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Published on: October 18, 2011
Metalloporphyrin antioxidants ameliorate normal tissue radiation damage in rat brain
Robert D Pearlstein1, Yoshinori Higuchi, Maria Moldovan
1Department of Surgery/Neurosurgery and School of Medicine, Duke University and Medical Center, Durham, North Carolina 27710, USA. robert.pearlstein@duke.edu
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.
Insights
Manganese (III) meso-tetrakis (diethyl-2-5-imidazole) porphyrin (MPA) protected neural tissue from radiation damage and enhanced tumor cell survival. Further research is needed to explore MPA as an adjunctive radioprotectant in cranial radiotherapy.
Area of Science:
- Oncology
- Radiotherapy
- Neuroscience
Background:
- Radiation therapy is a cornerstone of cancer treatment, but it can cause significant damage to healthy neural tissues.
- Developing effective radioprotectants is crucial for improving patient outcomes and reducing treatment-related toxicities.
Purpose of the Study:
- To investigate the radioprotective effects of manganese (III) meso-tetrakis (diethyl-2-5-imidazole) porphyrin (MPA), a metalloporphyrin antioxidant, on neural tissue in vivo and tumor cell radiosensitivity in vitro.
- To assess MPA's impact on radiation-induced apoptosis, blood-brain barrier integrity, and tumor cell survival.
Main Methods:
- MPA was administered intracerebroventricularly to rats before a 100 Gy radiation dose to the brain.
- In vitro studies involved primary neuronal cultures and rat glioma C6 cells exposed to radiation with or without MPA pretreatment.
- Assessed outcomes included apoptosis, blood-brain barrier damage, necrosis, clonogenic survival, SOD activity, DNA double-strand breaks, and heme-oxygenase 1 (HO-1) expression.
Main Results:
- MPA pretreatment protected against acute radiation-induced apoptosis and delayed damage to the blood-brain barrier and necrosis in vivo.
- In vitro, MPA protected neuronal cultures from radiation-induced apoptosis and increased survival of irradiated glioma cells.
- MPA increased mitochondrial SOD activity and upregulated HO-1 expression in C6 cells, but effects on DNA damage and HO-1 were not consistently observed across all cell types and tissues.
Conclusions:
- Metalloporphyrin antioxidants like MPA show promise as adjunctive radioprotectants for cranial radiotherapy and radiosurgery.
- Careful consideration of potential tumor protection is necessary when evaluating MPA for clinical applications.
