Free radical-induced damage makes an important contribution to secondary neuronal injury in stroke. No therapy exists at present to prevent or alleviate these effects. The use of catalytic degradation of free radicals is a promising therapeutic approach to address the secondary damage in CNS. Antioxidant enzymes and their low molecular weight mimetics have recently been proposed as potentially powerful therapeutic agents for reducing free radical-induced injury in stroke, and have been shown to be efficient in a number of animal models. However, therapeutic use of these agents for treatment of stroke is limited due to their inability to efficiently penetrate blood-brain barrier. Recently, ability of several targeted nanoparticulate an liposomal constructs to penetrate the blood-brain barrier has been demonstrated. Here, we propose to achieve targeted delivery of a SOD mimetic AEOL 10150 to the site of CNS injury using antibody-coated nanoparticles (NPs) and liposomes. Targeting will be achieved through conjugation of anti-NR1 receptor antibody, which was found to specifically target injured brain parenchyma in our preliminary studies. Our working hypothesis is that enhanced delivery of targeted antioxidant NPs to the site of injury can reduce free radical damage and reduce the degree of secondary neuronal damage in stroke. The strategic goal of this study is to develop a medication for intravenous administration, which could be used as neuroprotective treatment to reduce free radical mediated secondary neuronal damage in stroke. To accomplish this goal, we will first prepare optimized targeted conjugates with maximized binding ability. Experiments with rat cortical neuronal cultures will then be used to evaluate safety and efficacy in vitro, and estimate dosage ranges for animal experiments. Finally, a mouse stroke model will be used for the in vivo evaluation of the efficacy of the proposed therapeutic approach. The short-term goal of this project is to collect in vivo data necessary for translation to a large animal model. In th long term, this research will lead to the development of a novel therapy for treatment/prophylactics of secondary neuronal injury in stroke. More broadly, results of this research will have implications in development new targeting approaches for treatment of various CNS conditions including traumatic brain injury and spinal cord injury.
Secondary neuronal injury in stroke results in massive neuronal death days to weeks after the primary insult. Few treatment options are available to alleviate effects of the free radical-induce damage to brain. One recently discovered possibility is treatment by antioxidant enzymes or their artificial mimetics, which can serve as highly efficient free radical scavengers at the site f injury. However, these agents alone are unable to reach the site of injury because brain is separated from the blood stream by the blood-brain barrier. The goal of this project is to improve delivery of highly reactive antioxidant AEOL 10150 to central nervous system. If successful, this research can lead to considerable improvement of stroke outcomes and therefore enhance long-term quality of life for the stroke survivors. Here, we propose to test this approach using a mouse stroke model. Once established, the proposed approach can be further extended to improve outcomes of other neurological conditions that involve secondary injury, such as traumatic brain injury and spinal cord injury.
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