Elovanoid neuroprotection targets cell transcriptomics and proteomics to sustain synaptic integrity after brain injury.

Traumatic brain injury (TBI), a leading cause of death and disability, is the largest non-genetic, non-aging-related contributor to cognitive impairments. Currently, there are limited effective therapies to protect neurons after acute brain injury. Our results suggest that intranasal-delivered (IN) elovanoid (ELV) shortly after TBI elicits neuroprotection that involves synaptic and mitochondrial pathways that mediate neuroprotection. Using a single-cell multiome approach, we found an upregulation of genes involved in synaptic integrity. Furthermore, we discovered that ELVs improve synaptosomal mitochondrial function, reduce lipid peroxidation, and increase the activity of antioxidant transcriptional programs, including the NRF2 pathway, in neurons. We suggest that these changes, together with the induction of cell-type-specific gene regulation in glutamatergic neurons and other cells, underlie ELV-elicited neuroprotection.