Effects of electrical stimulation and gonadal steroids on rat facial nerve regenerative properties

Purpose: The neurotherapeutic effects of nerve electrical stimulation and gonadal steroids have independently been demonstrated. The purpose of this study was to investigate the therapeutic potential of a combinatorial treatment strategy of electrical stimulation and gonadal steroids on peripheral nerve regeneration. Methods: Following a facial nerve crush axotomy in gonadectomized adult male rats, testosterone propionate (TP), dihydrotestos- terone (DHT), or estradiol (E2) was systemically administered with/without daily electrical stimulation of the proximal nerve stump. Facial nerve outgrowth was assessed at 4 and 7 days post-axotomy using radioactive labeling. Results: Administration of electrical stimulation alone reduced the estimated delay in sprout formation but failed to accelerate the overall regeneration rate. Conversely, TP treatment alone accelerated the regeneration rate by ∼10% but had no effect on the sprouting delay. Combining TP with electrical stimulation, however, maintained the enhanced rate and reduced the sprouting delay. DHT treatment alone failed to alter the regeneration rate but combining it with electrical stimulation increased the rate by 10%. E2 treatment alone increased the regeneration rate by ∼5% but with electrical stimulation, there was no additional effect. Conclusions: Electrical stimulation and gonadal steroids differentially enhanced regenerative properties. TP, an aromatizable androgen, augmented regeneration most, suggesting a synergism between androgenic and estrogenic effects. Therapeutically, combining electrical stimulation with gonadal steroids may boost regenerative properties more than the use of either treatment alone.