title: TrkB receptor agonist 7, 8 dihydroxyflavone triggers profound gender- dependent neuroprotection in mice after perinatal hypoxia and ischemia.
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.
authors.affiliation: Department of Pediatrics, University of Wisconsin-Madison, School of Medicine and Public Health, Madison, WI 53705, USA.
authors.forename: Kutluay
authors.initials: K
authors.lastname: Uluc
authors.forename: Pınar
authors.initials: P
authors.lastname: Kendigelen
authors.forename: Emin
authors.initials: E
authors.lastname: Fidan
authors.forename: Louise
authors.initials: L
authors.lastname: Zhang
authors.forename: Vishal
authors.initials: V
authors.lastname: Chanana
authors.forename: Douglas
authors.initials: D
authors.lastname: Kintner
authors.forename: Erinc
authors.initials: E
authors.lastname: Akture
authors.forename: Chihwa
authors.initials: C
authors.lastname: Song
authors.forename: Keqiang
authors.initials: K
authors.lastname: Ye
authors.forename: Dandan
authors.initials: D
authors.lastname: Sun
authors.forename: Peter
authors.initials: P
authors.lastname: Ferrazzano
authors.forename: Pelin
authors.initials: P
authors.lastname: Cengiz
mesh_terms: D000375:Aging; D000818:Animals; D002540:Cerebral Cortex / Q000378:metabolism / Q000473:pathology; D003337:Corpus Callosum / Q000473:pathology; D005260:Female; D047309:Flavones / Q000494:pharmacology* / Q000627:therapeutic use; D005911:Gliosis / Q000150:complications / Q000188:drug therapy; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D020925:Hypoxia-Ischemia, Brain / Q000150:complications / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D007858:Learning / Q000187:drug effects; D008297:Male; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D004676:Myelin Basic Protein / Q000378:metabolism; D009410:Nerve Degeneration / Q000188:drug therapy*; D009413:Nerve Fibers, Myelinated / Q000473:pathology; D059906:Neuroimaging; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D020813:Receptor, trkB / Q000819:agonists*; D020127:Recovery of Function / Q000187:drug effects; D012727:Sex Characteristics
chemical_list: C485383:6,7-dihydroxyflavone; D047309:Flavones; D008869:Microtubule-Associated Proteins; D004676:Myelin Basic Protein; D018696:Neuroprotective Agents; D020813:Receptor, trkB