Testosterone as a neuroprotective/neurotherapeutic agent following partial neuronal depletion

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Date

2010-06-01

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[Bloomington, Ind.] : Indiana University

Abstract

Motoneuron loss is a significant medical problem that can result from traumatic injury or from disease processes. I have recently demonstrated that the unilateral injection of a retrogradely transported conjugate of the toxin saporin into the bulbocavernosus and levator ani muscles kills the majority of ipsilateral motoneurons that project to the injected musculature. In addition, and more importantly for this thesis, the contralateral motoneurons are also affected. While they are not killed, they display a massive retraction of their dendrites, as well as a loss of cross-sectional area. Morphological changes in surviving motoneurons might therefore account for some of the functional deficits produced by motoneuron loss. Treatment with exogenous testosterone, however, completely prevents the regressive morphological changes that follow partial motoneuron depletion, suggesting that steroid treatment could prove to be an important factor in combating the deleterious effects of motoneuron loss. The protective effect of testosterone treatment on the morphology of surviving motoneurons in this neuromuscular system raises several intriguing questions. In this thesis I describe a series of experiments undertaken in an attempt to answer some of these questions. In particular, I have explored the effects of motoneuron depletion and testosterone treatment on ipsilateral motoneuron pools; examined the effectiveness of testosterone treatment on the electrophysiological functioning of surviving motoneurons following motoneuron depletion; examined the effects of testosterone treatment after using another method of killing motoneurons--one which does not involve introducing an exogenous toxin into the spinal cord; and tested whether the beneficial effects of testosterone treatment following motoneuron depletion can be accounted for by its conversion to its metabolite estradiol. The most important findings are that testosterone treatment is effective in restoring some electrophysiological effects produced in surviving motoneurons following partial motoneuron depletion, and that the beneficial effects of testosterone on the morphology of surviving motoneurons is as androgen effect, rather than an estrogen effect.

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Thesis (PhD) - Indiana University, Neuroscience, 2006

Keywords

penile reflexes, steroids, cell death, spinal cord injury, saporin, ventral root avulsion

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Doctoral Dissertation