Effect of lipophilicity of Mn (III) ortho N-alkylpyridyl- and diortho N, N'-diethylimidazolylporphyrins in two in-vitro models of oxygen and glucose deprivation-induced neuronal death.
In vivo investigations have confirmed the beneficial effects of hydrophilic, cationic Mn(III) porphyrin-based catalytic antioxidants in different models of oxidative stress. Using a cell culture model of rat mixed neuronal/glial cells, this study investigated the effect of MnTnOct-2-PyP5+ on oxygen and glucose deprivation (OGD)-induced cell death as compared to the effects of widely studied hydrophilic analogues MnTE-2-PyP5+ and MnTDE-2-ImP5+ and a standard compound, dizocilpine (MK-801). It was hypothesized that the octylpyridylporphyrin, MnTnOct-2-PyP5+, a lipophilic but equally potent antioxidant as the other two porphyrins, would be more efficacious in reducing OGD-induced cell death due to its higher bioavailability. Cell death was evaluated at 24 h using lactate dehydrogenase (LDH) release and propidium iodide staining. At concentrations from 3-100 microM, all three porphyrins reduced cell death as compared to cultures exposed to OGD alone, the effects depending upon the concentrations and type of treatment. To assess the effect of lipophilicity the additional experiments were performed using submicromolar concentrations of MnTnOct-2-PyP5+ in an organotypic hippocampal slice model of OGD with propidium iodide and Sytox staining. When compared to oxygen and glucose deprivation alone, concentrations of MnTnOct-2-PyP5+ as low as 0.01 microM significantly (p<0.001; power 1.0) reduced neuronal cells similar to control. This is the first in vitro study on the mammalian cells which indicates that MnTnOct-2-PyP5+ is up to 3000-fold more efficacious than equally potent hydrophilic analogues, due entirely to its increased bioavailability. Such remarkable increase in efficacy parallels 5.7-orders of magnitude increase in lipophilicity of MnTnOct-2-PyP5+ (log P=-0.77) when compared to MnTE-2-PyP5+ (log POW=-6.43), POW being partition coefficient between n-octanol and water.
Wise-Faberowski
Lisa
L
Department of Anesthesiology, Duke University Medical Center, Durham, NC 27710, USA. lisa.faberowski@uchsc.edu
Warner
David S
DS
Spasojevic
Ivan
I
Batinic-Haberle
Ines
I
D000818:Animals; D001682:Biological Availability; D016923:Cell Death / Q000187:drug effects* / Q000502:physiology; D002478:Cells, Cultured; D018920:Coculture Techniques; D005947:Glucose / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008055:Lipids / Q000737:chemistry; D008345:Manganese / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D008665:Metalloporphyrins / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D008954:Models, Biological; D009457:Neuroglia / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D018696:Neuroprotective Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D009924:Organ Culture Techniques; D010100:Oxygen / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
D008055:Lipids; D008665:Metalloporphyrins; D018696:Neuroprotective Agents; C520506:manganese tetrakis-(N-ethyl-2 pyridyl) porphyrin; D008345:Manganese; D007770:L-Lactate Dehydrogenase; D005947:Glucose; D010100:Oxygen