ELOVANOID DRIVEN NEUROPROTECTION AFTER EXPERIMENTAL STROKE AND TRAUMATIC BRAIN INJURY: A SINGLE-CELL PERSPECTIVE

Examination Date

Summer 6-4-2026

Degree

Dissertation

Degree Program

Neuroscience

Examination Committee

Nicolas G. Bazan, Ludmila S. Belayev, Jorgelina Calandria, Xiaolin Tian, Eric D. Lazartigues, Shyamal D. Desai

Abstract

Traumatic brain injury (TBI) and ischemic stroke (ICS) remain major causes of death and long-term neurological disability. Effective therapies that preserve neuronal survival, limit inflammation, and promote long-term recovery are lacking. Elovanoids (ELV), lipid mediators derived from very-long-chain polyunsaturated fatty acids, are pro-homeostatic and neuroprotective molecular guardians of the central nervous system. However, their cell-type-specific mechanisms after acute injury remain only partially understood.

This dissertation investigated the therapeutic potential and cellular mechanisms of intranasally delivered ELV in experimental TBI and ICS using single-cell multiome sequencing, spatial transcriptomics, and immunohistochemical validation. We hypothesize that ELV mitigate inflammatory signaling, oxidative stress, and damaging glial activation through coordinated regulation of immune resolution, antioxidant defense, and neural repair pathways, thereby preserving neuronal viability, and supporting tissue recovery.

Using a controlled cortical impact model of TBI, intranasal ELV administration delivered 1 hour after injury reduced lipid peroxidation, improved synaptosomal mitochondrial function, and upregulated NRF2 to counteract oxidative stress. Single-cell multiome analysis revealed cell-type-specific transcriptional responses, including increased expression of genes associated with synaptic integrity. These findings suggest that ELV protect the injured brain after TBI by supporting synaptic and metabolic machinery required for neuronal resilience.

In ICS, single-cell multiome profiling demonstrated that ELV or its precursor reduced neuronal loss, restored homeostatic microglial states, and suppressed pro-inflammatory microglia expressing Spp1, Gpnmb, Lgals3, and Clec7a. ELV also shifted astrocytes, oligodendrocytes, and oligodendrocyte precursor cells away from pro-inflammatory phenotypes while promoting gene programs associated with synaptic organization and cell survival. High-resolution spatial transcriptomics further revealed that ELV selectively protected the cortical penumbra after middle cerebral artery occlusion by increasing homeostatic-like microglia and reducing pro-inflammatory microglia, neutrophil infiltration, blood–brain barrier disruptions while supporting astrocyte, neuronal, and oligodendrocyte-lineage survival. ELV treatment also increased expression of pro-survival genes, including Clu, Cryab, and Pea15, and reduced apoptotic cell death.

Together, these studies support the concept that ELV coordinate protection across neuronal, glial, immune, and vascular compartments after acute brain injury. Thus, this dissertation will examine ELV action at the single-cell and spatial resolution and establishes a mechanistic framework for understanding ELV neuroprotection in TBI, ICS, and related neurodegenerative conditions.

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