Hemodynamic effects of metalloporphyrin catalytic antioxidants: structure-activity relationships and species specificity

Ross, Aron D.; Sheng, Huaxin; Warner, David S.; Piantadosi, Claude A.; Batinić‐Haberle, Ines; Day, Brian J.; Crapo, James D.

doi:10.1016/s0891-5849(02)01140-1

Cited by 27 publications

(20 citation statements)

References 46 publications

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“…MnPorphyrins elicit known arterial hypotension responses unique to the rat, which are absent in other species (including mouse, dog, and baboon), plausibly because of the unique dimeric extracellular superoxide dismutase structure in the rat (Ross et al, 2002). Because arterial hypotension could confound brain perfusion and thus MCAO outcome, we conducted a dose escalation study to define the maximal MnTnHex-2-PyP dose tolerated so as to not cause a sustained change in blood pressure recorded at 5-min intervals over 60 min.…”

Section: Methodsmentioning

confidence: 99%

“…Rats are known to exhibit a species-specific arterial hypotensive response to MnPorphyrins (Ross et al, 2002). The mechanism for this remains undefined, and this also has limited preclinical MnPorphyrin evaluation as potential clinical therapeutics.…”

Section: Lipophilic Mnporphyrins In Experimental Mcao and Sah 913mentioning

confidence: 99%

“…To assure that MnTnHex-2-PyP had no effect on blood pressure in mice, as would be predicted from previous work with MnPorphyrins (Ross et al, 2002), four mice were anesthetized with 1.2% isoflurane, and the lungs were mechanically ventilated. A femoral artery was cannulated.…”

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confidence: 99%

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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: Methodsmentioning

confidence: 99%

Section: Lipophilic Mnporphyrins In Experimental Mcao and Sah 913mentioning

confidence: 99%

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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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“…AEOL 10113 and AEOL 10150 are positively charged, and the positive charges on the four pyridyl or imidizol groups in these compounds give them distribution and function profiles that mimic ECSOD. These compounds are not exact mimetics of ECSOD since there will be some differences in distribution and, as shown in figure 5 and table 1, they have broader antioxidant profiles than ECSOD, which only scavenges superoxide [9].…”

Section: Development Of Pharmaceutical Mimetics Of Extracellular Supementioning

confidence: 99%

Oxidative stress as an initiator of cytokine release and cell damage

Jd¹

2003

Eur Respir J

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“…Conventional antioxidants scavenge free radicals in an inefficient stoichiometric manner so that one molecule of the antioxidant would be needed to neutralize each free radical generated. Novel small molecular weight compounds that function as superoxide dismutase mimetics may offer more reliable benefits due to the catalytic properties that could permit enzymatic detoxification (30). The observation that PARP drives glucotoxicity through inhibition of GAPDH suggests PARP inhibitors as another therapeutic tool for complication prevention.…”

Section: Implications For Therapymentioning

confidence: 99%

Diabetes, microvascular complications, and cardiovascular complications: what is it about glucose?

Reusch¹

2003

J. Clin. Invest.

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Glycemic control is the primary mediator of diabetic microvascular complications and also contributes to macrovascular complications. A new study (see related article beginning on page 1049) reveals a previously unrecognized association between oxidant activation of poly(ADP ribose) polymerase (PARP) and upregulation of known mediators of glycemic injury. Inhibitors of PARP may have potential therapeutic roles in the prevention of diabetic complications.

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Hemodynamic effects of metalloporphyrin catalytic antioxidants: structure-activity relationships and species specificity

Cited by 27 publications

References 46 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

Oxidative stress as an initiator of cytokine release and cell damage

Diabetes, microvascular complications, and cardiovascular complications: what is it about glucose?

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