Iduna contributes to the therapeutic effect of DHA in a cell and mouse model of traumatic brain injury via Wnt/MDM2 pathway

Abstract

Traumatic brain injury (TBI) is a severe condition that leads to brain damage and affects brain function. Importantly, TBI incurs public health costs due to its high mortality, and effective treatment for TBI is still lacking. Docosahexaenoic acid (DHA) has a neuroprotective effect that can reduce oxidative, apoptosis, and inflammatory processes. Administration of DHA after TBI attenuates oxidative stress and protein accumulation and is regarded as a potential therapeutic. Iduna is a regulator of parthanatos, and upregulation of Iduna reduces cellular damage and mitochondrial dysfunction. Thus, we speculated that overexpression of Iduna might promote DHA therapy in the treatment of TBI. Here, we found that after combination overexpression of Iduna and DHA in a mouse model of TBI, the expression of inflammatory factors was reduced, while the secretion of neuroprotective factors was increased. In addition, we found that these effects might be mediated by the Wnt/MDM2 pathway, and Iduna might be a therapeutic target for TBI.

The role of regulatory necrosis in traumatic brain injury

“…Recent studies demonstrated that iduna is a newly discovered ubiquitin E3 ligase and an endogenous regulator of parthanatos, which can reduce PARP activation and nuclear translocation of AIF to prevent parthanatos, indicating that ubiquitin-proteasome pathway may also play a role in parthanatos (Xu et al, 2019). At the same time, iduna may promote docosahexaenoic acid 10.3389/fnmol.2022.1005422 (DHA) through Wnt/MDM2 pathway and reduce the damage of TBI cell and mitochondrial dysfunction (Shi et al, 2022). Based on these reports, targeting PARP1-dependent parthanatos may be a potential strategy for the treatment of secondary injury after TBI.…”