Thiol‐Based Neuroprotective Copolymers Acutely Restore Redox Metabolism and Mediate Vasogenic Edema in a Mouse Model of Traumatic Brain Injury

Effective pharmaceutical interventions for treating the secondary damage associated with traumatic brain injury (TBI) are limited due to poor delivery into the brain, insufficient target engagement, and an incomplete understanding of the pathophysiological changes that occur post-impact. Thus, nanoparticles (NP), which have an enhanced permeation and retention-like effect within the perturbed blood-brain barrier, have grown as a potential candidate for treating TBI. We have investigated the antioxidant capacity of thiol-based NP, termed neuroprotective copolymers (NPC3), and their ability to neutralize reactive oxygen species (ROS) and lipid peroxidation products (LPOx). Here, we assessed the efficacy of NPC3 for alleviating the secondary injury cascade in TBI with a specific focus on ameliorating molecular and structural deficits in a mouse controlled cortical impact (CCI) model. NPC3 delivered post-CCI alleviated oxidant burden, reducing both antioxidant enzyme expression and Nrf2 activation. These changes in redox signaling resulted in a shift in metabolic function, with increased AMPK activation with NPC3 treatment. T2-weighted and diffusion magnetic resonance imaging revealed vasogenic edema formation at 30 days post-CCI and alterations in mean diffusivity, which were moderated by NPC3. Furthermore, NPC3 reduced GFAP and Iba1 at multiple impact severities, which positively correlated with urinary 8-isoprostane. Overall, this work shows NPC3 reduced glial reactivity, affected redox metabolism, and ultimately contributed to improvements in structural deficits post-CCI.