Manganese porphyrin reduces retinal injury induced by ocular hypertension in rats

Doğan, Serdar; Ünal, Mustafa; Ozturk, Nihal; Yargiçoğlu, Pi̇raye; Çört, Ayşegül; Spasojević, Ivan; Batinić‐Haberle, Ines; Aslan, Mutay

doi:10.1016/j.exer.2011.05.008

Cited by 15 publications

(10 citation statements)

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“…Furthermore, 100 g/kg i.p. MnTnHex-2-PyP given daily for 6 weeks was efficacious in the study of rat ocular hypertension (Dogan et al, 2011). Further investigation is necessary to determine a full pharmacokinetic spectrum for MnTnHex-2-PyP in both normal and ischemic brain.…”

Section: Discussionmentioning

confidence: 99%

Neuroprotective Efficacy from a Lipophilic Redox-Modulating Mn(III) N-Hexylpyridylporphyrin, MnTnHex-2-PyP: Rodent Models of Ischemic Stroke and Subarachnoid Hemorrhage

Sheng

Spasojević²,

Tse³

et al. 2011

J Pharmacol Exp Ther

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Intracerebroventricular treatment with redox-regulating Mn(III) Nhexylpyridylporphyrin (MnPorphyrin) is remarkably efficacious in experimental central nervous system (CNS) injury. Clinical development has been arrested because of poor blood-brain barrier penetration. Mn(III) meso-tetrakis (N-hexylpyridinium-2-yl) porphyrin (MnTnHex-2-PyP) was synthesized to include four six-carbon (hexyl) side chains on the core MnPorphyrin structure. This has been shown to increase in vitro lipophilicity 13,500-fold relative to the hydrophilic ethyl analog Mn(III) meso-tetrakis(N-ethylpyridinium-2-yl)porphyrin (MnTE-2-PyP). In normal mice, we found brain MnTnHex-2-PyP accumulation to be ϳ9-fold greater than MnTE-2-PyP 24 h after a single intraperitoneal dose. We then evaluated MnTnHex-2-PyP efficacy in outcome-oriented models of focal cerebral ischemia and subarachnoid hemorrhage. For focal ischemia, rats underwent 90-min middle cerebral artery occlusion. Parenteral MnTnHex-2-PyP treatment began 5 min or 6 h after reperfusion onset and continued for 7 days. Neurologic function was improved with both early (P ϭ 0.002) and delayed (P ϭ 0.002) treatment onset. Total infarct size was decreased with both early (P ϭ 0.03) and delayed (P ϭ 0.01) treatment. MnTnHex-2-PyP attenuated nuclear factor B nuclear DNA binding activity and suppressed tumor necrosis factor-␣ and interleukin-6 expression. For subarachnoid hemorrhage, mice underwent perforation of the anterior cerebral artery and were treated with intraperitoneal MnTnHex-2-PyP or vehicle for 3 days. Neurologic function was improved (P ϭ 0.02), and vasoconstriction of the anterior cerebral (P ϭ 0.0005), middle cerebral (P ϭ 0.003), and internal carotid (P ϭ 0.015) arteries was decreased by MnTnHex-2-PyP. Side-chain elongation preserved MnPorphyrin redox activity, but improved CNS bioavailability sufficient to cause improved outcome from acute CNS injury, despite delay in parenteral treatment onset of up to 6 h. This advance now allows consideration of MnPorphyrins for treatment of cerebrovascular disease.

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Section: Discussionmentioning

confidence: 99%

Neuroprotective Efficacy from a Lipophilic Redox-Modulating Mn(III) N-Hexylpyridylporphyrin, MnTnHex-2-PyP: Rodent Models of Ischemic Stroke and Subarachnoid Hemorrhage

Sheng

Spasojević²,

Tse³

et al. 2011

J Pharmacol Exp Ther

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“…The hydrophilic MnTE-2-PyP 5+ was up to 120-fold less efficacious at 6 to 15 mg/kg single or multiple doses (ip, iv, sc, icv) in animal models, and from ~20 to 50 μM in cellular models [44, 46]. MnTnHex-2-PyP 5+ was remarkably efficacious in stroke and hemorrhage rodent models [112, 150], rabbit cerebral palsy [163, 191], brain glioma study [192], organotypic hyppocampal slice model of oxygen glucose deprivation [190], rat eye hypertension [193], rat lung radiation [194], rat renal ischemia reperfusion model [144, 195], E. coli model [116], and ataxia telangiectasia radiation cellular model [196]. The most remarkable efficacy of MnTnHex-2-PyP 5+ was found in the rabbit cerebral palsy model (see below under Cerebral palsy ).…”

Section: Mechanism Of Action Of Mn Porphyrinsmentioning

confidence: 99%

Manganese superoxide dismutase, MnSOD and its mimics

Miriyala

Spasojević

Tovmasyan

et al. 2012

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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348

335

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Increased understanding of the role of mitochondria under physiological and pathological conditions parallels increased exploration of synthetic and natural compounds able to mimic MnSOD – endogenous mitochondrial antioxidant defense essential for the existence of virtually all aerobic organisms from bacteria to humans. This review describes most successful mitochondrially-targeted redox-active compounds, Mn porphyrins and MitoQ10 in detail, and briefly addresses several other compounds that are either catalysts of O2·− dismutation, or its non-catalytic scavengers, and that reportedly attenuate mitochondrial dysfunction. While not a true catalyst (SOD mimic) of O2·− dismutation, MitoQ10 oxidizes O2·− to O2 with a high rate constant. In vivo it is readily reduced to quinol, MitoQH2, which in turn reduces ONOO− to ·NO2, producing semiquinone radical that subsequently dismutes to MitoQ10 and MitoQH2, completing the “catalytic” cycle. In MitoQ10, the redox-active unit was coupled to alkyl chain and monocationic triphenylphosphonium ion in order to reach mitochondria. Mn porphyrin-based SOD mimics, however, were designed so that their multiple cationic charge and alkyl chains determine both their remarkable SOD potency and carry them into mitochondria. Several animal efficacy studies such as skin carcinogenesis and UVB-mediated mtDNA damage, and subcellular distribution studies of Saccharomyces cerevisiae and mouse heart provided unambiguous evidence that Mn porphyrins mimic the site and action of MnSOD, which in turn contributes to their efficacy in numerous in vitro and in vivo models of oxidative stress. Within a class of Mn porphyrins, lipophilic analogues are particularly effective for treating central nervous system injuries where mitochondria play key role.

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“…MnBuOE accumulates in mitochondria, a site of oxidative stress after RT 8 . Analogues of MnBuOE reduced injury following radiation induce erectile dysfunction 9 , ocular hypertension 10 , renal ischemia 11 , pulmonary radiation injury 12–14 , and spinal cord contusion 15 . In this paper, we compare the effects of MnBuOE on radiotherapy response of tumor using the FaDu HNSCC model vs. relevant normal tissues of the head and neck.…”

Section: Introductionmentioning

confidence: 99%

Novel Manganese-Porphyrin Superoxide Dismutase-Mimetic Widens the Therapeutic Margin in a Preclinical Head and Neck Cancer Model

Ashcraft

Boss

Tovmasyan

et al. 2015

International Journal of Radiation Oncology*Biology*Physics

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Purpose Normal tissue injury is dose limiting for radiotherapy (RT) in nearly every application. This provides strong rationale for developing new classes of novel radioprotectors. The caveat is that radioprotective drugs must be selective for normal tissue and not tumor. Here we tested the effects of a novel Mn porphyrin oxidative stress modifier, MnBuOE for its radioprotective and radiosensitizing properties in normal tissue vs. tumor, respectively. Methods Murine oral mucosa and salivary glands were treated with a range of radiation doses, ±MnBuOE to establish the dose effect curves for mucositis and xerostomia. Radiation injury was quantified by intravital NIR imaging of cathepsin activity, assessment of salivation and histological analysis. To evaluate effects of MnBuOE on the tumor radiation response, we administered the drug as an adjuvant to fractionated radiation of FaDu xenografts. Again, a range of RT doses were administered to establish the radiation dose effect curve. The TCD50 values ±MnBuOE and dose modifying factor were determined. Results MnBuOE protected normal tissue by reducing RT-mediated mucositis, xerostomia and fibrosis. The dose modifying factor for protection against xerostomia was 0.77. In contrast, MnBuOE increased tumor local control rates, compared to controls. The dose modifying factor, based on the ratio of TCD50 values, was 1.3. Immunohistochemistry showed that MnBuOE-treated tumors exhibited a significant influx of M1 tumor-associated macrophages, which provides mechanistic insight into its radiosensitizing effects in tumors. Conclusions MnBuOE widens the therapeutic margin by decreasing the dose of radiation required to control tumor, while increasing normal tissue resistance to RT-mediated injury. This is the first study to quantitatively demonstrate the magnitude of a single drug’s ability to radioprotect normal tissue while radiosensitizing tumor.

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Manganese porphyrin reduces retinal injury induced by ocular hypertension in rats

Cited by 15 publications

References 50 publications

Neuroprotective Efficacy from a Lipophilic Redox-Modulating Mn(III) N-Hexylpyridylporphyrin, MnTnHex-2-PyP: Rodent Models of Ischemic Stroke and Subarachnoid Hemorrhage

Neuroprotective Efficacy from a Lipophilic Redox-Modulating Mn(III) N-Hexylpyridylporphyrin, MnTnHex-2-PyP: Rodent Models of Ischemic Stroke and Subarachnoid Hemorrhage

Manganese superoxide dismutase, MnSOD and its mimics

Novel Manganese-Porphyrin Superoxide Dismutase-Mimetic Widens the Therapeutic Margin in a Preclinical Head and Neck Cancer Model

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