Inhibition of the Accelerative Effects of Testosterone on Hamster Facial Nerve Regeneration by the Antiandrogen Flutamide

doi:10.1006/exnr.1995.1016

Experimental Neurology

Volume 133, Issue 2, June 1995, Pages 138-143

https://doi.org/10.1006/exnr.1995.1016 Get rights and content

Abstract

We have previously demonstrated that systemic administration of testosterone propionate (TP) to adult hamsters accelerates the rate of facial nerve regeneration following crush axotomy of the facial nerve at its exit from the stylomastoid foramen. In this study, we utilized flutamide, a potent nonsteroidal antiandrogen, in conjunction with radioisotopic labeling procedures for the assessment of facial nerve regeneration rates to test the hypothesis that TP exerts its accelerative effects on facial nerve regeneration through a receptor-mediated mechanism. Castrated adult male hamsters were subjected to right facial nerve crush axotomies and divided into three groups of axotomized animals: castrate plus one subcutaneous TP implant plus daily injections of flutamide, castrate plus one subcutaneous TP implant plus vehicle injections, and castrate only plus sham implant and vehicle injections. There were two postoperative timepoints: 4 and 7 days. In agreement with previous studies, systemic administration of TP resulted in an approximately 26% increase in the rate of regeneration of the fastest growing population of axons. Exposure to flutamide completely abolished the TP-induced accelerative effects on facial nerve regeneration rate. As a bioassay for the effectiveness of systemic administration of flutamide by subcutaneous injection, seminal vesicle weights were collected from all groups at the end of the postoperative time and compared as a percentage of the seminal vesicle weights of intact (nongonadectomized) male control animals. Castration greatly reduced seminal vesicle weights, whereas exogenous TP restored the seminal vesicle weights to those of the intact male. Flutamide blocked the effects of exogenous TP on seminal vesicle weights and reduced them to castrate levels. Thus, the results indicate that the mechanism by which gonadal steroids act to alter the regenerative properties of peripheral neurons is receptor-mediated.

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This chapter explores the role that sex hormones play in the development and progression of renal disease. Possible pathogenic mechanisms are described including the effects of sex hormones on cell biology and on the synthesis and release of vasoactive factors and inflammatory and profibrotic cytokines. Next, the role of sex hormones in influencing repair and regeneration following renal injury is discussed and possible pathogenic mechanisms explored. In light of the paucity of data that examine interactions between sex hormones and regeneration in the kidney, this chapter also draws on data which examine the role of sex hormones in the regeneration of nonrenal tissue to suggest avenues for future translational research involving the kidney.
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The importance of androgens for peripheral nerve regeneration after crush injury is well established in animal models. Treatment of hamsters with exogenous testosterone increases axonal regeneration rates and functional recovery of the facial nerve after crush injury [21]. Axonal regeneration is mediated by neuritin, a protein closely associated with re‐establishment of neuronal connectivity after injury.
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As functional recovery following peripheral nerve injury is dependent upon successful repair and regeneration, treatments that enhance different regenerative events may be advantageous. Using a rat facial nerve crush axotomy model, our lab has previously investigated the effects of a combinatorial treatment strategy, consisting of electrical stimulation (ES) of the proximal nerve stump and testosterone propionate (TP) administration. Results indicated that the two treatments differentially enhance facial nerve regenerative properties, whereby ES reduced the delay before sprout formation, TP accelerated the overall regeneration rate, and the combinatorial treatment had additive effects. To delineate the molecular mechanisms underlying such treatments, the present study investigated the effects of ES and TP on expression of specific regeneration-associated genes. Following a right facial nerve crush at the stylomastoid foramen, gonadectomized adult male rats were administered only ES, only TP, a combination of both, or left untreated. Real time RT-PCR analysis was used to assess fold changes in mRNA levels in the facial motor nucleus at 0 h, 6 h, 1 d, 2 d, 7 d, and 21 d post-axotomy. The candidate genes analyzed included two tubulin isoforms (α₁-tubulin and β_II-tubulin), 43-kiloDalton growth-associated protein (GAP-43), brain derived neurotrophic factor (BDNF), pituitary adenylate cyclase-activating peptide (PACAP), and neuritin (candidate plasticity-related gene 15). The two treatments have differential effects on gene expression, with ES leading to early but transient upregulation and TP producing late but steady increases in mRNA levels. In comparison to individual treatments, the combinatorial treatment strategy has the most enhanced effects on the transcriptional program activated following injury.

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Regular ArticleInhibition of the Accelerative Effects of Testosterone on Hamster Facial Nerve Regeneration by the Antiandrogen Flutamide

Abstract

Regular Article
Inhibition of the Accelerative Effects of Testosterone on Hamster Facial Nerve Regeneration by the Antiandrogen Flutamide