Urabe Takao
Department of Neurology, Juntendo University.
Rinsho Shinkeigaku. 2012;52(11):908-10. doi: 10.5692/clinicalneurol.52.908.
Brain white matter lesions (WMLs), which are often observed in patients with ischemic cerebrovascular diseases, contribute to cognitive decline. We analyzed the pathologic and regenerative processes in brain white matter lesions of patients diagnosed with vascular dementia. There was a significant increase in the number of oligodendrocyte progenitor cells (OPCs) in the brains of patients with vascular dementia as well as in rats with cerebral hypoperfusion. WMLs can be induced experimentally by bilateral common carotid artery ligation (BCCAL) of rats to cause chronic cerebral ischemia. After chronic cerebral hypoperfusion injury, oxygen free radicals and activated microglia acting as inflammatory elements contribute to chronic cerebral hypoperfusion-induced WMLs. The cell death of oligodendrocytes (OLGs) contributes directly to WMLs. The activation for intracellular signaling pathway of cAMP responsive element binding protein (CREB) phosphorylation in the white matter was suppressed after BCCAL. Type III phosphodiesterase inhibitor (PDE3-I) has potential therapeutic and brain-protective effects based on multitarget mechanism through cell signaling pathway of CREB phosphorylation. The OPCs subsequently underwent cell death and the number of OLGs decreased. In the rat model, PDE3-I prevented cell death, markedly increased the mature OLGs, and promoted restoration of white matter and recovery of cognitive decline.
脑白质病变（WMLs）常见于缺血性脑血管疾病患者，可导致认知功能下降。我们分析了被诊断为血管性痴呆患者脑白质病变中的病理和再生过程。血管性痴呆患者以及脑灌注不足大鼠的大脑中少突胶质前体细胞（OPCs）数量显著增加。可通过大鼠双侧颈总动脉结扎（BCCAL）诱导实验性WMLs，以引起慢性脑缺血。慢性脑灌注不足损伤后，作为炎症因子的氧自由基和活化的小胶质细胞会导致慢性脑灌注不足诱导的WMLs。少突胶质细胞（OLGs）的细胞死亡直接导致WMLs。BCCAL后，白质中cAMP反应元件结合蛋白（CREB）磷酸化的细胞内信号通路激活受到抑制。III型磷酸二酯酶抑制剂（PDE3-I）基于通过CREB磷酸化的细胞信号通路的多靶点机制具有潜在的治疗和脑保护作用。随后OPCs发生细胞死亡，OLGs数量减少。在大鼠模型中，PDE3-I可防止细胞死亡，显著增加成熟OLGs数量，并促进白质恢复和认知功能下降的恢复。
