Title: Suppression of microglia activation after hypoxia-ischemia results in age-dependent improvements in neurologic injury.
Legend: P9 and P30 mice were exposed to unilateral hypoxia-ischemia and treated with minocycline or vehicle. A, B. Double immunohistological staining for Iba1 (green) and MAP2 (red) proteins in the CA1 region of the hippocampus at 2 days post-HI is shown. Nuclei were stained with DAPI (blue). The contralateral hippocampi demonstrate microglia with ramified morphology characteristic of quiescent microglia. Ipsilateral hippocampi of P9 and P30 brains treated with vehicle demonstrate microglial proliferation and an activated, amoeboid morphology. Minocycline treatment suppressed microglial activation in ipsilateral hippocampus in the P9 and P30 mice. Insets: magnification (240X) of representative microglia demonstrating either ramified (arrow) or amoeboid (arrowhead) morphology. C. Representative T2-weighted images from P9 and P30 Sham, HI, HI + minocycline-treated mice at 60 days post-HI. HI resulted in cerebral atrophy in ipsilateral hemisphere as demonstrated by ventriculomegaly and cortical thinning in both age-groups. Minocycline treatment resulted in improved atrophy in only P30 mice. D. Summary figure of T2-weighted IL/CL hemispheric volumes from P9 and P30 mice with and without minocycline treatment at day 60 post-HI. Data are mean ± sem. * p<0.05 vs. sham, n = 5-8 treated and controls, 4-9 shams.
Citation: U. Cikla, V. Chanana, D. Kintner , L. Cover , T. Dewall, A. Waldman, P. Rowley, P. Cengiz, P. Ferrazzano. J. of Neuroimmunology (2015) under review
Abstract: We previously described regional and age-dependent differences in the microglial response to hypoxia-ischemia (HI). The aim of the current study was to assess for differences in the effect of microglial suppression on HI-induced brain injury in infant and juvenile mice. HI was induced in P9 and P30 mice and minocycline or vehicle was administered at 2 hours and 24 hours post-HI. P9 minocycline-treated mice demonstrated early improvements in neuronal injury; however no improvement in cerebral atrophy or Morris-Water-Maze was seen at 60 days post-HI. Conversely, P30 mice demonstrated significant improvement in cerebral atrophy and Morris Water Maze performance at 60 days post-HI.
About the investigator: By identifying MRI biomarkers in animal models of pediatric brain injury, Ferrazzano hopes to provide a means for selecting the patients most likely to benefit from a particular neuroprotective intervention in subsequent clinical trials. Basing patient selection on the physiologic target of therapy rather than simply the disease state will reduce the sample size needed, increase the likelihood of observing a drug effect, and facilitate the translation of promising neuroprotective interventions into clinical use.