Neuroprotective effect of MnTMPyP, a superoxide dismutase/catalase mimetic in global cerebral ischemia is mediated through reduction of oxidative stress and DNA fragmentation

Abstract

Excessive generation of free radicals and decreased levels of the antioxidant enzymes such as superoxide dismutase (SOD) and catalase have been observed after brain ischemic reperfusion injury. In the present study, we have investigated the neuroprotective potential of MnTMPyP (Mn(III)tetrakis(1-methyl-4-pyridyl)porphyrin pentachloride), a SOD/Catalase mimetic in bilateral carotid artery occlusion model of global cerebral ischemia in Mongolian gerbils. Five minutes of bilateral carotid artery occlusion produced global cerebral ischemia, which was evident from the neurological deficits, spontaneous motor activity and the decrease in the number of viable hippocampal CA1 neurons. Global ischemia was also associated with increased levels of malondialdehyde, decreased levels of SOD and catalase, and increased TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling) positive cells, indicating oxidative stress and DNA fragmentation. Administration of a single dose of MnTMPyP, 1 mg/kg i.p. (30 min before occlusion), produced no significant neuroprotection; however, 3 mg/kg i.p. (30 min before to occlusion) produced significant reduction in neurological score, spontaneous motor activity and CA1 pyramidal neuronal damage. MnTMPyP also attenuated the increased levels of malondialdehyde and improved the levels of SOD and catalase, and inhibited DNA fragmentation in the ischemic animals. Multiple administration of MnTMPyP, 3 mg/kg i.p. (three times: 30 min before, 1 h and 3 h after occlusion), produced better neuroprotection as compared to single dose administration. This study demonstrates that the neuroprotective effect of MnTMPyP in global ischemia is mediated through reduction in oxidative stress and DNA fragmentation.