Hydrogel-mediated local delivery of dexamethasone reduces neuroinflammation after traumatic brain injury

Abstract

Excessive and prolonged neuroinflammation leads to neuronal cell death and limits functional recovery after traumatic brain injury (TBI). Dexamethasone (DX) is a steroidal anti-inflammatory agent that is known to attenuate early expression of pro-inflammatory cytokines associated with activated microglia/macrophages. In this study, we investigated the effect of dexamethasone-conjugated hyaluronic acid (HA-DXM) incorporated in a hydrolytically degradable, photo-cross-linkable poly (ethylene) glycol-bis-(acryloyloxy acetate) (PEG-bis-AA) hydrogel on the inflammatory response, apoptosis, and functional recovery in a controlled cortical impact (CCI) rat TBI model. In vitro, DX release from PEG-bis-AA/HA-DXM hydrogel was slow in phosphate-buffered saline without enzymes, but significantly increased in the presence of hyauronidase/esterase enzymes. TBI was generated by a CCI device armed with a 3 mm tip (3.5 m s−1, depth: 2 mm) and treated immediately with PEG-bis-AA/HA-DXM hydrogel. PEG-bis-AA/HA hydrogel without DX was used for comparison and untreated TBI group was used as a control. Significant reductions in cavity size, inflammatory response, and apoptosis were observed in animals treated with PEG-bis-AA/HA-DXM compared to those receiving PEG-bis-AA/HA and untreated. Animals receiving the PEG-bis-AA/HA-DXM hydrogel also exhibited higher neuronal cell survival and improved motor functional recovery compared to the other two groups.

The Therapeutic Effect of Intranasal Administration of Dexamethasone in Neuroinflammation Induced by Experimental Pulmonary Tuberculosis

“…Interestingly, relatively low dose DEX administration (1 mg/kg, intraperitoneal injection) has been shown to attenuate inflammation and decrease ED1-positive cells and three markers of inflammatory activation of microglia/macrophage in murine models of traumatic brain injury (TBI) [ 12 , 45 ]. Similar results were found with hydrogel-mediated local delivery of dexamethasone that reduced neuroinflammation and improved functional motor recovery [ 46 ]. Another study reported that dexamethasone alone (0.025 mg/kg) and the co-administration of melatonin and dexamethasone 24 h after TBI improved locomotor function and brain injury [ 47 ].…”

Genipin-Crosslinked, Proteosaccharide Scaffolds for Potential Neural Tissue Engineering Applications

“…Dexamethasone-21-phosphate is a synthetic glucocorticoid steroid with anti-inflammatory activity. DEX can therefore play an important role in TBIs due to its ability to bind to astrocyte glucocorticoid receptors and prevent the proliferation of astrocytes [40,41]. Furthermore, DEX can lower the production of cytokines such as IL-1β, INF-γ and TNF-α [40].…”

A Prosperous Application of Hydrogels With Extracellular Vesicles Release for Traumatic Brain Injury

“…It has advantages in the treatment of diseases like TBI where damage factors exist for a prolonged period. Jeong et al placed dexamethasone in a hydrogel constructed by PEG-bis-AA/HA [photo-cross-linkable poly (ethylene) glycol-bis-(acryloyloxy acetate)/hyaluronic acid], demonstrating that compared with traditional intraperitoneal injection, this new drug delivery strategy markedly reduced the dosage of dexamethasone, as much as half above ( 48 ).…”