目的 观察高压氧对缺氧缺血性脑损伤新生大鼠脑皮质线粒体生物合成的影响及其相关信号通路。方法 新生7日龄Wistar大鼠48只随机分为假手术组(Sham,16只),HIBD模型组(HIBD,16只)和高压氧治疗HIBD组(HBO+HIBD,16只)。结扎左侧颈总动脉后暴露于92% 氮气和8%氧气缺氧环境中2 h 制备HIBD 模型。HIBD +HBO 组在缺氧缺血后给予高压氧干预,每次持续90 min,每日1次,连续7 d。末次高压氧干预后24 h,每组动物随机抽取8只处死,检测脑皮质COXⅣ、PGC-1α、Tfam和NRF1表达。剩余动物饲养至40日龄进行Morris水迷宫检测。结果 HBO+HIBD组与HIBD组比较,逃避潜伏期显著缩短[(21.49 ±3.77)s vs (42.50±6.46)s,P<0.01],穿越平台次数、COXⅣ、PGC-1α、Tfam和NRF1表达均显著升高[分别为(7.41±1.13)次 vs (5.26±0.78)次,(82.15±14.84)kPa vs (62.83±11.02)kPa,(112.19±18.41)kPa vs (67.26±10.40)kPa,(92.15±13.99)kPa vs (76.40±9.32)kPa和(72.29±12.88)kPa vs (49.28±7.14)kPa,P<0.05~0.01]。结论 高压氧可通过上调PGC-1过-NRF1/Tfam通路促进脑皮质线粒体生物合成,从而改善大鼠HIBD后空间学习记忆能力。
Abstract
Objective To observe the effect of hyperbaric oxygenation on mitochondrial biogenesis and related signal pathways in the cerebral cortex of neonatal rats after hypoxic ischemic brain damage.Methods Forty-eight 7-day postnatal Wistar rats were randomly divided into 3 groups: sham operation group (Sham, n=16), hypoxic-ischemic brain damage group (HIBD,n=16) and hyperbaric oxygenation treated group (HBO+HIBD, n=16). An HIBD model was established via ligation of the right common carotid artery followed by hypoxia exposure (8%O2+92%N2) for two hours. In HBO+HIBD group, rats received hyperbaric oxygenation (90 min a day, for 7 consecutive days) after HIBD.Eight rats in each group were sacrificed at 24 h after HBO, and the cerebral cortex was used to detect the expressions of COXⅣ, PGC-1α, Tfam and NRF1. Other rats were tested with Morris water maze at 40 days old.Results As compared with HIBD group, the escape latency in HBO+HIBD group was obviously shorter(21.49±3.77 vs 42.50±6.46,P<0.01). The number of times of crossing the platform and the expressions of COXⅣ, PGC-1α, Tfam, and NRF1 were significantly increased (7.41±1.13 vs 5.26±0.78, 82.15±14.84 vs 62.83±11.02, 112.19±18.41 vs 67.26±10.40, 92.15±13.99 vs 76.40±9.32, and 72.29±12.88 vs 49.28±7.14, respectively, P<0.05~0.01).Conclusions Hyperbaric oxygenation can ameliorate spatial learning and memory impairment in neonatal rats after HIBD. The protective mechanism of HBO may be related to the promotion of PGC-1a-NRF1/Tfam mediated mitochondrial biogenesis in the cerebral cortex.
关键词
高压氧 /
新生大鼠 /
缺氧缺血性脑损伤 /
PGC-1脑 /
线粒体生物合成
Key words
hyperbaric oxygenation /
neonatal rats /
hypoxic ischemic brain damage /
PGC-1 /
mitochondrial biogenesis
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参考文献
[1] Nabetani M, Shintaku H, Hamazaki T.Future perspectives of cell therapy for neonatal hypoxic-ischemic encephalopathy[J]. Pediatr Res, 2018,83(1):356-363.
[2] Wei L, Ren Q, Zhang Y, et al. Effects of hyperbaric oxygen and nerve growth factor on the long-term neural behavior of neonatal rats with hypoxic ischemic brain damage[J]. Acta Cir Bras, 2017, 32(4): 270-279.
[3] Lu Y, Tucker D, Dong Y, et al. Role of mitochondria in neonatal hypoxic-ischemic brain injury[J]. J Neurosci Rehabil, 2015, 2(1): 1-14.
[4] 张小春, 黑明燕, 罗娅丽, 等. 高压氧对缺氧缺血1周内新生大鼠脑皮质细胞线粒体膜电势的影响[J]. 中国循证儿科杂志, 2014, 9(3): 211-215.
[5] Vaarmann A, Mandel M, Zeb A, et al. Mitochondrial biogenesis is required for axonal growth[J]. Development, 2016, 143(11): 1981-1992.
[6] Golpich M, Amini E, Mohamed Z, et al. Mitochondrial dysfunction and biogenesis in neurodegenerative diseases: pathogenesis and treatment[J]. CNS Neurosci Ther, 2017, 23(1): 5-22.
[7] Demarest T G, Schuh R A, Waddell J, et al. Sex-dependent mitochondrial respiratory impairment and oxidative stress in a rat model of neonatal hypoxic-ischemic encephalopathy[J]. J Neurochem, 2016, 137(5): 714-729.
[8] You Y, Hou Y, Zhai X, et al. Protective effects of PGC-1alpha via the mitochondrial pathway in rat brains after intracerebral hemorrhage[J]. Brain Res, 2016, 1646: 34-43.
[9] Sosunov S A, Ameer X, Niatsetskaya Z V, et al. Isoflurane anesthesia initiated at the onset of reperfusion attenuates oxidative and hypoxic-ischemic brain injury[J]. PLoS One, 2015, 10(3): e0120456.
[10] Eisele P S, Salatino S, Sobek J, et al. The peroxisome proliferator-activated receptor gamma coactivator 1alpha/beta (PGC-1) coactivators repress the transcriptional activity of NF-kappaB in skeletal muscle cells[J]. J Biol Chem, 2013, 288(4): 2246-2260.
[11] Gu Y, Zhang Y, Bi Y, et al. Mesenchymal stem cells suppress neuronal apoptosis and decrease IL-10 release via the TLR2/NFkappaB pathway in rats with hypoxic-ischemic brain damage[J]. Mol Brain, 2015, 8(1): 65.
[12] Choi K H, Park M S, Kim H S, et al. Alpha-lipoic acid treatment is neurorestorative and promotes functional recovery after stroke in rats[J]. Mol Brain, 2015, 8: 9.
[13] Susilo I, Devi A, Purwandhono A, et al. Effects of hyperbaric oxygen therapy on the increase of iNOS and NFKB expressions and the acceleration of wound healing process during inflammation and proliferation phases[J]. J Appl Environ Biol Sci, 2016, 6(9): 105-110.
[14] Singh S P, Schragenheim J, Cao J, et al. PGC-1 alpha regulates HO-1 expression, mitochondrial dynamics and biogenesis: role of epoxyeicosatrienoic acid[J]. Prostaglandins Other Lipid Mediat, 2016, 125: 8-18.
[15] Zhu M, Lu M, Li Q J, et al. Hyperbaric oxygen suppresses hypoxic-ischemic brain damage in newborn rats[J]. J Child Neurol, 2015, 30(1): 75-82.
