Metalloporphyrin antioxidants ameliorate normal tissue radiation damage in rat brain

Int J Radiat Biol. 2010 Feb;86(2):145-63. doi: 10.3109/09553000903419965.

Abstract

Purpose: We examined the effects of manganese (III) meso-tetrakis (diethyl-2-5-imidazole) porphyrin, a metalloporphyrin antioxidant (MPA), on neural tissue radiation toxicity in vivo and on tumour cell radiosensitivity in vitro.

Materials and methods: MPA was administered directly into the right lateral ventricle of young adult, male Sprague-Dawley rats (0 or 3.4 microg) 3 h before treatment with a single fraction, 100 Gy radiation dose delivered to the left brain hemisphere. The effects of treatment on radiation responses were assessed at different time points following irradiation.

Results: MPA treatment prior to brain irradiation protected against acute radiation-induced apoptosis and ameliorated delayed damage to the blood-brain barrier and radiation necrosis, but without producing a discernible increase in tissue superoxide disumtase (SOD) activity. In vitro, MPA pretreatment protected against radiation-induced apoptosis in primary neuronal cultures and increased clonogenic survival of irradiated rat glioma C6 cells, but had no discernible effect on radiation-induced DNA double-strand breaks. MPA, a low molecular weight SOD mimic, significantly increased mitochondrial SOD activity in C6 cells, but not total cellular SOD activity. MPA up-regulated C6 expression of heme-oxygenase 1 (HO-1), an endogenous radioprotectant, but had no effect on HO-1 levels in human astrocytoma U-251 cells, human prostatic carcinoma LNCaP cells, or primary rat brain microvascular endothelial cells in vitro, nor on brain tissue HO-1 expression levels in vivo.

Conclusions: Metalloporphyrin antioxidants merit further exploration as adjunctive radioprotectants for cranial radiotherapy/radiosurgery applications, although the potential for tumour protection must be carefully considered.

MeSH terms

  • Animals
  • Antioxidants / pharmacology*
  • Apoptosis / drug effects
  • Apoptosis / radiation effects
  • Blood-Brain Barrier / drug effects
  • Blood-Brain Barrier / radiation effects
  • Brain / drug effects*
  • Brain / metabolism
  • Brain / pathology
  • Brain / radiation effects*
  • Brain Injuries / metabolism
  • Brain Injuries / pathology
  • Brain Injuries / prevention & control
  • Cell Line, Tumor
  • Cells, Cultured
  • DNA Breaks, Double-Stranded
  • Heme Oxygenase (Decyclizing) / metabolism
  • Humans
  • Male
  • Metalloporphyrins / pharmacology*
  • Neuroglia / cytology
  • Neuroglia / drug effects
  • Neuroglia / radiation effects
  • Neurons / cytology
  • Neurons / drug effects
  • Neurons / radiation effects
  • Radiation Injuries, Experimental / metabolism
  • Radiation Injuries, Experimental / pathology
  • Radiation Injuries, Experimental / prevention & control*
  • Radiation Tolerance / drug effects
  • Radiation-Protective Agents / pharmacology*
  • Rats
  • Rats, Sprague-Dawley
  • Superoxide Dismutase / metabolism

Substances

  • AEOL 10150
  • Antioxidants
  • Metalloporphyrins
  • Radiation-Protective Agents
  • Heme Oxygenase (Decyclizing)
  • Hmox1 protein, rat
  • Superoxide Dismutase