(833.11) Novel mitoNEET ligand NL-1 improves therapeutic outcomes in an aged rat model of cerebral ischemia/reperfusion injury

Poster Board Number: B26

Aruvi Vijikumar (West Virginia University), Pushkar Saralkar (West Virginia University), Werner Geldenhuys (West Virginia University), Jason Huber (West Virginia University)

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 after ischemia/reperfusion-injury after stroke. Previously, we identified mitoNEET, a [2Fe-2S] redox mitochondrial protein, as a putative drug target for stroke. In this study, we tested the novel mitoNEET ligand, NL-1, 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 drugs were administered at time of reperfusion via IV dosing. Results demonstrated that NL-1 (10 mg/kg) treatment markedly reduced infarct volume and hemispheric swelling in the brain as compared rats treated with vehicle or a lower concentration of NL-1 (0.25 mg/kg). Surprisingly, 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 oxidative stress using immunohistochemical staining corroborated the protective actions of NL-1, showing reduced extravasation of IgG and decreased levels of 4-hydroxynonenal (4-HNE) 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. 

Support or Funding Information

NIH R41 NS110070 amp; P20 GM109098 to WJG

NIH P20 GM103434 to WVU Microscopy Core

NIH RO1 NS099918 to JDH

lt;pgt;lt;span style="font-size: 1em;"gt;NIH R41 NS110070 amp;amp; P20 GM109098 to WJGlt;/spangt;lt;/pgt;lt;pgt;lt;span style="font-size: 1em;"gt;NIH P20 GM103434 to WVU Microscopy Corelt;/spangt;lt;/pgt;lt;pgt;lt;span style="font-size: 1em;"gt;NIH RO1 NS099918 to JDHlt;/spangt;lt;brgt;lt;/pgt;