Abstract 10968: Neuroprotectin D1 Induces Protection After Brain Ischemic Injury in a Mouse Stroke Model by Blocking Mitochondria-mediated Cell Death Pathways

• Published in: Circulation (New York, N.Y.) Vol. 140; no. Suppl_1 Suppl 1; p. A10968
• Main Authors: Zirpoli, Hylde, Sosunov, Sergey A, Niatsetskaya, Zoya V, Mayurasakorn, Korapat, Manual Kollareth, Denny Joseph, Norris, Paul C, Serhan, Charles N, Ten, Vadim S, Deckelbaum, Richard J
• Format: Journal Article
• Language: English
• Published: by the American College of Cardiology Foundation and the American Heart Association, Inc 19.11.2019
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/circ.140.suppl_1.10968

IntroductionNeonatal hypoxic-ischemic (HI) brain injury is a major cause of mortality and morbidity in newborn infants. Neurons may undergo apoptosis in the ischemic area and the penumbra zone after few hours/days following the insult and BAX is one of the cardinal executioners of this cell death pathway. We have recently reported that acute injection of docosahexaenoic acid (DHA) immediately after HI brain injury, confers neuroprotection in neonatal mice. This was associated with an increase of 10R,17S-dihydroxydocosa-4Z,7Z,11E,13E,15Z,19Z-hexaenoic acid (NPD1) levels in the ischemic brain. Based on these findings, we examined whether a direct administration of NPD1 could lead to neuroprotection after HI brain injury, reducing mitochondria-mediated apoptosis.Methods and ResultsWe found that acute injection of NPD1 immediately after HI injury reduced infarct volume by ~40% compared to the control group; while another DHA derivative, Resolvin D2, did not show equal effectiveness compared to NPD1. At 7 days after HI insult, neuroanatomical analysis demonstrated a substantial preservation of the ipsilateral hemisphere in NPD1 treated mice compared to the control group (p<0.05). We also observed that NPD1 treatment improved sensorimotor performances (longer wire-holding and shorter bridge-crossing times, p<0.05). Neuroprotective effects of NPD1 were associated with reduced BAX mitochondrial insertion and oligomerization. BAX deactivation induced by NPD1 treatment leaded to a decrease of AIF localization into the nuclei by 40% (p<0.05). To confirm if NPD1 directly blocks BAX translocation, we assessed the effects of NPD1 in the presence of a pro-apoptotic agent, staurosporine, using an in vitro model, mouse embryonic fibroblasts (MEFs). NPD1 exposure markedly inhibited mitochondria-mediated apoptosis, detected by confocal microscopy, reducing BAX translocation from cytosol to mitochondria and subsequently decreasing caspase-3 activation.ConclusionOur findings show that acute injection of a DHA derived mediator, namely NPD1, directly provides neuroprotection after HI injury as a stroke model, and this is associated with preservation of mitochondrial outer membrane functionality and with inhibition of apoptotic pathways.