Drury Paul P, Davidson Joanne O, Mathai Sam, van den Heuij Lotte G, Ji Haitao, Bennet Laura, Tan Sidhartha, Silverman Richard B, Gunn Alistair J
Department of Physiology, University of Auckland, Auckland, New Zealand.
Department of Chemistry, Department of Molecular Biosciences, Chemistry of Life Processes Institute, Center for Molecular Innovation and Drug Discovery, Northwestern University, Evanston, IL 60208-3113, USA; Department of Chemistry, University of Utah, Salt Lake City, UT, USA.
Neuropharmacology. 2014 Aug;83:62-70. doi: 10.1016/j.neuropharm.2014.03.017. Epub 2014 Apr 12.
Basal ganglia injury after hypoxia-ischemia remains common in preterm infants, and is closely associated with later cerebral palsy. In the present study we tested the hypothesis that a highly selective neuronal nitric oxide synthase (nNOS) inhibitor, JI-10, would improve survival of striatal phenotypic neurons after profound asphyxia, and that the subsequent seizure burden and recovery of EEG are associated with neural outcome. 24 chronically instrumented preterm fetal sheep were randomized to either JI-10 (3 ml of 0.022 mg/ml, n = 8) or saline (n = 8) infusion 15 min before 25 min complete umbilical cord occlusion, or saline plus sham-occlusion (n = 8). Umbilical cord occlusion was associated with reduced numbers of calbindin-28k-, GAD-, NPY-, PV-, Calretinin- and nNOS-positive striatal neurons (p < 0.05 vs. sham occlusion) but not ChAT-positive neurons. JI-10 was associated with increased numbers of calbindin-28k-, GAD-, nNOS-, NPY-, PV-, Calretinin- and ChAT-positive striatal neurons (p < 0.05 vs. saline + occlusion). Seizure burden was strongly associated with loss of calbindin-positive cells (p < 0.05), greater seizure amplitude was associated with loss of GAD-positive cells (p < 0.05), and with more activated microglia in the white matter tracts (p < 0.05). There was no relationship between EEG power after 7 days recovery and total striatal cell loss, but better survival of NPY-positive neurons was associated with lower EEG power. In summary, these findings suggest that selective nNOS inhibition during asphyxia is associated with protection of phenotypic striatal projection neurons and has potential to help reduce basal ganglia injury in some premature babies.
缺氧缺血后基底神经节损伤在早产儿中仍然很常见，并且与后期的脑瘫密切相关。在本研究中，我们测试了以下假设：一种高度选择性的神经元型一氧化氮合酶（nNOS）抑制剂JI-10，将改善深度窒息后纹状体表型神经元的存活，并且随后的癫痫发作负担和脑电图恢复与神经结局相关。24只长期植入仪器的早产胎羊在完全脐带闭塞25分钟前15分钟被随机分为JI-10组（0.022mg/ml的3ml，n = 8）或生理盐水组（n = 8）输注，或生理盐水加假闭塞组（n = 8）。脐带闭塞与钙结合蛋白-28k、谷氨酸脱羧酶（GAD）、神经肽Y（NPY）、小白蛋白（PV）、钙视网膜蛋白和nNOS阳性纹状体神经元数量减少有关（与假闭塞相比，p < 0.05），但与胆碱乙酰转移酶（ChAT）阳性神经元无关。JI-10与钙结合蛋白-28k、GAD、nNOS、NPY、PV、钙视网膜蛋白和ChAT阳性纹状体神经元数量增加有关（与生理盐水加闭塞相比，p < 0.05）。癫痫发作负担与钙结合蛋白阳性细胞的丢失密切相关（p < 0.05），更大的癫痫发作幅度与GAD阳性细胞的丢失有关（p < 0.05），并且与白质束中更多活化的小胶质细胞有关（p < 0.05）。恢复7天后的脑电图功率与纹状体总细胞丢失之间没有关系，但NPY阳性神经元更好的存活与较低的脑电图功率有关。总之，这些发现表明，窒息期间选择性nNOS抑制与表型纹状体投射神经元的保护有关，并且有可能帮助减少一些早产儿的基底神经节损伤。
