4.7 Article

CNS bioavailability and radiation protection of normal hippocampal neurogenesis by a lipophilic Mn porphyrin-based superoxide dismutase mimic, MnTnBuOE-2-PyP5+

期刊

REDOX BIOLOGY
卷 12, 期 -, 页码 864-871

出版社

ELSEVIER SCIENCE BV
DOI: 10.1016/j.redox.2017.04.027

关键词

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

资金

  1. VA Merit review [BX-0024-71]
  2. Palo Alto Veterans Institute for Research
  3. NIH/NCI Duke Comprehensive Cancer Center Core Grant [5-P30-CA14236-29]
  4. NC Biotechnology Center BIG Award [2016-BIG-6518]
  5. BioMimetix JVLLC [186103]
  6. Department of Radiation Oncology
  7. Brazilian CNPq [402976/2012-6, 485443/2012-0, 552500/2011-9, 307348/2013-0]
  8. CAPES [24001015030P-4]

向作者/读者索取更多资源

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.

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