CNS bioavailability and radiation protection of normal hippocampal neurogenesis by a lipophilic Mn porphyrin-based superoxide dismutase mimic, MnTnBuOE-2-PyP

Authors

David Leu, Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA; Palo Alto Veterans Institute for Research, Palo Alto, CA, USA.
Ivan Spasojevic, Duke Cancer Institute, Pharmaceutical Research Shared Resource, PK/PD Core laboratory, Duke University Medical Center, Durham, NC, USA; Department of Medicine, Duke University Medical Center, Durham, NC, USA.
Huy Nguyen, Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.
Brian Deng, Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA; Palo Alto Veterans Institute for Research, Palo Alto, CA, USA.
Artak Tovmasyan, Department of Radiation Oncology, Duke University Medical Center, Durham, NC, USA.
Tin Weitner, Department of Radiation Oncology, Duke University Medical Center, Durham, NC, USA.
Romulo S. Sampaio, Department of Radiation Oncology, Duke University Medical Center, Durham, NC, USA.
Ines Batinic-Haberle, Department of Radiation Oncology, Duke University Medical Center, Durham, NC, USA.
Ting-Ting Huang, Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA; Geriatric Research, Education, and Clinical Center, VA Palo Alto Health Care System, Palo Alto, CA, USA.

Document Type

Article

Abstract

Although radiation therapy can be effective against cancer, potential damage to normal tissues limits the amount that can be safely administered. In central nervous system (CNS), radiation damage to normal tissues is presented, in part, as suppressed hippocampal neurogenesis and impaired cognitive functions. Mn porphyrin (MnP)-based redox active drugs have demonstrated differential effects on cancer and normal tissues in experimental animals that lead to protection of normal tissues and radio- and chemo-sensitization of cancers. To test the efficacy of MnPs in CNS radioprotection, we first examined the tissue levels of three different MnPs - MnTE-2-PyP(MnE), MnTnHex-2-PyP(MnHex), and MnTnBuOE-2-PyP(MnBuOE). Nanomolar concentrations of MnHex and MnBuOE were detected in various brain regions after daily subcutaneous administration, and MnBuOE was well tolerated at a daily dose of 3mg/kg. Administration of MnBuOE for one week before cranial irradiation and continued for one week afterwards supported production and long-term survival of newborn neurons in the hippocampal dentate gyrus. MnP-driven S-glutathionylation in cortex and hippocampus showed differential responses to MnP administration and radiation in these two brain regions. A better understanding of how preserved hippocampal neurogenesis correlates with cognitive functions following cranial irradiation will be helpful in designing better MnP-based radioprotection strategies.

Keywords

BMX-001, Bioavailability, Hippocampus, Mn porphyrin, Neurogenesis, Radioprotection

Medical Subject Headings

Animals; Biological Availability; Central Nervous System (chemistry, drug effects, radiation effects); Cerebral Cortex (chemistry, drug effects, radiation effects); Cranial Irradiation (adverse effects); Female; Hippocampus (chemistry, drug effects, radiation effects); Male; Metalloporphyrins (administration & dosage, pharmacokinetics); Mice, Inbred C57BL; Neurogenesis (drug effects, radiation effects); Oxidative Stress (drug effects); Radiation-Protective Agents (administration & dosage, pharmacokinetics)

Publication Date

8-1-2017

Publication Title

Redox biology

E-ISSN

2213-2317

Volume

12

First Page

864

Last Page

871

PubMed ID

28454069

Digital Object Identifier (DOI)

10.1016/j.redox.2017.04.027

Recommended Citation

Leu, David; Spasojevic, Ivan; Nguyen, Huy; Deng, Brian; Tovmasyan, Artak; Weitner, Tin; Sampaio, Romulo S.; Batinic-Haberle, Ines; and Huang, Ting-Ting, "CNS bioavailability and radiation protection of normal hippocampal neurogenesis by a lipophilic Mn porphyrin-based superoxide dismutase mimic, MnTnBuOE-2-PyP" (2017). Translational Neuroscience. 1259.
https://scholar.barrowneuro.org/neurobiology/1259