Neurochemical Research Unit, Department of Psychiatry, University of Alberta, Edmonton, Alta., Canada.
J Psychiatry Neurosci. 2010 Jan;35(1):20-32. doi: 10.1503/jpn.090061.
Neonatal hypoxia-ischemia (HI) is a major cause of perinatal brain injury and is associated with a spectrum of neuropsychiatric disorders. Although very few treatment options are currently available, doxycycline (DOXY) has been reported to be neuroprotective in neontatal HI. Our objective was to investigate the effects of DOXY on neonatal brain development in normal and HI rat pups. We hypothesized that DOXY would inhibit microglial activation but that developmentally important processes, including cytogenesis and trophic responses, would not be impaired.
To investigate the putative neurodevelopmental consequences of DOXY administration in a clinically relevant animal model of HI, we performed a time-course analysis such that postnatal rat pups received DOXY (10mg/kg) or vehicle immediately before HI (n >or= 6). We then assessed cytogenesis, proinflammatory cytokines, brain-derived neurotrophic factor (BDNF) and matrix metalloproteinases regionally and longitudinally.
We found that DOXY significantly inhibits neuroinflammation in the frontal cortex, striatum and hippocampus; decreases interleukin-1Beta (IL-1Beta) and tumour necrosis factor-alpha (TNF-alpha); and augments BDNF following HI. In addition, DOXY-treated pups have significantly fewer 2-bromo-5-deoxyuridine (BrdU)-positive cells in the subventricular zone 6 hours post-HI. However, DOXY does not persistently affect cytogenesis in the subventricular zone or dentate gyrus up to 7 days post-HI. The BrdU-positive cells not expressing markers for mature neurons colabel with nestin, an intermediate filament protein typical of neuronal precursors.
Our study investigates "acute" neurodevelopment over the first 7 days of life after HI injury. Further long-term investigations into adulthood are underway.
Taken together, our results suggest the putative clinical potential of DOXY in the management of neonatal cerebral HI injury.
新生儿缺氧缺血（HI）是围产期脑损伤的主要原因，并与一系列神经精神疾病有关。虽然目前可用的治疗方法很少，但多西环素（DOXY）已被报道对新生儿 HI 具有神经保护作用。我们的目的是研究 DOXY 对正常和 HI 大鼠幼仔脑发育的影响。我们假设 DOXY 会抑制小胶质细胞的激活，但不会损害包括细胞发生和营养反应在内的发育重要过程。
为了在 HI 的临床相关动物模型中研究 DOXY 给药的潜在神经发育后果，我们进行了时间过程分析，使得新生大鼠幼仔在 HI 前立即接受 DOXY（10mg/kg）或载体（n>或=6）。然后，我们在区域和纵向水平上评估细胞发生、促炎细胞因子、脑源性神经营养因子（BDNF）和基质金属蛋白酶。
我们发现 DOXY 可显著抑制额皮质、纹状体和海马中的神经炎症；降低白细胞介素-1β（IL-1β）和肿瘤坏死因子-α（TNF-α）；并在 HI 后增强 BDNF。此外，与 HI 后 6 小时接受 DOXY 治疗的幼仔相比，少突胶质细胞前体细胞（OPC）的 BrdU 阳性细胞明显减少。然而，DOXY 不会持续影响 HI 后 7 天内的脑室下区或齿状回的细胞发生。BrdU 阳性细胞不表达成熟神经元标志物，与巢蛋白共标记，巢蛋白是神经元前体的中间丝蛋白。
我们的研究调查了 HI 损伤后前 7 天生命中的“急性”神经发育。进一步的成年期长期研究正在进行中。
综上所述，我们的结果表明 DOXY 在管理新生儿脑 HI 损伤方面具有潜在的临床潜力。
