title: Cognitive impairments following cranial irradiation can be mitigated by treatment with a tropomyosin receptor kinase B agonist.
abstract: Brain radiotherapy is frequently used successfully to treat brain tumors. However, radiotherapy is often associated with declines in short-term and long-term memory, learning ability, and verbal fluency. We previously identified a downregulation of the brain-derived neurotrophic factor (BDNF) following cranial irradiation in experimental animals. In the present study, we investigated whether targeting the BDNF high affinity receptor, tropomysin receptor kinase B (TrkB), could mitigate radiation-induced cognitive deficits. After irradiation, chronic treatment with a small molecule TrkB agonist, 7,8-dihydroxyflavone (DHF) in mice led to enhanced activation of TrkB and its downstream targets ERK and AKT, both important factors in neuronal development. DHF treatment significantly restored spatial, contextual, and working memory, and the positive effects persisted for at least 3months after completion of the treatment. Consistent with preservation of cognitive functions, chronic DHF treatment mitigated radiation-induced suppression of hippocampal neurogenesis. Spine density and major components of the excitatory synapses, including glutamate receptors and postsynaptic density protein 95 (PSD-95), were also maintained at normal levels by DHF treatment after irradiation. Taken together, our results show that chronic treatment with DHF after irradiation significantly mitigates radiation-induced cognitive defects. This is achieved most likely by preservation of hippocampal neurogenesis and synaptic plasticity.
authors.affiliation: Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA; Palo Alto Veterans Institute for Research, Palo Alto, CA 94304, USA.
authors.forename: Phillip
authors.initials: P
authors.lastname: Yang
authors.affiliation: Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA; Palo Alto Veterans Institute for Research, Palo Alto, CA 94304, USA.
authors.forename: David
authors.initials: D
authors.lastname: Leu
authors.affiliation: Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA 30322, USA.
authors.forename: Keqiang
authors.initials: K
authors.lastname: Ye
authors.affiliation: Department of Chemistry and Biochemistry, California State University Fullerton, CA 92831, USA.
authors.forename: Chandra
authors.initials: C
authors.lastname: Srinivasan
authors.affiliation: Brain and Spinal Injury Center, Department of Neurological Surgery, University of California, San Francisco, CA 94143, USA.
authors.forename: John R
authors.initials: JR
authors.lastname: Fike
authors.affiliation: Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA; Geriatric Research, Education, and Clinical Center, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA 94304, USA. Electronic address: tthuang@stanford.edu.
authors.forename: Ting-Ting
authors.initials: TT
authors.lastname: Huang
mesh_terms: D000818:Animals; D001921:Brain / Q000528:radiation effects*; D019208:Brain-Derived Neurotrophic Factor / Q000096:biosynthesis; D003072:Cognition Disorders / Q000188:drug therapy* / Q000209:etiology*; D015536:Down-Regulation / Q000528:radiation effects; D047309:Flavones / Q000494:pharmacology; D006624:Hippocampus / Q000473:pathology / Q000528:radiation effects; D008297:Male; D008570:Memory, Short-Term / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D020929:Mitogen-Activated Protein Kinase Kinases / Q000187:drug effects; D055495:Neurogenesis / Q000528:radiation effects; D009473:Neuronal Plasticity / Q000187:drug effects; D051058:Oncogene Protein v-akt / Q000187:drug effects; D011832:Radiation Injuries / Q000188:drug therapy* / Q000473:pathology; D020813:Receptor, trkB / Q000819:agonists*; D017470:Receptors, Glutamate / Q000187:drug effects; D065852:Spatial Memory / Q000187:drug effects; D013569:Synapses / Q000187:drug effects / Q000528:radiation effects
chemical_list: C485383:6,7-dihydroxyflavone; D019208:Brain-Derived Neurotrophic Factor; D047309:Flavones; D017470:Receptors, Glutamate; D020813:Receptor, trkB; D051058:Oncogene Protein v-akt; D020929:Mitogen-Activated Protein Kinase Kinases
keywords: Cognitive function; Hippocampus; Irradiation; Neurogenesis; Synaptic plasticity; TrkB