Z-Bisdehydrodoisynolic acid (Z-BDDA): An estrogenic seco-steroid that enhances behavioral recovery following moderate fluid percussion brain injury in male rats

Several lines of research suggest that estrogens (and estrogenic compounds) are neuroprotective following experimental traumatic brain injury. However, therapeutic use of estrogens in this and other regards remains controversial. Therefore, analysis of estrogen-like compounds without potential problems similar to estrogens seems warranted. (±) Z-Bisdehydrodoisynolic acid (Z-BDDA) is a seco-steroid that has potent estrogenic as well as antioxidant activities in vitro and in vivo. We evaluated the therapeutic potential of Z-BDDA (300 μg/0.1 cc/100 g body weight, sc) to promote the recovery of behavioral function following lateral fluid percussion injury (FPI) to the brain in male rats. Two hours subsequent to FPI, treatment with Z-BDDA began with a bolus subcutaneous (sc) injection followed by booster treatments given 24 and 48 h later. Behavioral testing was initiated on the second day after FPI and results of Z-BDDA treatments were compared to treatment with vehicle only and to sham FPI surgery. Z-BDDA effectively enhanced recovery of coordinated limb movement assessed by locomotor placing performance across the duration of the study. Z-BDDA treated animals also performed better on a spatial memory task in the Morris water maze, showing improved learning curves across days of testing. Vestibulomotor function, measured by beam walk performance, appeared to improve in Z-BDDA treated animals, however these results did not reach statistical significance (p > 0.05). Following cessation of the behavioral testing, all animals underwent assessments of gross neuroanatomical pathology. Cortical lesion size and cell death analysis with Fluoro-jade B failed to reveal Z-BDDA enhanced neuroprotection. These findings support our hypothesis that Z-BDDA can facilitate behavioral recovery following FPI in adult male rats although the mechanism(s) of these effects remain to be determined.

Research Highlights
► Z-BDDA enhances behavioral recovery after lateral fluid percussion brain injury
► Z-BDDA enhances behavioral recovery of locomotor placing after brain injury
► Z-BDDA enhances behavioral recovery on Morris water maze after brain injury