Effect of Endogenous Androgens on 17β-Estradiol-Mediated Protection after Spinal Cord Injury in Male Rats

Abstract

Several groups have recently shown that 17b-estradiol is protective in spinal cord injury (SCI). Testosterone can be aromatized to 17b-estradiol and may increase estrogen-mediated protection. Alternatively, testosterone has been shown to increase excitotoxicity in models of central nervous system (CNS) injury. These experiments test the hypothesis that endogenous testosterone in male rats alters 17b-estradiol-mediated protection by evaluating a delayed administration over a clinically relevant dose range and manipulating testicular-derived testosterone. Adult male Sprague Dawley rats were either gonadectomized or left gonad-intact prior to SCI. SCI was produced by a midthoracic crush injury. At 30 min post SCI, animals received a subcutaneous pellet of 0.0, 0.05, 0.5, or 5.0 mg of 17b-estradiol, released over 21 days. Hindlimb locomotion was analyzed weekly in the open field. Spinal cords were collected and analyzed for cell death, expression of Bcl-family proteins, and white-matter sparing. Post-SCI administration of the 0.5-or 5.0-mg pellet improved hindlimb locomotion, reduced urinary bladder size, increased neuronal survival, reduced apoptosis, improved the Bax=Bcl-xL protein ratio, and increased white-matter sparing. In the absence of endogenous testicular-derived androgens, SCI induced greater apoptosis, yet 17b-estradiol administration reduced apoptosis to the same extent in gonadectomized and gonadintact male rats. These data suggest that delayed post-SCI administration of a clinically relevant dose of 17b-estradiol is protective in male rats, and endogenous androgens do not alter estrogen-mediated protection. These data suggest that 17b-estradiol is an effective therapeutic intervention for reducing secondary damage after SCI in males, which could be readily translated to clinical trials.

17β-Estradiol Confers Protection after Traumatic Brain Injury in the Rat and Involves Activation of G Protein-Coupled Estrogen Receptor 1

“…The majority of data suggest that E2 does indeed protect against apoptotic cell death, and this is perhaps mediated through mitochondrial anti-apoptotic mechanisms, as some studies investigating estrogen in CNS trauma have reported favorable modulation of Bcl family proteins. 15,17,20,25,48,49 Astrogliosis is characterized by hypertrophy of astrocytic processes and upregulation of GFAP expression in astrocytes, features which are both commonly observed following TBI. 31,50 We found a significant dose-dependent reduction in GFAP-IR staining in both cortex and hippocampus in treatment groups that received E2, similar to previously reported findings.…”

“…Our research group has previously reported that E2 administration confers protection in models of spinal cord injury (SCI) and severe blood loss. [13][14][15][16][17][18][19][20][21] In prior TBI research, E2 has been shown to reduce cortical contusion volumes, apoptosis, blood-brain barrier permeability, edema, levels of pro-inflammatory cytokines, and intracranial pressure (ICP), as well as to upregulate expression of anti-apoptotic protein Bcl-2, increase cerebral perfusion pressure (CPP), and improve neurological scores. [22][23][24][25][26][27] Taken together, these data suggest that E2 is protective and warrants further study as a potential therapeutic for treatment of TBI.…”

Characterization of a Graded Cervical Hemicontusion Spinal Cord Injury Model in Adult Male Rats

“…This analysis was conducted with an Olympus BX-51 microscope linked to a MicroFire Ò true color CCD digital camera (Optronics, Goleta, CA) at 400Â magnification. The optical fractionator probe in StereoInvestigator software (Microbrightfield, Inc., Williston, VT) was used to determine the total number of neurons in the ventral horn at the lesion epicenter as previously described (Chaovipoch et al, 2006;Kachadroka et al, 2010). The formula employed by StereoInvestigator software for the estimation of cell populations is:…”

Single-Walled Carbon Nanotubes Chemically Functionalized with Polyethylene Glycol Promote Tissue Repair in a Rat Model of Spinal Cord Injury

“…We evaluated the effects of delayed administration of SWNT-PEG on functional recovery of hindlimb locomotion using the Basso-Beattie-Bresnahan (BBB) open field test as previously described (Basso et al, 1995;Chaovipoch et al, 2006;Kachadroka et al, 2010), and kinematic analysis of hindlimb use with the CatWalk gait analysis system (Hamers et al, 2006). Behavioral tests were conducted on post-SCI day 5 (prior to administration of SWNT-PEG), and then once per week for 35 days post-SCI beginning 7 days after the administration of SWNT-PEG, which corresponds to post-SCI day 14.…”