanisms controlling SR-activity in the neurovascular unit (NVU) during cerebral ischemia remain to be clarified. We investigated the effects of SR inhibition on neurovascular protection after ischemia. The SR inhibitor phenazine methosulfate (PMS) alleviated neuronal damage in an ex vivo ischemic model (oxygen glucose deprivation [OGD]) using primary neuronal cultures, and in an in vivo mouse model of ischemia (middle cerebral artery occlusion [MCAO]). Ischemic preconditioning (IP) and PMS-treatment inhibited SR phosphorylation after ischemia ex vivo. In addition, SR phosphorylation after MCAO was also decreased in PMS-treated mice. Reductions in regional cerebral blood flow (CBF) after MCAO were improved by administration of PMS. Treatment with PMS increased phosphorylation of endothelial nitric oxide synthase (eNOS) in the ischemic core and penumbra region. In neuron-endothelial cell co-cultures, PMS promoted nitric oxide production after OGD. These findings indicate that SR inhibition acts as a neuroprotectant in the NVU and ameliorant of CBF abnormalities post-stroke. Thus, pharmacologic SR inhibition has potential clinical applications.
目前尚无针对急性脑缺血的有效神经保护药物。丝氨酸消旋酶（SR）合成D-丝氨酸，其参与N-甲基-D-天冬氨酸（NMDA）受体诱导的神经毒性。最近，有报道称SR缺失可预防局灶性脑缺血。然而，脑缺血期间神经血管单元（NVU）中控制SR活性的调节机制仍有待阐明。我们研究了SR抑制对缺血后神经血管保护的影响。SR抑制剂吩嗪硫酸甲酯（PMS）在使用原代神经元培养物的离体缺血模型（氧葡萄糖剥夺[OGD]）以及体内缺血小鼠模型（大脑中动脉闭塞[MCAO]）中减轻了神经元损伤。缺血预处理（IP）和PMS处理在离体缺血后抑制了SR磷酸化。此外，PMS处理的小鼠MCAO后SR磷酸化也降低。PMS给药改善了MCAO后局部脑血流量（CBF）的减少。PMS处理增加了缺血核心和半暗带区域内皮型一氧化氮合酶（eNOS）的磷酸化。在神经元-内皮细胞共培养物中，PMS促进了OGD后的一氧化氮产生。这些发现表明，SR抑制在NVU中起神经保护作用，并改善中风后CBF异常。因此，药物性SR抑制具有潜在的临床应用价值。
