Abstract
In this study, we investigated the effects of a bioactive high-affinity TrkB receptor agonist 7,8- dihydroxyflavone (7,8 DHF) on neonatal brain injury in female and male mice after hypoxia ischemia (HI). HI was induced by exposure of postnatal day 9 (P9) mice to 10% O2 for 50 minutes at 37°C after unilateral ligation of the left common carotid artery. Animals were randomly assigned to HI-vehicle control group [phosphate buffered saline (PBS), intraperitoneally (i.p.)] or HI + 7,8 DHF-treated groups (5 mg/kg in PBS, i.p at 10 min, 24 h, or with subsequent daily injections up to 7 days after HI). The HI-vehicle control mice exhibited neuronal degeneration in the ipsilateral hippocampus and cortex with increased Fluoro-Jade C positive staining and loss of microtubule associated protein 2 expression. In contrast, the 7,8 DHF-treated mice showed less hippocampal neurodegeneration and astrogliosis, with more profound effects in female than in male mice. Moreover, 7,8 DHF-treated mice improved motor learning and spatial learning at P30-60 compared to the HI-vehicle control mice. Diffusion tensor imaging of ex vivo brain tissues at P90 after HI revealed less reduction of fractional anisotropy values in the ipsilateral corpus callosum of 7,8 DHF-treated brains, which was accompanied with better preserved myelin basic protein expression and CA1 hippocampal structure. Taken together, these findings strongly suggest that TrkB agonist 7,8 DHF is protective against HI-mediated hippocampal neuronal death, white matter injury, and improves neurological function, with a more profound response in female than in male mice.
Keywords: Tyrosine kinase B (TrkB), 7, 8 dihydroxyflavone (7, 8 DHF), brain derived neurotropic factor (BDNF), rotarod test, Morris water maze test, fractional anisotropy.
CNS & Neurological Disorders - Drug Targets
Title:TrkB Receptor Agonist 7, 8 Dihydroxyflavone Triggers Profound Gender- Dependent Neuroprotection in Mice After Perinatal Hypoxia and Ischemia
Volume: 12 Issue: 3
Author(s): Kutluay Uluc, Pınar Kendigelen, Emin Fidan, Louise Zhang, Vishal Chanana, Douglas Kintner, Erinc Akture, Chihwa Song, Keqiang Ye, Dandan Sun, Peter Ferrazzano and Pelin Cengiz
Affiliation:
Keywords: Tyrosine kinase B (TrkB), 7, 8 dihydroxyflavone (7, 8 DHF), brain derived neurotropic factor (BDNF), rotarod test, Morris water maze test, fractional anisotropy.
Abstract: In this study, we investigated the effects of a bioactive high-affinity TrkB receptor agonist 7,8- dihydroxyflavone (7,8 DHF) on neonatal brain injury in female and male mice after hypoxia ischemia (HI). HI was induced by exposure of postnatal day 9 (P9) mice to 10% O2 for 50 minutes at 37°C after unilateral ligation of the left common carotid artery. Animals were randomly assigned to HI-vehicle control group [phosphate buffered saline (PBS), intraperitoneally (i.p.)] or HI + 7,8 DHF-treated groups (5 mg/kg in PBS, i.p at 10 min, 24 h, or with subsequent daily injections up to 7 days after HI). The HI-vehicle control mice exhibited neuronal degeneration in the ipsilateral hippocampus and cortex with increased Fluoro-Jade C positive staining and loss of microtubule associated protein 2 expression. In contrast, the 7,8 DHF-treated mice showed less hippocampal neurodegeneration and astrogliosis, with more profound effects in female than in male mice. Moreover, 7,8 DHF-treated mice improved motor learning and spatial learning at P30-60 compared to the HI-vehicle control mice. Diffusion tensor imaging of ex vivo brain tissues at P90 after HI revealed less reduction of fractional anisotropy values in the ipsilateral corpus callosum of 7,8 DHF-treated brains, which was accompanied with better preserved myelin basic protein expression and CA1 hippocampal structure. Taken together, these findings strongly suggest that TrkB agonist 7,8 DHF is protective against HI-mediated hippocampal neuronal death, white matter injury, and improves neurological function, with a more profound response in female than in male mice.
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Uluc Kutluay, Kendigelen Pınar, Fidan Emin, Zhang Louise, Chanana Vishal, Kintner Douglas, Akture Erinc, Song Chihwa, Ye Keqiang, Sun Dandan, Ferrazzano Peter and Cengiz Pelin, TrkB Receptor Agonist 7, 8 Dihydroxyflavone Triggers Profound Gender- Dependent Neuroprotection in Mice After Perinatal Hypoxia and Ischemia, CNS & Neurological Disorders - Drug Targets 2013; 12 (3) . https://dx.doi.org/10.2174/18715273113129990061
DOI https://dx.doi.org/10.2174/18715273113129990061 |
Print ISSN 1871-5273 |
Publisher Name Bentham Science Publisher |
Online ISSN 1996-3181 |
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