Currently, there are no effective drugs for stroke other than thrombolytics. In the early phase of stroke mitochondria contribute to the production of reactive species. Thus therapeutics able to accumulate in mitochondria are preferable. Superoxide dismutase, both mitochondrial MnSOD and cytosolic Cu,ZnSOD isoform, plays a key role in ischemic stroke, maintaining the physiological redox status of the cell. These enzymes operate via redox-based reactions of their metal site (Fe, Cu, Ni and Mn) with O2-. Our focus has been study of redox-active metal complexes as therapeutics which can penetrate cell and mitochondrial membranes and the blood brain barrier (BBB). We have developed cationic complexes of Mn(III) with N- substituted pyridylporphyrins;a cyclic porphyrin ligand assures the extreme stability of the metal complex and thus integrity of the metal site where redox reactions of interest occur. The potency of these compounds approaches that of SOD enzymes. Like SOD enzymes, Mn porphyrins suppress oxidative stress and excessive inflammation via direct reactions with reactive species (e.g., O2-, .NO, and OONO-) and via redox modulation of NF-?B, HIF-1?, AP-1, and SP-1 transcription. The early generation redox-active and lipophilic cationic compound (H2O)MnTnHex-2-PyP5+ crosses BBB and accumulates in mitochondria 3.6-fold more than in cytosol. It improved neurologic outcome and decreased infarct size and inflammation in a rat middle cerebral artery occlusion stroke model. Yet, the dose and the therapeutic efficacy of Mn porphyrin were limited due to an adverse effect of arterial hypotension. Its Fe analog, (OH)FeTnHex-2-PyP4+, was recently synthesized and fully characterized. Both Fe and Mn porphyrins are equally lipophilic, have similar ability to mimic SOD enzymes, but bear different coordination geometry of the metal site. Due to different molecular structure, Fe porphyrin does not cause arterial hypotension in experimental animals, it is less toxic, and exerts ~2-orders of magnitude higher efficacy in a SOD-deficient E. coli screening model of oxidative stress. When compared to Fe porphyrin, the failure of free radical scavenger, nitrone NXY-059 in stroke clinical trials may be attributed to its ~100-fold lower efficacy in scavenging free radicals, failure in E. coli screening model of oxidative stress, and inability to accumulate in mitochondria due to its anionic charge. We propose to define efficacy of Fe analog in a mouse stroke model, which will open access to a whole new class of drugs with higher potency and safety, not only for stroke but potentially other CNS disorders including CNS malignancies.
We propose to define efficacy of a lipophilic, cationic Fe porphyrin in a mouse stroke model, which will open access to a whole new class of redox-active drugs with higher potency and safety, not only for stroke but potentially other CNS disorders associated with oxidative stress.
