Abstract TMP109: Elovanoid Precursors Are Neuroprotective in Experimental Ischemic Stroke

Abstract

Objective: Ischemic stroke triggers oxidative and biochemical responses that disrupt cell homeostasis. We previously demonstrated that Elovanoids (ELVs), a novel class of homeostatic lipid mediators, reduced infarct volumes and improved neurologic function when administered IV following middle cerebral artery occlusion (MCAo). The present study defines neuroprotection by very long-chain polyunsaturated fatty acid (VLC-PUFA) ELV precursors (C-32:6 and C-34:6) delivered intranasally following experimental ischemic stroke. Methods: Male SD rats underwent 2 hours of MCAo. Treatments with C-32:6, C-34:6 (1μg/μl, 20 μg per rat), or vehicle were administered at 1, 24, and 48h after onset of MCAo. Behavior testing was performed on days 1, 2, 3, and 7. Ischemic core and penumbra were computed from T2WI on day 7 followed by immunohistochemistry. RT-qPCR gene expression was investigated in a separate cohort of rats treated as above at 72 h. Results: C-32:6 and C-34:6 improved behavioral function on days three by (41% and 20%) and seven by (45% and 24%); T2WI total lesion volumes were reduced by (87% and 61%), respectively, compared to the vehicle. In the ischemic penumbra, C-32:6 and C-34:6 reduced TMEM119 + microglia by (38% and 29%), increased NeuN + neurons by (87% and 110%), reduced IgG staining by (54% and 25%), and increased the number of SMI-71 + vessels by (50% and 26%). In the core, C-32:6 and C-34:6 reduced TMEM119 + microglia by (12% and 15%), increased NeuN + neurons by (251% and 89%) and increased the number of SMI-71 + vessels by (31% and 70%). Anti-inflammatory marker genes for protective microglia and astrocyte phenotypes Tm4sf1, Thbs1, Ptx3, Gpc4, Fizz1, Cd14, Msr1, Manf , and Osmr were upregulated with C-32:6 and genes Fcrls, S1pr3, and Vim were downregulated with C-34:6. Conclusion: These data suggest that IN administered C-32:6 C-34:6 improved behavior, protected the ischemic penumbra, increased neurogenesis and angiogenesis, and reduced the number of microglia cells. The overall gene expression changes observed from free fatty acid C-32:6 indicate that its modulatory effects promote the biological activity of astrocytes, microglia, and cerebrovascular cells involved in plasticity.