Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
J Pineal Res. 2011 Mar;50(2):159-70. doi: 10.1111/j.1600-079X.2010.00825.x. Epub 2010 Nov 9.
Acute bacterial meningitis caused by Klebsiella pneumoniae (K. pneumoniae) is a major health threat with a high mortality rate and severe neuro-cognitive sequelae. The intense pro-inflammatory cytokine released from calcium-mediated microglial activation plays an important role in eliciting neuronal damage in the hippocampal region. Considering melatonin possesses anti-inflammatory and immuno-modulatory properties, the present study determined whether melatonin can effectively decrease inflammatory responses and prevent hippocampal damage in animals subjected to K. pneumoniae. Adult rats inoculated with K. pneumoniae received a melatonin injection immediately thereafter at doses of 5, 25, 50, or 100 mg/kg. Following 24 h of survival, all experimental animals were processed for time-of-flight secondary ion mass spectrometry (for detecting glial calcium intensity), isolectin-B4 histochemistry (reliable marker for microglial activation), pro-inflammatory cytokine measurement as well as cytochrome oxidase and in situ dUTP end-labeling (representing neuronal bio-energetic status and apoptotic changes, respectively). Results indicate that in K. pneumoniae-infected rats, numerous calcium-enriched microglia, enhanced pro-inflammatory cytokine, and various apoptotic neurons with low bio-energetic activity were detected in hippocampus. Following melatonin administration, however, all parameters including glial calcium intensity, microglial activation, pro-inflammatory cytokine levels, and number of apoptotic neurons were successfully decreased with maximal change observed at a melatonin dose of 100 mg/kg. Enzymatic data corresponded well with above findings in which all surviving neurons displayed high bio-energetic activity. As effectively reducing glia-mediated inflammatory response is neuro-protective to hippocampal neurons, the present study supports the clinical use of melatonin as a potential therapeutic agent to counteract K. pneumoniae meningitis-induced neuro-cognitive damage.
肺炎克雷伯菌（Klebsiella pneumoniae，K. pneumoniae）引起的急性细菌性脑膜炎是一种严重的健康威胁，具有高死亡率和严重的神经认知后遗症。钙介导的小胶质细胞激活释放的强烈促炎细胞因子在引发海马区神经元损伤中发挥重要作用。鉴于褪黑素具有抗炎和免疫调节特性，本研究旨在确定褪黑素是否能有效降低炎症反应并预防 K. pneumoniae 感染动物的海马损伤。成年大鼠接种 K. pneumoniae 后，立即给予褪黑素注射，剂量分别为 5、25、50 或 100mg/kg。存活 24 小时后，所有实验动物均进行飞行时间二次离子质谱（用于检测神经胶质钙强度）、异硫氰酸荧光素-B4 组织化学（小胶质细胞激活的可靠标志物）、促炎细胞因子测定以及细胞色素氧化酶和原位 dUTP 末端标记（分别代表神经元生物能量状态和凋亡变化）。结果表明，在 K. pneumoniae 感染大鼠的海马区，检测到大量富含钙的小胶质细胞、增强的促炎细胞因子和各种具有低生物能量活性的凋亡神经元。然而，褪黑素给药后，所有参数（包括神经胶质钙强度、小胶质细胞激活、促炎细胞因子水平和凋亡神经元数量）均成功降低，在褪黑素剂量为 100mg/kg 时观察到最大变化。酶学数据与上述发现相符，所有存活的神经元均显示出高生物能量活性。由于有效降低神经胶质介导的炎症反应对海马神经元具有神经保护作用，本研究支持褪黑素作为一种潜在治疗药物用于对抗 K. pneumoniae 脑膜炎引起的神经认知损伤的临床应用。
