A Novel Dehydroepiandrosterone Analog Improves Functional Recovery in a Rat Traumatic Brain Injury Model

Abstract

The purpose of this study was to investigate the efficacy of a novel steroid, fluasterone (DHEF, a dehydroepiandrosterone (DHEA) analog), at improving functional recovery in a rat model of traumatic brain injury (TBI). The lateral cortical impact model was utilized in two studies of efficacy and therapeutic window. DHEF was given (25 mg/kg, intraperitoneally) at the initial time point and once a day for 2 more days. Study A included four groups: sham injury, vehicle treated (n = 22); injured, vehicle treated (n = 30); injured, pretreated (5-10 min prior to injury, n = 24); and injured, posttreated (initial dose 30 min postinjury, n = 15). Study B (therapeutic window) included five groups: sham injury, vehicle treated (n = 17); injured, vehicle treated (n = 26); and three posttreatment groups: initial dose at 30 min (n = 18), 2 h (n = 23), or 12 h (n = 16) postinjury. Three criteria were used to grade functional recovery. In study A, DHEF improved beam walk performance both with pretreatment (79%) and 30-min posttreatment group (54%; p < 0.01, Dunnett vs. injured vehicle). In study B, the 12-h posttreatment group showed a 97% improvement in beam walk performance (p < 0.01, Dunnett). The 30-min and 12-h posttreatment groups showed a decreased incidence of falls from the beam, which reached statistical significance (p < 0.05, Dunnett). Tests of memory (Morris water maze) and neurological reflexes both revealed significant improvements in all DHEF treatment groups. In cultured rat mesangial cells, DHEF (and DHEA) potently inhibited interleukin-1beta-induced cyclooxygenase-2 (COX2) mRNA and prostaglandin (PGE2) production. In contrast, DHEF treatment did not alter injury-induced COX2 mRNA levels in the cortex or hippocampus. However, DHEF (and DHEA) relaxed ex vivo bovine middle cerebral artery preparations by about 30%, with an IC(50) approximately 40 microM. This was a direct effect on the vascular smooth muscle, independent of the endothelial cell layer. Fluasterone (DHEF) treatments improved functional recovery in a rat TBI model. Possible mechanisms of action for this novel DHEA analog are discussed. These findings suggest an exciting potential use for this agent in the clinical treatment of traumatic brain injury.

Cyclooxygenase-2-specific Inhibitor Improves Functional Outcomes, Provides Neuroprotection, and Reduces Inflammation in a Rat Model of Traumatic Brain Injury

“…Morris Water Maze-The water maze, used to assess hippocampal-dependent spatial memory function (34), was conducted exactly as described previously (51). The best score from three probe trials was used for each animal.…”

Current Therapeutic Modalities, Enzyme Kinetics, and Redox Proteomics in Traumatic Brain Injury

“…Both PROG and ALLO have beneficial effects in reducing blood-brain barrier dysfunction and intracranial pressure following TBI, and also in reducing brain swelling and edema that are associated with TBI [49]. DHEAS and its analog, fluasterone (DHEF), can also improve recovery of function in male rats after TBI [50,51]. These findings altogether bolster the neuroprotective effects of neurosteroids and their analogs thereby, leading to plausible future therapeutic strategies in the clinical treatment of TBI.…”

Neurosteroids and their neuroprotective actions

“…Possible DHEF mechanisms of action are still unclear. According to Malik et al (2003), this neurosteroid exhibited anti-inflammatory action, markedly inhibiting synthesis of prostaglandin (PGE2) and interleukin-1βa-induced cyclooxygenase-2 (COX2) in cultures of rat mesangial, but not cortical or hippocampal cells (Malik, et al 2003).…”