Abstract T P326: Additive Neuroprotection of a 20-hete Inhibitor with Delayed Therapeutic Hypothermia after Asphyxic Cardiac Arrest in Neonatal Piglets
The arachidonic acid metabolite 20-hydroxyeicosatetraenoic acid (20-HETE) has been found to contribute to neurodegeneration after asphyxic cardiac arrest in neonatal piglets. Current therapy involving hypothermia is only partially effective, in part, because initiation of hypothermia is often delayed. Therefore, an unmet need is to find a neuroprotective drug that can be safely given early after resuscitation and that provides additional protection compared to delayed hypothermia alone. Here, we tested whether administration of the 20-HETE-synthesis inhibitor HET0016 (1 mg/kg) at 5 min after return of spontaneous circulation (ROSC) combined with whole body cooling initiated at 3 h of ROSC enhances the neuroprotection compared to delayed hypothermia alone. Anesthetized piglets (3-4-day-old) were subjected to 45 min ventilation with 10% O2, 7 min of airway occlusion, and CPR. In hypothermic groups, cooling started at 3 h ROSC and rewarming occurred over 4 h starting at 20 h ROSC. The density of viable neurons at 10 days ROSC was significantly increased with delayed hypothermia alone (n=12) compared to normothermic recovery (n=6) in sensorimotor cortex (63±5% to 71±6%; % of sham; ±SD), ventral posterolateral thalamus (41±6% to 57±8%), putamen (23±2% to 61±75%), caudate nucleus (58±5% to 72±6%), and CA3 hippocampus (59±3% to 71±5%). Further significant increases occurred with HET0016+hypothermia (n=12) in cortex (86±6%), thalamus (73±8%), and putamen (70±6%), but values remained less than in the sham group (n=6). Neurologic deficits with combined treatment were less than in the normothermic group through 6 days ROSC. Early treatment with the 20-HETE inhibitor HET0016 enhances the therapeutic benefit of delayed hypothermia in protecting regionally vulnerable neurons from asphyxic arrest.
Author Disclosures: J. Zhu: None. B. Wang: None. J. Lee: None. J. Armstrong: None. U. Bhalala: None. Z. Yang: None. L. Martin: None. R. Koehler: None.
This research has received full or partial funding support from the American Heart Association, Mid-Atlantic Affiliate - District of Columbia, Maryland, North Carolina, South Carolina, Virginia.
- © 2014 by American Heart Association, Inc.