期刊
JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM
卷 27, 期 7, 页码 1339-1351出版社
SAGE PUBLICATIONS INC
DOI: 10.1038/sj.jcbfm.9600440
关键词
cardiac arrest; DARPP-32; global cerebral ischemia; Na,K-ATPase; neonate; nitric oxide; nitrotyrosine; NMDA receptor; peroxynitrite
资金
- NINDS NIH HHS [NS20020, P01 NS020020] Funding Source: Medline
Dopamine receptors regulate glutamatergic neurotransmission and Na+,K+-ATPase via protein kinase A (PKA) and dopamine- and cAMP-regulated phosphoprotein of 32kDa (DARPP-32)-dependent signaling. Consequently, dopamine receptor activation may modulate neonatal hypoxic-ischemic (H-I) neuronal damage in the selectively vulnerable putamen enriched with dopaminergic receptors. Piglets subjected to two durations of hypoxia followed by asphyxic cardiac arrest were treated with a D1-like (SCH23390) or D2-like (sulpiride) receptor antagonist. At 4 days of recovery from less severe H-I, the remaining viable neurons in putamen were 60% of control, but nearly completely salvaged by pretreatment with SCH23390 or sulpiride. After more severe H-I in which only 18% of neurons were viable, partial neuroprotection was seen with SCH23390 pretreatment (50%) and posttreatment (39%) and with sulpirlde pretreatment (35%), but not with sulpiride posttreatment (24%). Dopamine was significantly elevated in microdialysis samples from putamen during asphyxia and the first 15mins of reoxygenation. Pretreatment with SCH23390 or sulpiride largely attenuated the increased nitrotyrosine and the decreased Na+,K+-ATPase activity that occurred at 3 h after severe H-I. Pretreatment with SCH23390, but not sulpiride, also attenuated H-I-induced increases in PKA-dependent phosphorylation of Thr34 on DARPP-32, Ser943 on the alpha subunit of Na+,K+-ATPase, and Ser897 of the N-methyl-D-aspartate (NMDA) receptor NR1 subunit. These findings indicate that D1 and D2 dopamine receptor activation contribute to neuronal death in newborn putamen after H-I in association with increased protein nitration and decreased Na+, K+, ATPase activity. Furthermore, mechanisms of D1 receptor toxicity
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据