Neuroprotection from Delayed Postischemic Administration of a Metalloporphyrin Catalytic Antioxidant

Abstract

Reactive oxygen species contribute to ischemic brain injury. This study examined whether the porphyrin catalytic antioxidant manganese (III) meso-tetrakis (N-ethylpyridinium-2-yl)porphyrin (MnTE-2-PyP 5ϩ ) reduces oxidative stress and improves outcome from experimental cerebral ischemia. Rats that were subjected to 90 min focal ischemia and 7 d recovery were given MnTE-2-PyP 5ϩ (or vehicle) intracerebroventricularly 60 min before ischemia, or 5 or 90 min or 6 or 12 hr after reperfusion. Biomarkers of brain oxidative stress were measured at 4 hr after postischemic treatment (5 min or 6 hr). MnTE-2-PyP 5ϩ , given 60 min before ischemia, improved neurologic scores and reduced total infarct size by 70%. MnTE-2-PyP 5ϩ , given 5 or 90 min after reperfusion, reduced infarct size by 70-77% and had no effect on temperature. MnTE-2-PyP 5ϩ treatment 6 hr after ischemia reduced total infarct volume by 54% (vehicle, 131 Ϯ 60 mm 3 ; MnTE-2-PyP 5ϩ , 300 ng, 60 Ϯ 68 mm 3 ). Protection was observed in both cortex and caudoputamen, and neurologic scores were improved. No MnTE-2-PyP 5ϩ effect was observed if it was given 12 hr after ischemia. MnTE-2-PyP 5ϩ prevented mitochondrial aconitase inactivation and reduced 8-hydroxy-2Ј-deoxyguanosine formation when it was given 5 min or 6 hr after ischemia. In mice, MnTE-2-PyP 5ϩ reduced infarct size and improved neurologic scores when it was given intravenously 5 min after ischemia. There was no effect of 150 or 300 ng of MnTE-2-PyP 5ϩ pretreatment on selective neuronal necrosis resulting from 10 min forebrain ischemia and 5 d recovery in rats. Administration of a metalloporphyrin catalytic antioxidant had marked neuroprotective effects against focal ischemic insults when it was given up to 6 hr after ischemia. This was associated with decreased postischemic superoxidemediated oxidative stress.

SOD-like activity of Mn(II) β-octabromo-meso-tetrakis(N-methylpyridinium-3-yl)porphyrin equals that of the enzyme itself

“…Our further synthetic efforts in searching for a potential therapeutic based on the SAR led us to Mn(III) ortho N-alkylpyridylporphyrins as the most potent candidates for forwarding them into animal models where superoxide-mediated damage is involved. Thus remarkable effects were observed in cancer, radiation, diabetes, ALS, Alzheimer's disease etc [13][14][15][16][17][18][19][20][21][22][23]. Further, along with our mechanistic studies we observed a dramatic impact of the positive charges of the Mn porphyrin on the O 2 •− dismutation; the rate constants are more than two orders of magnitude higher when compared to the neutral or negatively charged porphyrins [3,4].…”

“…In all previous studies the data obtained with E. coli parallel the trends obtained in in vivo animal model studies [1][2][3][4][5][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28]37]. Here we compare the effect of Mn II Br 8 TM-3-PyP 4+ , its metal-free porphyrin HBr 8 TM-3-PyP 3+ , and the para analogue Mn II Br 8 TM-4-PyP 4+ on the aerobic growth of an SOD-deficient E. coli strain.…”

Superoxide Dismutase Mimics: Chemistry, Pharmacology, and Therapeutic Potential

“…Stroke. The very first study on central nervous system injuries was done with MnTE-2-PyP 5þ at Duke University in a rat stroke model (199). Rats were subjected to a 90-min focal ischemia (via middle cerebral artery occlusion, MCAO).…”

Electrostatic Contribution in the Catalysis of O 2·_Dismutation by Superoxide Dismutase Mimics

“…The compound has further proven effective in protection of SOD-deficient E. coli (26) and in stroke (28,29), spinal cord injury (30,31), diabetes (32,33), sickle cell disease (34), and radiation/cancer (35-38) rodent models of oxidative stress injuries. Much like SOD (1, 9, 21, 22) its high catalytic potency has been ascribed both to the favorable redox properties of the metal center and to the effect of the positively charged ortho-N-ethylpyridyl nitrogens that provide electrostatic facilitation for the approach of the negatively charged superoxide (23).…”