Title: Suppression of microglia activation after hypoxia-ischemia results in age-dependent improvements in neurologic injury.
Legend: Figure 1. Minocycline treatment suppresses the microglial response to hypoxia-ischemia (HI) in neonatal and juvenile mice. The number of CD11b+/CD45+ cells in ipsilateral hippocampus (A) cortex (B), and striatum (C) relative to the corresponding contralateral brain region (IL/CL) were determined using flow cytometry at either day 2 (D2) or day 9 (D9) post-HI in neonatal (P9) and juvenile (P30) mice treated with minocycline or vehicle. Data are mean ± sem. * = p < 0.05 vs untreated. n = 3 samples. Figure 2. Minocycline treatment improves neurologic injury early after HI in neonatal mice.A. Representative whole brain slices from P9 and P30 brains at day 2 post-HI with and without minocycline treatment are shown. Arrow: loss of hippocampal volume and MAP2 staining in the non-treated mice. B. Summary of neurological damage scores in P9 and P30 brains at day 2 (D2) and day 9 (D9) post-HI with and without minocycline treatment. * = p < 0.05 vs corresponding untreated. n = 8-14. Figure 3. Minocycline treatment results in sustained improvements in memory and learning in juvenile but not neonatal mice. Mice were subjected to HI at P9 or P30 with and without minocycline treatment and Morris water maze MWM testing was performed at 60 days post-HI. Time to platform over the four days of training in sham, HI and HI + minocycline-treated is shown for P9 (A) and P30 (B) mice. Data are mean ± sem. n = 9-12 * p < 0.05 vs Day 1 value. Summary of platform crossings for each quadrant in sham, HI and HI + minocycline-treated is shown for P9 (C) and P30 (D) mice. Q1 = Training Quadrant; *p<0.05, n=9-12.
Citation: Cikla U, Chanana V, Kintner D, Covert C, Dewall T, Waldman A, Rowley P, Cengiz P, Ferrazzano P. (2016) Suppression of microglia activation after hypoxia-ischemia results in age-dependent improvements in neurologic injury. Journal of Neuroimmunology, 291:18-27. PMC4748173.
Abstract: We have 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 minocycline-treated 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.