Macromolecular Dexamethasone Prodrug Ameliorates Neuroinflammation and Prevents Bone Loss Associated with Traumatic Brain Injury.

Abstract

Traumatic brain injury (TBI) is one of the leading causes of death and disability among children and young adults in the United States. In this manuscript, we assessed the utility of an N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-based dexamethasone (Dex) prodrug (P-Dex) in the treatment of TBI. Using a controlled cortical impact TBI mouse model, P-Dex was found to passively target and sustain at the traumatic/inflammatory brain tissue for over 14 days after systemic administration. The histological evidence supports P-Dex's therapeutic potential in ameliorating neuroinflammation and mitigating neurodegeneration. Behaviorally, the P-Dex-treated animals showed statistically significant improvement in balance recovery. A trend of neurological severity score improvement at the early time point post-TBI was also noted but did not achieve statistical significance. While probing the potential glucocorticoid side effects that may associate with P-Dex treatment, we discovered that the TBI mice develop osteopenia. Interestingly, the P-Dex-treated TBI mice demonstrated higher bone mineral density and better bone microarchitecture parameters when compared to free Dex and the saline control, revealing the osteoprotective effect of P-Dex in addition to its neuronal protection benefits post-TBI.