Abstract W MP75: Docosahexaenoic Acid Upregulates Iduna Expression in the Ischemic Penumbra and Protects Rat Brains Against Focal Ischemia

Abstract

Introduction: Ring finger protein 146, also called Iduna, has been identified, as a neuroprotective protein. Iduna facilitates DNA repair and protects against cell death induced by NMDA receptor-mediated glutamate excitotoxicity or cerebral ischemia. Recently, we have shown that docosahexaenoic acid (DHA; 22:6n-3) therapy improves functional and histological outcomes following experimental stroke. This study evaluated the time course expression of Iduna in the ischemic penumbra and the role of DHA in cerebral ischemia and its potential mechanism. METHODS: Thirty-six male SD rats were anesthetized with isoflurane and subjected to 2 h of middle cerebral artery occlusion (MCAo) by poly-L-lysine-coated intraluminal suture. DHA (5 mg/kg) or vehicle (saline) was administered IV at 3 h after the onset of MCAo and animals were sacrificed on days 1, 3 and 7 (n=6 rats per group). The neurological function was evaluated during occlusion (60 min), and on days 1, 3 and 7 after MCAo; a grading scale of 0-12 was employed (0=normal and 12=maximal deficit). Western blot and double immunostaining (Iduna/NeuN and Iduna/GFAP) were used to analyze Iduna expression in the ischemic penumbra on days 1, 3 and 7. RESULTS: All animals showed similar values for rectal and cranial temperatures, arterial blood gases, and plasma glucose during and after MCAo. Behavioral deficit was significantly improved by treatment with DHA compared to vehicle on days 1 (by 30%), 3 (by 31%) and 7 (by 32%). Western-blot analysis showed that DHA treatment increased Iduna expression in the ischemic penumbra compared to vehicle on day 1 (2.2±0.3 vs. 0.6±0.1) and day 3 (0.44±0.05 vs. 0.3±0.01, respectively). There were no differences in Iduna expression on day 7 between DHA and vehicle-treated groups (0.33±0.02 and 0.35±0.02). Immunostaining revealed that Iduna expression was increased in the penumbra of DHA-treated rats. Conclusions: DHA protected the brain from severe damage caused by MCAo. This effect may be through upregulation of Iduna expression in the ischemic penumbra. Thus, it is reasonable to hypothesize that DHA has potential for the effective treatment of ischemic stroke in patients.