Abstract TP240: Novel Lipid Mediators C-36:6 And C-38:6 Administered Intranasally Are Neuroprotective In Experimental Ischemic Stroke

Abstract

Objective: Ischemic stroke induces multiple pathophysiological processes involving oxidative stress, loss of homeostasis, excitotoxicity, disruption of the blood-brain barrier and neurovascular unit, contributing to neuronal death. In the early phases following the onset of ischemic damage, neuroinflammation contributes to tissue damage and enlargement of the infarct area. Elovanoids (ELVs) are a class of pro-homeostatic lipid mediators that are derivatives of very long-chain polyunsaturated fatty acids (VLC-PUFAs). VLC-PUFAs are synthesized by ELOVL4 an enzyme primarily expressed in neurons. ELVs have been shown to reduce infarct volume and promote cell survival when administered IV following 2h of middle cerebral artery occlusion (MCAo). This study aimed to test the neuroprotective efficacy of these VLC-PUFA ELV precursors when administered intranasally (IN) in a model of experimental ischemic stroke. Methods: Male Sprague-Dawley rats received 2h of the middle cerebral artery occlusion (MCAo). Treatment with C-36:6, C-38:6 (1μg/μl, 20 μg) or vehicle (saline + ethanol) was administered at 1, 24, and 48h after onset MCAo. Behavior was evaluated using a composite neurological battery; a grading scale of 0-12 was employed (normal score=0, maximal deficit=12). Behavior testing was performed on days 1, 2, 3, and 7, followed by ex vivo MRI for lesion volumes and edema (T2WI) and immunohistochemistry on day 7. Results: Following drug administration, no behavioral side effects were observed. Neurologic function was improved on days 1, 3, and 7 by 24%, 37%, and 28% in animals receiving C-36:6 and by 26%, 26%, and 29% in the group receiving C-38:6. Total, core, and penumbra lesion volumes, computed using T2WI, were reduced with C-36:6 by 60%, 68%, and 53%, and C-38:6 by 35%, 43% 25% vs vehicle. Total, cortical and subcortical infarct areas and volumes were reduced by treatments with C-36:6 (by 42% 48% and 34%) and C-38:6 (by 28% 31% and 20%) vs vehicle. Conclusion: IN delivered ELV precursors demonstrated neuroprotective efficacy improving behavior and reducing infarct volume compared to vehicle. We are exploring neuroprotective molecular mechanisms exerted by intranasally delivered VLC-PUFAs as an experimental therapeutic approach.