TrkB Receptor Agonist 7, 8 Dihydroxyflavone Triggers Profound Gender-Dependent Neuroprotection in Mice After Perinatal Hypoxia and Ischemia

• Type of Material: Article
• Authors: Kutluay Uluc, University of Wisconsin; Pinar Kendigelen, University of Wisconsin; Emin Fidan, University of Wisconsin; Louise Zhang, University of Wisconsin; Vishal Chanana, University of Wisconsin; Douglas Kintner, University of Wisconsin; Erinc Aktuere, University of Wisconsin; Chihwa Song, University of Wisconsin; Keqiang Ye, Emory University; Dandan Sun, University of Pittsburgh; Peter Ferrazzano, University of Wisconsin; Pelin Cengiz, University of Wisconsin
• Language: English
• Date: 2013-05-01
• Publisher: Bentham Science Publishers
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2013 Bentham Science Publishers.
• Final Published Version (URL): http://dx.doi.org/10.2174/18715273113129990061
• Title of Journal or Parent Work: CNS and Neurological Disorders - Drug Targets
• ISSN: 1871-5273
• Volume: 12
• Issue: 3
• Start Page: 360
• End Page: 370
• Grant/Funding Information: University of Wisconsin Department of Pediatrics Research & Development Grant (Cengiz P); 9U54TR000021 from the Clinical and Translational Science Award program of NCATS (Cengiz P & Ferrazzano P); NIH grants RO1NS38118 and RO1NS48216 (Sun D); NIH grant NIH RO1 DC010204 (Ye K); and NIH P30 HD03352 (Waisman Center).
• Keywords: Neurosciences & Neurology; rotarod test; 7,8 dihydroxyflavone (7,8 DHF); BRAIN; Neurosciences; fractional anisotropy; SURVIVAL; BDNF; Pharmacology & Pharmacy; Life Sciences & Biomedicine; STROKE; EXPRESSION; Tyrosine kinase B (TrkB); Morris water maze test; brain derived neurotropic factor (BDNF); FULL-LENGTH; Science & Technology; NEUROTROPHIC FACTOR
• Research Categories: Biology, Neuroscience; Health Sciences, Pathology

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.