STEROID HORMONES AND NEURONAL REGENERATION

从性腺类固醇激素对大脑作用的研究来看， 一般认为，这些药物对许多人产生神经营养作用， 神经元的活力和功能。 最近的临床和 实验证据表明，性腺可能具有治疗作用， 促进神经再生。 我们最近已经证明， 系统给予雄激素丙酸睾酮（TP）， 成年雄性仓鼠加速面瘫的功能恢复 是由面部神经挤压引起的 重要的是，面部运动神经元含有 雄激素受体 TP是如何实现这种治疗效果的， 知道的 我们研究的长期目标是确定 TP促进面神经损伤修复的机制 损害 为实现这一目标，本提案的具体目标是 测试以下四个假设。 第一个要检验的假设是 TP能加速面神经损伤后面瘫的恢复， 通过增加再生轴突的生长速率来压碎，和/或 缩短了芽形成的初期延迟。 两个系列的 实验，涉及放射性同位素标记的轴突运输 蛋白质，将被用来评估TP对轴突的影响， 再生性能 第二个要检验的假设是， TP促进周围神经损伤后的功能恢复 损伤是雄激素受体介导的。 两个系列的实验将是 以确定TP对受损神经元的作用是否是雄激素 受体介导的 首先，雄激素受体将被阻断， 切断面神经，TP对功能的影响 恢复确定。 在第二种情况下，运动神经元的群体， 没有雄激素受体（颅神经VI）将受到挤压 确定轴突切断术和TP对功能恢复的影响。 的 第三个要检验的假设是，TP加速了面部 面神经损伤后的麻痹涉及核糖体的改变 面神经运动神经元RNA基因的表达。 性腺的影响 大脑中的类固醇被认为是通过神经元的改变发生的。 基因表达。 核糖体RNA代表了一种丰富的，容易 已知受轴突切断术和轴突损伤影响的可定量RNA种类， 类固醇激素对靶神经元作用。 原位杂交技术 将使用基因组核糖体DNA探针来确定是否显著 损伤的面部组织中rRNA表达模式发生改变， TP暴露后的神经元。 第四个要检验的假设是， TP促进面神经损伤后面瘫的恢复 涉及面神经运动神经元内蛋白质合成的改变。 激素调节靶组织功能通常被认为是 通过蛋白质表达的选择性变化发生。 轴突切开 也被证明可以选择性地影响蛋白质的合成， 再生神经元 放射性标记和二维凝胶 将进行电泳以鉴定TP诱导的蛋白质变化 受损的面部神经元的合成。

From studies of gonadal steroid hormone action on the brain, it is generally established that these agents exert neurotrophic effects on many aspects of neuronal viability and functioning. Recent clinical and experimental evidence suggests that gonadal may have a therapeutic role in promoting neuronal regeneration. We have recently demonstrated that systematic administration of the androgen, testosterone propionate(TP), to adult male hamsters accelerates functional recovery from facial paralysis induced by facial nerve crush. Importantly, facial motoneurons contain androgen receptors. How TP accomplishes this therapeutic effect is not known. The long term objective of our research is to determine the mechanism underlying the TP-acceleration of recovery from facial nerve damage. Toward that objective, the specific aims of this proposal will be to test the following 4 hypotheses. The first hypothesis to be tested is that TP accelerates recovery from facial paralysis following facial nerve crush by increasing the growth rate of regenerating axons and/or shortening the initial delay of sprout formation. Two series of experiments, involving radioisotopic labeling of axonally transported proteins, will be employed to assess the effects of TP on axonal regenerative properties. The second hypothesis to be tested is that the TP-induced acceleration of functional recovery following peripheral nerve injury is androgen receptor-mediated. Two series of experiments will be done to determine if the action of TP on injured neurons is androgen receptor-mediated. In the first, androgen receptors will be blocked, the facial nerve crush axotomized, and the effects of TP on functional recovery determined. In the second, a population of motor neurons that do not have androgen receptors (cranial nerve VI) will be subjected to crush axotomy and the effects of TP on functional recovery determined. The third hypothesis to be tested is that TP-accelerated recovery from facial paralysis following facial nerve crush involves alterations in ribosomal RNA gene expression in facial motoneurons. The effects of gonadal steroids in the brain are thought to occur through alterations in neuronal gene expression. Ribosomal RNA represents an abundant, readily quantifiable RNA species that is known to be affected by axotomy and by steroid hormone action on target neurons. In situ hybridization with a genomic ribosomal DNA probe will be employed to determine if significant alterations in the pattern of rRNA expression occur in injured facial neurons following TP exposure. The fourth hypothesis to be tested is that TP-accelerated recovery from facial paralysis following facial nerve crush involves alterations in protein synthesis within faci: motoneurons. Hormonal regulation of target tissue functioning is generally considered to occur through selective changes in the expression of proteins. Axotomy also has been demonstrated to selectively affect protein synthesis in regenerating neurons. Radioactive labeling and two-dimensional gel electrophoresis will be done to identify TP-induced changes in protein synthesis in injured facial neurons.