Forrest M. Kievit
Date of this Version
Tarudji, Aria W., "UNDERSTANDING THE ROLE OF ANTIOXIDANT NANOPARTICLES IN IMPROVING THE OUTCOME OF SECONDARY INJURY IN TRAUMATIC BRAIN INJURY" (2022). ETD collection for University of Nebraska - Lincoln.
Following traumatic brain injury (TBI), excess reactive oxygen species (ROS) and other free radicals are released, inducing the cascade of secondary injury that exacerbate the outcomes of TBI. Antioxidant nanoparticles (ANPs) have shown promising outcomes in reducing the progression of TBI, which may be due to the higher accumulation and retention of ANPs in the injured brain. However, there is limited knowledge of: 1) antioxidant activities needed in TBI treatment, 2) correlation between longer retention, bioavailability, and target engagement with antioxidant treatments, and 3) sexual dimorphism to ANP treatments.
This dissertation assesses multiple ANPs with various scavenging activities and durations to overcome the current limitations in reducing the secondary injury of TBI. First, an ROS scavenger NP (NP1) with thioether bonds that react within hours was utilized, and showed reductions in oxidative stress in the acute phase of injury and neuroinflammation in the chronic phase of injury in female mice. Next, a large size ANP (Pro-NP™) with multiple antioxidant enzymes and scavenging activity of more than 24 hours was tested in male and female TBI mice. Pro-NP™ showed more benefit in reducing the secondary injury in males than females in the acute phase, but exacerbate the TBI progression in the subacute phase of injury in males. Next, a small size ANP (NPC3) with multiple free radical scavenging capabilities that react within minutes was tested in male and female TBI mice. We found a reduction in secondary injury at 1-day post-injury, but the progression returned at 3-day post-injury. NPC3 also showed more reduction in oxidative stress biomarkers in males. Finally, a ligand to target disrupted blood-brain barrier was assessed for multiple administrations of ANPs. The results suggested ANPs with multiple free radical scavengers were more effective in mitigating the TBI progression than ANPs with ROS-only scavengers, minimal benefit from longer retention and scavenging activity when antioxidants were administered immediately following an injury, and males benefited more from ANPs treatment than females.
Advisor: Forrest M. Kievit