Modulation of TLR4-mediated inflammatory pathways and oxidative stress by cerium oxide nanoparticles in traumatic brain injury.

OBJECTS: Traumatic brain injury (TBI) induces secondary neurodegeneration by interdependent inflammatory and oxidative processes. While cerium oxide nanoparticles (CeO2) exhibit antioxidant potential, regulation of Toll-like receptor 4 (TLR4)-driven neuroinflammation remains to be disclosed. The current study investigates the neuroprotective function of CeO2 in rat models of diffuse TBI focusing on the modulation of the TLR4 signaling pathway.

METHOD: Thirty-six male Wistar rats (n = 6/group) were randomly assigned to six groups: Sham, DMSO, TBI, and three TBI groups receiving CeO2 at 0.1, 0.5, or 1 µg/kg. Neuroinflammation (TLR4, TNF-α, IL-1β), markers of oxidative stress (MDA, NO, SOD, GPx), functional recovery through Veterinary Coma Scale (VCS), and histopathological changes were examined.

RESULTS

CeO2 treatment demonstrated significant TLR4 suppression, corresponding with reduced pro-inflammatory cytokine release. The nanoparticles also concurrently inhibited oxidative damage by enhancing endogenous antioxidants. These molecular effects improved neural function, and treated animals were more responsive in motor and alertness tests. Histological analysis showed a reduction in edema in the CeO2 treated groups compared to the TBI group.

CONCLUSION

The study establishes that CeO2 exert neuroprotection through following mechanisms: (1) TLR4-mediated anti-inflammatory action and (2) catalytic ROS scavenging. Notably, we identify TLR4 modulation as a previously unrecognized therapeutic target of CeO2 in TBI. These findings position CeO2 as a promising multitarget nanotherapeutic for TBI that can treat neuroinflammation and oxidative stress - two principal drivers of secondary injury simultaneously. This research provides groundbreaking evidence for the development of CeO2 based neuroprotective strategies and offers potential advantages over current pharmacological approaches under clinical evaluation.