Intracerebroventricular treatment with redox-regulating MnPorphyrins is remarkably efficacious in experimental central nervous system (CNS) injury. Clinical development has been arrested because of poor blood-brain barrier penetration. MnTnHex-2-PyP was synthesized to include 4 6-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 MnTE-2PyP. In normal mice, we found brain MnTnHex-2-PyP accumulation to be ~9-fold greater than MnTE-2-PyP 24 hrs after a single intraperitoneal dose. We then evaluated MnTnHex-2-PyP efficacy in outcome-oriented models of focal cerebral ischemia and subarachnoid hemorrhage (SAH). For focal ischemia, rats underwent 90 min middle cerebral artery occlusion. Parenteral MnTnHex-2-PyP treatment was begun 5 min or 6 h after reperfusion onset and continued 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 inhibited NF-κB nuclear DNA binding activity and suppressed TNF-α and IL-6 expression. For subarachnoid hemorrhage, mice underwent perforation of the anterior cerebral artery (ACA) 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 arteries (P=0.015) 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 hrs. This advance now allows consideration of MnPorphyrins for treatment of cerebrovascular disease.
- Received November 7, 2010.
- Revision received June 3, 2011.
- Accepted June 3, 2011.
- The American Society for Pharmacology and Experimental Therapeutics