Fan Lir-Wan, Lin Shuying, Pang Yi, Rhodes Philip G, Cai Zhengwei
Department of Pediatrics, Division of Newborn Medicine, University of Mississippi Medical Center, Jackson, 39216, USA.
Eur J Neurosci. 2006 Jul;24(2):341-50. doi: 10.1111/j.1460-9568.2006.04918.x. Epub 2006 Jul 12.
To investigate whether minocycline provides long-lasting protection against neonatal hypoxia-ischemia-induced brain injury and neurobehavioral deficits, minocycline was administered intraperitoneally in postnatal day 4 Sprague-Dawley rats subjected to bilateral carotid artery occlusion followed by exposure to hypoxia (8% oxygen for 15 min). Brain injury and myelination were examined on postnatal day 21 (P21) and tests for neurobehavioral toxicity were performed from P3 to P21. Hypoxic-ischemic insults resulted in severe white matter injury, enlarged ventricles, deficits in the hippocampus, reduction in numbers of mature oligodendrocytes and tyrosine hydroxylase-positive neurons, damage to axons and dendrites, and impaired myelination, as indicated by the decrease in myelin basic protein immunostaining in the P21 rat brain. Hypoxic-ischemic insult also significantly affected physical development (body weight gain and eye opening) and neurobehavioral performance, including sensorimotor and locomotor function, anxiety and cognitive ability in the P21 rat. Treatments with minocycline significantly attenuated the hypoxia-ischemia-induced brain injury and improved neurobehavioral performance. The protection of minocycline was associated with its ability to reduce microglial activation. The present results show that minocycline has long-lasting protective effects in the neonatal rat brain in terms of both hypoxia-ischemia-induced brain injury and the associated neurological dysfunction.
为研究米诺环素是否能对新生大鼠缺氧缺血性脑损伤及神经行为缺陷提供持久保护，对出生后第4天的Sprague-Dawley大鼠进行双侧颈动脉闭塞，随后暴露于低氧环境（8%氧气，持续15分钟），并腹腔注射米诺环素。在出生后第21天（P21）检查脑损伤和髓鞘形成情况，并在出生后第3天至第21天进行神经行为毒性测试。缺氧缺血性损伤导致严重的白质损伤、脑室扩大、海马体缺陷、成熟少突胶质细胞和酪氨酸羟化酶阳性神经元数量减少、轴突和树突损伤以及髓鞘形成受损，P21大鼠脑内髓鞘碱性蛋白免疫染色减少即表明了这一点。缺氧缺血性损伤还显著影响P21大鼠的身体发育（体重增加和睁眼）以及神经行为表现，包括感觉运动和运动功能、焦虑和认知能力。米诺环素治疗显著减轻了缺氧缺血性脑损伤并改善了神经行为表现。米诺环素的保护作用与其降低小胶质细胞激活的能力有关。目前的结果表明，米诺环素在新生大鼠脑内对缺氧缺血性脑损伤及相关神经功能障碍均具有持久的保护作用。
