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Published Online: 17 December 2014

Targeted Overexpression of Mitochondrial Catalase Prevents Radiation-Induced Cognitive Dysfunction

Publication: Antioxidants & Redox Signaling
Volume 22, Issue Number 1

Abstract

Aims: Radiation-induced disruption of mitochondrial function can elevate oxidative stress and contribute to the metabolic perturbations believed to compromise the functionality of the central nervous system. To clarify the role of mitochondrial oxidative stress in mediating the adverse effects of radiation in the brain, we analyzed transgenic (mitochondrial catalase [MCAT]) mice that overexpress human catalase localized to the mitochondria. Results: Compared with wild-type (WT) controls, overexpression of the MCAT transgene significantly decreased cognitive dysfunction after proton irradiation. Significant improvements in behavioral performance found on novel object recognition and object recognition in place tasks were associated with a preservation of neuronal morphology. While the architecture of hippocampal CA1 neurons was significantly compromised in irradiated WT mice, the same neurons in MCAT mice did not exhibit extensive and significant radiation-induced reductions in dendritic complexity. Irradiated neurons from MCAT mice maintained dendritic branching and length compared with WT mice. Protected neuronal morphology in irradiated MCAT mice was also associated with a stabilization of radiation-induced variations in long-term potentiation. Stabilized synaptic activity in MCAT mice coincided with an altered composition of the synaptic AMPA receptor subunits GluR1/2. Innovation: Our findings provide the first evidence that neurocognitive sequelae associated with radiation exposure can be reduced by overexpression of MCAT, operating through a mechanism involving the preservation of neuronal morphology. Conclusion: Our article documents the neuroprotective properties of reducing mitochondrial reactive oxygen species through the targeted overexpression of catalase and how this ameliorates the adverse effects of proton irradiation in the brain. Antioxid. Redox Signal. 22, 78–91.

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Published In

cover image Antioxidants & Redox Signaling
Antioxidants & Redox Signaling
Volume 22Issue Number 1January 1, 2015
Pages: 78 - 91
PubMed: 24949841

History

Published in print: January 1, 2015
Published online: 17 December 2014
Published ahead of print: 29 July 2014
Published ahead of production: 20 June 2014
Accepted: 20 June 2014
Revision received: 11 June 2014
Received: 26 March 2014

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Vipan K. Parihar
Department of Radiation Oncology, University of California, Irvine, Irvine, California.
Barrett D. Allen
Department of Radiation Oncology, University of California, Irvine, Irvine, California.
Katherine K. Tran
Department of Radiation Oncology, University of California, Irvine, Irvine, California.
Nicole N. Chmielewski
Department of Radiation Oncology, University of California, Irvine, Irvine, California.
Brianna M. Craver
Department of Radiation Oncology, University of California, Irvine, Irvine, California.
Vahan Martirosian
Department of Radiation Oncology, University of California, Irvine, Irvine, California.
Josh M. Morganti
Departments of Physical Therapy Rehabilitation Science and Neurological Surgery, University of California, San Francisco, San Francisco, California.
Susanna Rosi
Departments of Physical Therapy Rehabilitation Science and Neurological Surgery, University of California, San Francisco, San Francisco, California.
Brain and Spinal Injury Center, University of California, San Francisco, San Francisco, California.
Roman Vlkolinsky
Departments of Radiation Medicine and Basic Sciences, Loma Linda University, Loma Linda, California.
Munjal M. Acharya
Department of Radiation Oncology, University of California, Irvine, Irvine, California.
Gregory A. Nelson
Departments of Radiation Medicine and Basic Sciences, Loma Linda University, Loma Linda, California.
Antiño R. Allen
Division of Radiation Health, University of Arkansas Medical School, Little Rock, Arkansas.
Charles L. Limoli
Department of Radiation Oncology, University of California, Irvine, Irvine, California.

Notes

Address correspondence to:Prof. Charles L. LimoliDepartment of Radiation OncologyUniversity of California, IrvineMedical Sciences IRoom B-146BIrvine, CA 92697-2695E-mail: [email protected]

Author Disclosure Statement

No competing financial interests exist.

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