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Author Notes:

Corresponding author: Ting-Ting Huang, PhD, 3801 Miranda Avenue, Mail Stop 154I, Building 100, D3-101, Palo Alto, CA 94304, Phone (650) 496-2581, tthuang@stanford.edu

We thank Hsun Yang and Melody Khosravi for technical assistance in tissue processing, and Huy Nugyen for critical reading of the manuscript and assistance in graphical design.

Subjects:

Research Funding:

This work was supported by funding from the Department of Veterans Affairs Merit review BX-0024-71 (to TTH), National Institutes of Health Grant NS046051 (to JRF), and the resources and facilities at the Veteran’s Affairs Palo Alto Health Care System.

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Neurosciences
  • Neurosciences & Neurology
  • Cognitive function
  • TrkB
  • Irradiation
  • Neurogenesis
  • Synaptic plasticity
  • Hippocampus
  • ADULT HIPPOCAMPAL NEUROGENESIS
  • ACUTE LYMPHOBLASTIC-LEUKEMIA
  • NEUROTROPHIC FACTOR
  • MOUSE MODEL
  • SYNAPTIC PLASTICITY
  • ALZHEIMERS-DISEASE
  • SIGNALING PATHWAYS
  • RADIATION-THERAPY
  • OXIDATIVE STRESS
  • GRANULE CELLS

Cognitive impairments following cranial irradiation can be mitigated by treatment with a tropomyosin receptor kinase B agonist

Journal Title:

Experimental Neurology

Volume:

Volume 279

Publisher:

, Pages 178-186

Type of Work:

Article | Post-print: After Peer Review

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 3 months 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.

Copyright information:

© 2015 Published by Elsevier Inc.

This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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