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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
1I01RX001450-01A1
Application #
8779212
Study Section
Brain Injury: TBI & Stroke (RRD1)
Project Start
2014-10-01
Project End
2018-09-30
Budget Start
2014-10-01
Budget End
2015-09-30
Support Year
1
Fiscal Year
2015
Total Cost
Indirect Cost
Name
Ralph H Johnson VA Medical Center
Department
Type
DUNS #
039807318
City
Charleston
State
SC
Country
United States
Zip Code
29401
Gwak, So-Jung; Macks, Christian; Jeong, Da Un et al. (2017) RhoA knockdown by cationic amphiphilic copolymer/siRhoA polyplexes enhances axonal regeneration in rat spinal cord injury model. Biomaterials 121:155-166
Kindy, Mark S; Yu, Jin; Zhu, Hong et al. (2016) A therapeutic cancer vaccine against GL261 murine glioma. J Transl Med 14:1
Kuang, Serena Y; Wang, Zhonghai; Huang, Ting et al. (2015) Prolonging life in chick forebrain-neuron culture and acquiring spontaneous spiking activity on a microelectrode array. Biotechnol Lett 37:499-509
Hook, Gregory; Jacobsen, J Steven; Grabstein, Kenneth et al. (2015) Cathepsin B is a New Drug Target for Traumatic Brain Injury Therapeutics: Evidence for E64d as a Promising Lead Drug Candidate. Front Neurol 6:178
Yun, Xiang; Maximov, Victor D; Yu, Jin et al. (2013) Nanoparticles for targeted delivery of antioxidant enzymes to the brain after cerebral ischemia and reperfusion injury. J Cereb Blood Flow Metab 33:583-92