期刊
EXPERIMENTAL NEUROLOGY
卷 355, 期 -, 页码 -出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.expneurol.2022.114128
关键词
tMCAO; Mitochondria; Electron transport chain; Oxidative stress; Mitoceutical
资金
- National Institutes of Health [U54 GM104942, UL1 TR001998, R41 NS110070, P20 GM109098, RO1 NS099918]
- [P20 GM103434]
NL-1 is a potential drug target for treating ischemic stroke, as it reduces neuronal cell loss and brain injury, leading to improved survival rates. Encapsulating NL-1 in nanoparticles enhances its protective effects. Targeting the mitoNEET pathway may be a promising avenue for further research.
Cerebral ischemic stroke is a leading cause of mortality and disability worldwide. Currently, there are a lack of drugs capable of reducing neuronal cell loss due to ischemia/reperfusion-injury after stroke. Previously, we identified mitoNEET, a [2Fe-2S] redox mitochondrial protein, as a putative drug target for ischemic stroke. In this study, we tested NL-1, a novel mitoNEET ligand, in a preclinical model of ischemic stroke with reperfusion using aged female rats. Using a transient middle cerebral artery occlusion (tMCAO), we induced a 2 h ischemic injury and then evaluated the effects of NL-1 treatment on ischemic/reperfusion brain injury at 24 and 72 h. Test compounds were administered at time of reperfusion via intravenous dosing. Results of the study demonstrated that NL-C1 (10 mg/kg) treatment markedly improved survival and reduced infarct volume and hemispheric swelling in the brain as compared aged rats treated with vehicle or a lower dose of NL-1 (0.25 mg/kg). Interestingly, the protective effect of NL-1 was significantly improved when encapsulated in PLGA nanoparticles, where a 40-fold lesser dose (0.25 mg/kg) of NL-1 produced an equivalent effect as the 10 mg/kg dose. Evaluation of changes in blood-brain barrier permeability and lipid peroxidation corroborated the protective actions of NL-1 (10 mg/kg) or NL-1 NP treatment demonstrated a reduced accumulation of parenchymal IgG, decreased levels of 4-hydroxynonenal (4-HNE) and a decreased TUNEL positive cells in the brains of aged female rats at 72 h after tMCAO with reperfusion. Our studies indicate that targeting mitoNEET following ischemia/reperfusion-injury is a novel drug target pathway that warrants further investigation.
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