Samaiya Puneet K, Narayan Gopeshwar, Kumar Ashok, Krishnamurthy Sairam
Neurotherapeutics Lab, Department of Pharmaceutics, Indian Institute of Technology (Banaras Hindu University), Varanasi 221005, India.
Department of Molecular and Human Genetics, Banaras Hindu University, Varanasi 221005, India.
J Neurol Sci. 2017 Apr 15;375:58-67. doi: 10.1016/j.jns.2017.01.021. Epub 2017 Jan 7.
Anoxia leads to a robust generation of reactive oxygen species/nitrogen species which can result in mitochondrial dysfunction and associated cell death in the cerebral cortex of neonates.
The present study investigated the pharmacological role of tempol in the treatment of rat neonatal cortical mitochondrial dysfunction induced insult progression (day-1 to day-7) and associated neurobehavioral alterations post-anoxia.
Rat pups of 30h age or postnatal day 2 (PND2) were randomly divided into 5 groups (n=5 per group): (1) Control; (2) Anoxia; (3) Anoxia+Tempol 75mg/kg; (4) Anoxia+Tempol 150mg/kg; and (5) Anoxia+Tempol 300mg/kg, and subjected to two episode of anoxia (10min each) at 24h of time interval in an enclosed chamber supplied with 100% N.
Tempol significantly decreased nitric oxide (NO) formation and simultaneously improved superoxide dismutase (SOD) and catalase (CAT) activities. Further, we observed a significantly (P<0.05) improvement in mitochondrial respiration, complex enzyme activities, mitochondrial membrane potential (MMP) along with attenuation of transition pore opening (MPT) after treatment with tempol. Furthermore, tempol decreased expression of mitochondrial Bax, cytochrome-C, caspase-9 and caspase-3 while the increase in expression of cytoplasmic Bax, mitochondrial Bcl-2 on day-7 in cortical region indicating regulation of intrinsic pathway of apoptosis. Further, it improved anoxia-induced neurobehavioral outcome (hanging and reflex latencies).
Biochemical, molecular and behavioral studies suggest the role of tempol in preserving mitochondrial function and associated neurobehavioral outcomes after neonatal anoxia.
缺氧会导致大量活性氧/氮物种的产生，这可能会导致新生儿大脑皮层线粒体功能障碍及相关细胞死亡。
本研究调查了Tempol在治疗大鼠新生儿皮质线粒体功能障碍诱导的损伤进展（第1天至第7天）以及缺氧后相关神经行为改变中的药理作用。
30小时龄或出生后第2天（PND2）的幼鼠被随机分为5组（每组n = 5）：（1）对照组；（2）缺氧组；（3）缺氧+75mg/kg Tempol组；（4）缺氧+150mg/kg Tempol组；（5）缺氧+300mg/kg Tempol组，并在充满100%氮气的封闭舱内，每隔24小时进行两次缺氧发作（每次10分钟）。
Tempol显著降低了一氧化氮（NO）的生成，同时提高了超氧化物歧化酶（SOD）和过氧化氢酶（CAT）的活性。此外，我们观察到，用Tempol治疗后，线粒体呼吸、复合酶活性、线粒体膜电位（MMP）有显著改善（P<0.05），同时过渡孔开放（MPT）减弱。此外，Tempol降低了线粒体Bax、细胞色素C、半胱天冬酶-9和半胱天冬酶-3的表达，而在皮质区域第7天细胞质Bax、线粒体Bcl-2的表达增加，表明对凋亡内在途径有调节作用。此外，它改善了缺氧诱导的神经行为结果（悬吊和反射潜伏期）。
生化、分子和行为学研究表明，Tempol在新生儿缺氧后保护线粒体功能及相关神经行为结果中发挥作用。
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