Macromolecular Dexamethasone Prodrug Ameliorates Neuroinflammation and Prevents Bone Loss Associated with Traumatic Brain Injury (S28.001)

Abstract

<h3>Objective:</h3> We hypothesized that systemically administered N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer-based dexamethasone (Dex) prodrugs (P-Dex) will target the brain trauma injury sites, substantially enhance the Glucocorticoid therapy efficacy, and improve its systemic safety. <h3>Background:</h3> Traumatic brain injury is (TBI) a leading cause of morbidity and mortality in children and adults. The pathology of TBI is heterogeneous, resulting from both primary and secondary injury mechanisms, the latter being attributed to the inflammatory response. Use of conventional glucocorticoid formulations (free DEX) leads to limited distribution to the brain, pulsatile brain tissue concentration and systemic side effects, with controversial benefit in being neuroprotective. Dex and prodrugs (P-Dex) passively target inflammation through the leaky vasculature associated with the underlying pathologies. Given the compromised blood brain barrier (BBB) and brain inflammation in the secondary injury phase of the TBI patients, we hypothesized that the systemically administrated P-Dex will passively target the brain trauma injury sites and reduce inflammation with least systemic side effects. <h3>Design/Methods:</h3> 30 mice were randomly assigned into 2 groups: TBI (Cortical impact model) and healthy mice. All mice received Saline, P-Dex or free Dex. They underwent optical imaging, Neurological severity score, Static weight bearing, Immunohistochemistry and Mico-CT analysis. <h3>Results:</h3> We found that P-Dex passively targeted the traumatic brain tissue and had sustained accumulation at the inflamed tissue for over 14 days. Histological evidence demonstrates the P-Dex’s therapeutic effect on the amelioration of neuroinflammation and prevention of neurodegeneration. Behaviorally, the P-Dex treated animals showed better recovery of the imbalance and better neurological severity score post-TBI. Higher bone mineral density and better bone microarchitecture was found in the skeletal tissues from P-Dex treated animals, comparing to the free Dex, and Saline treated animals, confirming the P-Dex bone protection effect. <h3>Conclusions:</h3> P-Dex can be a potential therapy targeting neuro-inflammation and preserving the neurons from death, avoiding bone loss post-TBI. <b>Disclosure:</b> Dr. Wei has nothing to disclose. Dr. Zhao has nothing to disclose. Jia Zhenshan has nothing to disclose. Zhao Zhifeng has nothing to disclose. Dr. Chen has nothing to disclose. Miss Sun has nothing to disclose. Dr. Kelso has received personal compensation for serving as an employee of Agilent Technologies. Dr. Kelso has stock in Agilent Technologies. Dr. Rathore has nothing to disclose. Dr. Wang has nothing to disclose.