Abstract
Intracerebroventricular treatment with redox-regulating Mn(III) N-hexylpyridylporphyrin (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 ∼9-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 = 0.002) and delayed (P = 0.002) treatment onset. Total infarct size was decreased with both early (P = 0.03) and delayed (P = 0.01) treatment. MnTnHex-2-PyP attenuated nuclear factor κB nuclear DNA binding activity and suppressed tumor necrosis factor-α 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 = 0.02), and vasoconstriction of the anterior cerebral (P = 0.0005), middle cerebral (P = 0.003), and internal carotid (P = 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.
Footnotes
This work was supported by, in part, by the National Institutes of Health National Center for Research Resources [Clinical and Translational Science Award 1 UL1 RR-024128–01] (to D.S.W., I.B.H., H.S., and I.S.).
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.110.176701.
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ABBREVIATIONS:
- MnPorphyrin
- Mn(III) N-alkylpyridylporphyrin
- SOD
- superoxide dismutase
- ACA
- anterior cerebral artery
- BBB
- blood-brain barrier
- CNS
- central nervous system
- ICA
- internal carotid artery
- IL-6
- interleukin-6
- LDF
- laser Doppler flow
- MAP
- mean arterial pressure
- MCA
- middle cerebral artery
- MCAO
- MCA occlusion
- NF-κB
- nuclear factor κB
- PaCO2
- partial pressure of carbon dioxide
- PaO2
- partial pressure of oxygen
- PBS
- phosphate-buffered saline
- ROI
- region of interest
- SAH
- subarachnoid hemorrhage
- TNF-α
- tumor necrosis factor-α
- MnTE-2-PyP
- Mn(III) meso-tetrakis(N-ethylpyridinium-2-yl)porphyrin
- MnTnHex-2-PyP
- Mn(III) meso-tetrakis (N-hexylpyridinium-2-yl) porphyrin
- MnTDE-2-ImP
- Mn(III) N,N′-dialkylimidazolyl porphyrin
- MnTBAP
- Mn(III) tetrakis (4-benzoic acid)porphyrin chloride
- DTT
- dithiothreitol
- PMSF
- phenylmethylsulfonyl fluoride.
- Received November 7, 2010.
- Accepted June 3, 2011.
- Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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