Abstract
Neuroinflammation is widely recognized as a key pathological hallmark of Alzheimer's disease (AD). Recently, inhibiting soluble epoxide hydrolase (sEH) has emerged as a promising therapeutic strategy for AD. sEH plays a pivotal role in neuroinflammation by hydrolyzing epoxyeicosatrienoic acids (EETs), which have anti-inflammatory and neuroprotective properties, into pro-inflammatory dihydroepoxyeicosatrienoic acids (DHETs). Furthermore, the overexpression of the enzyme in the brains of AD patients and animal models of the disease highlights its relevance as a therapeutic target. Our previous studies, using the inhibitor UB-SCG-51 demonstrated that sEH inhibition regulates neuroinflammation and other mechanisms, such as the unfolded protein response pathway, while reducing autophagy, apoptosis, and neuronal death, thereby promoting neuroprotection. Building on these findings, we evaluated the arginine salt of the compound, designated UB-SCG-74, which offers improved oral absorption compared to that of UB-SCG-51 while retaining high permeability, potency, and selectivity. In experiments using 5XFAD mice, UB-SCG-74 treatment significantly improved cognition and synaptic plasticity, outperforming donepezil, a standard AD drug, and ibuprofen, an anti-inflammatory drug. Remarkably, these benefits persisted for 4 weeks after administration cessation, suggesting lasting therapeutic effects. Safety pharmacology studies showed no toxicity, supporting the advancement of UB-SCG-74 into preclinical regulatory evaluation. Our findings further indicate that sEH inhibition engages multiple neuroprotective pathways, potentially modifying both AD symptoms and disease progression, thus reinforcing its therapeutic potential.