RESUMEN
SIGNIFICANCE: Metalloporphyrins, characterized by a redox-active transitional metal (Mn or Fe) coordinated to a cyclic porphyrin core ligand, mitigate oxidative/nitrosative stress in biological systems. Side-chain substitutions tune redox properties of metalloporphyrins to act as potent superoxide dismutase mimics, peroxynitrite decomposition catalysts, and redox regulators of transcription factor function. With oxidative/nitrosative stress central to pathogenesis of CNS injury, metalloporphyrins offer unique pharmacologic activity to improve the course of disease. RECENT ADVANCES: Metalloporphyrins are efficacious in models of amyotrophic lateral sclerosis, Alzheimer's disease, epilepsy, neuropathic pain, opioid tolerance, Parkinson's disease, spinal cord injury, and stroke and have proved to be useful tools in defining roles of superoxide, nitric oxide, and peroxynitrite in disease progression. The most substantive recent advance has been the synthesis of lipophilic metalloporphyrins offering improved blood-brain barrier penetration to allow intravenous, subcutaneous, or oral treatment. CRITICAL ISSUES: Insufficient preclinical data have accumulated to enable clinical development of metalloporphyrins for any single indication. An improved definition of mechanisms of action will facilitate preclinical modeling to define and validate optimal dosing strategies to enable appropriate clinical trial design. Due to previous failures of "antioxidants" in clinical trials, with most having markedly less biologic activity and bioavailability than current-generation metalloporphyrins, a stigma against antioxidants has discouraged the development of metalloporphyrins as CNS therapeutics, despite the consistent definition of efficacy in a wide array of CNS disorders. FUTURE DIRECTIONS: Further definition of the metalloporphyrin mechanism of action, side-by-side comparison with "failed" antioxidants, and intense effort to optimize therapeutic dosing strategies are required to inform and encourage clinical trial design.