CNS bioavailability and radiation protection of normal hippocampal neurogenesis by a lipophilic Mn porphyrin-based superoxide dismutase mimic, MnTnBuOE-2-PyP5+
David Leu,
Ivan Spasojevic,
Huy Nguyen,
Brian Deng,
Artak Tovmasyan,
Tin Weitner,
Romulo S. Sampaio,
Ines Batinic-Haberle,
Ting-Ting Huang
Affiliations
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; Correspondence to: Department of Radiation Oncology, Duke University Medical Center, 281b MSRB I, Research Drive, Durham, NC 27710, 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; Correspondence to: Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Geriatric Research, Education, and Clinical Center, VA Palo Alto Health Care System, 3801 Miranda Avenue, Building 100, D3-101, Palo Alto, CA 94304, USA.
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-PyP5+(MnE), MnTnHex-2-PyP5+(MnHex), and MnTnBuOE-2-PyP5+(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 3 mg/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: Mn porphyrin, Bioavailability, BMX-001, Hippocampus, Neurogenesis, Radioprotection
