Dexamethasone-Loaded Hydrogels Improve Motor and Cognitive Functions in a Rat Mild Traumatic Brain Injury Model

Abstract

Functional recovery following traumatic brain injury (TBI) is limited due to progressive neuronal damage resulting from secondary injury-associated neuroinflammation. Steroidal anti-inflammatory drugs, such as dexamethasone (DX), can reduce neuroinflammation by activated microglia and infiltrated macrophages. In our previous work, we developed hydrolytically degradable poly(ethylene) glycol-bis-(acryloyloxy acetate) (PEG-bis-AA) hydrogels with dexamethasone (DX)-conjugated hyaluronic acid (HA-DXM) and demonstrated that dexamethasone-loaded hydrogels (PEG-bis-AA/HA-DXM) can reduce neuroinflammation, apoptosis, and lesion volume and improve neuronal cell survival and motor function recovery at seven days post-injury (DPI) in a rat mild-TBI model. In this study, we investigate the effects of the local application of PEG-bis-AA/HA-DXM hydrogels on motor function recovery at 7 DPI and cognitive functional recovery as well as secondary injury at 14 DPI in a rat mild-CCI TBI model. We observed that PEG-bis-AA/HA-DXM-treated animals exhibit significantly improved motor functions by the rotarod test and cognitive functions by the Morris water maze test compared to untreated TBI animals. We also observed that PEG-bis-AA/HA-DXM hydrogels reduce the inflammatory response, apoptosis, and lesion volume compared to untreated animals at 14 DPI. Therefore, PEG-bis-AA/HA-DXM hydrogels can be promising a therapeutic intervention for TBI treatment.

Context is key: glucocorticoid receptor and corticosteroid therapeutics in outcomes after traumatic brain injury

“…However, the promising anti-inflammatory effects of glucocorticoids have continued to encourage studies aimed at exploiting the benefits of GC treatment while circumventing the negative side effects. Recent preclinical work has investigated the use of dexamethasone-containing hydrogels for local controlled delivery of GC at the site of injury (Jeong et al, 2021 ; Macks et al, 2022 ). Hydrogel treatment significantly reduced inflammation and improved functional recovery in a rat CCI TBI model, and local delivery avoids risk of systemic side effects (Macks et al, 2022 ).…”

“…Recent preclinical work has investigated the use of dexamethasone-containing hydrogels for local controlled delivery of GC at the site of injury (Jeong et al, 2021 ; Macks et al, 2022 ). Hydrogel treatment significantly reduced inflammation and improved functional recovery in a rat CCI TBI model, and local delivery avoids risk of systemic side effects (Macks et al, 2022 ). Another strategy that has emerged is the use of macromolecular GC prodrugs.…”

Applications of Degradable Hydrogels in Novel Approaches to Disease Treatment and New Modes of Drug Delivery

“…The study of delivering therapeutic agents to the brain is still an area of ongoing research since it requires spatially and temporally restricted exposure [154]. Several researchers [155] have, therefore, designed a scheme to encapsulate poly(lactic-co-glycolic acid (PLGA) microparticles in degradable PEG hydrogel to achieve the local release of two different types of neurotrophins (NFs) with two separate release curves. The biodegradable hydrogels delivered brain-derived neurotrophic factor (BDNF) and glial-derived neurotrophic factor (GDNF) to Parkinson's disease-related brain regions, with BDNF localized in the striatum and GDNF localized in the substantia nigra.…”

The Effect of Dexamethasone on Neuroinflammation and Cerebral Edema in Rats With Traumatic Brain Injury Combined With Seawater Drowning

“…However, several studies have reported that low-dose DX can reduce secondary injury and improve functional recovery [10][11][12]. DX hydrogels covering the surface of the brain reduce the inflammatory response, apoptosis, and lesion volume compared to untreated animals at 14 days after injury [13]. DX prodrug-treated TBI mice demonstrated that their neuronal protection has benefits after TBI [14].…”