Background/Readiness: Chronic, neuropathic pain occurs in 60-80% of persons with spinal cord injury

(SCI), yet less than 10% of patients show complete recovery, either spontaneously or following treatment. Alarmingly, clinical approaches are largely ineffective in the treatment of neuropathic pain and adjuvant medications (i.e. antidepressants and anticonvulsants) demonstrate only marginal effectiveness. Although the neurobiological mechanisms which underlie neuropathic pain are poorly understood, a prevalent hypothesis is that SCI induces the formation of reactive oxygen species (ROS) and activation of nuclear factor κB (NF-κB) signaling which leads to inflammation and neuropathic pain (for review see). In support of this hypothesis, a body of research demonstrates that SCI results in formation of ROS and activation of the transcription factor NF-κB. Administration of ROS scavengers reduces neuropathic pain in animal models. Additionally, various methods to inhibit NF-κB activity have been shown to decrease neuropathic pain including the use of NF-ĸB decoys and inhibition of NF-ĸB with pyrrolidine dithiocarbamate. We recently found that inhibition of NFκB with sulfasalazine blocks development of neuropathic pain in a rodent model of cervical SCI, yet the bloodbrain barrier (BBB) penetration of sulfasalazine is very limited and thereby necessitated very high and poorly tolerated systemic dosing (unpublished). Collectively, these data demonstrate that dissipating ROS and blocking NF-κB signaling are therapeutic targets to alleviate neuropathic pain after SCI. We hypothesize that a highly efficacious treatment for neuropathic pain after SCI would be a compound that scavenges ROS, inhibits NF-ĸB activation, is bioavailable to the central nervous system (CNS), and is well-tolerated. Our group has discovered that a therapeutic approach that both dissipates ROS and inhibits NF-κB activation is to employ catalytic oxidoreductants, specifically Mn (III) N-alkylpyridylporphyrins (MnPorphyrins). In contrast to the more passive scavenging activity of “classical” antioxidants, MnPorphyrins are catalytically active oxidoreductants which confer pharmacological properties superior to other compounds (see ). They are efficient in dissipating a broad range of ROS and reactive nitrogen species including superoxide, hydrogen peroxide, peroxynitrite, and hypochlorous acid (see ). We have extensive experience in the development and characterization of MnPorphyrins and our previous published studies demonstrate marked protection conferred by MnPorphyrins in models of CNS insults and spinal cord injury. Intriguingly, in addition to their highly efficacious cytoprotectant effects due to catalytic redox-regulating activity, MnPorphyrins are potent inhibitors of NF-κB signaling 9, . A main limitation in the development of MnPorphyrins as therapeutics for CNS injury has been the CNS bioavailability. To overcome this, we have recently synthesized a highly lipophilic MnPorphyrin, MnTnBuOE (BuOE), and demonstrated robust brain penetration as well as neuroresuscitation in rodent CNS injury models and prevention of morphine tolerance. Moreover, we found that BuOE is also a potent NF-κB inhibitor. Since dissipation of ROS and suppression of NF-κB signaling both inhibit neuropathic pain after SCI, we hypothesize that BuOE can be developed as a novel therapeutic to treat neuropathic pain after SCI by offering the unique and simultaneous chemistry of direct redox-regulation of inflammation and catalytic reduction of superoxide and peroxynitrite. Indeed, our preliminary data in a rat model of cervical SCI strongly support this hypothesis. Thus, the proposed research is a comprehensive animal validation study which will provide the necessary data and infrastructure to plan first-inhuman clinical trials as next step in the translational process.