Preclinical Development of Oleoylethanolamide as a Medical Countermeasure for Long-Term Neurotoxicity Following Organophosphate Exposure

Organophosphate (OP) agents, including pesticides like chlorpyrifos (CPF) and nerve agents used in warfare or terrorism, pose a significant threat to civilian and military populations. While acute OP toxicity is attributed to cholinergic overstimulation, growing evidence indicates that survivors often experience long-term and chronic neurobehavioral and autonomic dysfunction that persists long after the resolution of acute symptoms. These chronic sequelae, including fatigue, anxiety, cognitive impairment, and autonomic dysregulation, are increasingly linked to brainstem pathology and persistent neuroinflammation in autonomic nuclei such as the nucleus tractus solitarius (NTS) and dorsal vagal complex. Currently, there is no FDA-approved medical countermeasure therapeutic strategy available for reducing the risk of this chronic sequalae of acute neurotoxic OP exposure. This project will evaluate oleoylethanolamide (OEA), an orally bioavailable endogenous lipid, as a repurposed therapeutic countermeasure that acts via the gut–vagal–brainstem axis. Oleoylethanolamide activates peroxisome proliferator-activated receptor alpha (PPAR-α) in the intestinal epithelial and surrounding cells, stimulates enteroendocrine peptide release, and triggers vagal afferent signaling to the brainstem nuclei involved in mood, fatigue, arousal, and autonomic regulation. Our preclinical studies and pilot clinical trial of OEA has shown promising effects in reducing fatigue and improving mood associated with Gulf War Illness (GWI), a chronic multisymptom illness (CMI) with overlapping etiology and symptomatology of survivors if Tokyo Subway and Matsumoto sarin attack. In Aim 1, we will define the pharmacokinetics (PK) and pharmacodynamics (PD) of orally administered OEA in mice and identify an optimal formulation and dose that achieve gut target engagement and vagal activation. In Aim 2, we will evaluate the efficacy of OEA in mitigating long-term behavioral, autonomic, and neuropathological outcomes in a validated mouse model of acute CPF exposure. Both acute and delayed post-exposure treatment paradigms will be tested. Endpoints will include behavioral assays of fatigue and anxiety, autonomic function (e.g., heart rate variability), and immunohistochemical and molecular markers of neuroinflammation and neuronal injury in brainstem regions. This project directly addresses the NIH CounterACT program’s mission by supporting the discovery and development of orally available, scalable, and mechanistically defined medical countermeasures for high- consequence chemical threats. Successful completion of these studies will provide proof-of-concept data and translational justification for advancing OEA toward regulatory development as a therapeutic for treating CMI associated with OP exposure. Project Number: 1R21NS147992-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Neurological Disorders and Stroke (NINDS) | Principal Investigator: Laila Abdullah | Institution: ROSKAMP INSTITUTE, INC., SARASOTA, FL | Award Amount: $468,875 | Activity Code: R21 | Study Section: Special Emphasis Panel[ZRG1 KUDS-K (54)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11336609