Neuroprotective effects of testosterone in two models of spinal motoneuron injury
We have demonstrated that the gonadal steroid testosterone has therapeutic effects in the spinal cord, protecting surviving motor neurons from atrophy after the death of neighboring motor neurons, and regulating the expression of receptors for trophic factors, proteins critical for the maintenance of normal structure and function. This work has important implications in that if the appropriate trophic support can be provided to injured motor neurons, then the progression of neurodegenerative diseases could be slowed, or the time required for the recovery of motor function after injury could be reduced.
These findings are important because they demonstrate that testosterone, a powerful hormone long associated with such things as sex, aggression, and athletic performance enhancement, could also be playing an important role in the maintenance and repair of the nervous system after injury or disease. These results are directly relevant to clinical application as potential treatment strategies, as well as to basic neuroscience questions on the maintenance of important cellular features.
Our work concentrates on a particular aspect of motor neuron cellular structure, the dendrites. Dendrites are long, heavily branched processes that extend from the neuron cell body, and are essential for the reception and integration of information. Dendrites in motor neurons atrophy after the loss of neighboring motor neurons or peripheral nerve damage, but despite their important functional role, prevention from, or restoration after, atrophy has been largely ignored. This work is novel because while testosterone is known to be important in the development and adult maintenance of highly hormone-sensitive spinal motor neurons involved with reproductive behavior, in our studies we examined testosterone effects in the more typical motor neurons innervating muscles of the leg. Our work demonstrates for the first time that dendritic morphology, and expression of proteins critical for its maintenance, in these general limb motor neurons respond to testosterone, suggesting that the potential therapeutic effects of gonadal steroids on motor neurons apply to all spinal motor neurons.
We have begun to develop two models in the adult rat spinal cord, utilizing induced motor neuron death or peripheral nerve damage that allow us to examine potential ways of preventing, or accelerating recovery from, dendritic atrophy in motor neurons that survive initial insult. In our first model, we selectively killed a subpopulation of motor neurons that innervate the quadriceps muscle of the thigh. We then examined the dendritic structure of surviving motor neurons and found that the death of neighboring motor neurons causes the dendrites of the remaining motor neurons to atrophy. However, treatment with testosterone can prevent or reverse that atrophy. In our second model, we have previously shown that brain-derived neurotrophic factor (BDNF) and testosterone have a combinatorial effect in the maintenance of motor neurons after peripheral nerve damage in that dendritic morphology is supported by BDNF treatment, but only in the presence of testosterone. Using immunohistochemical methods, we have now demonstrated that the expression of the BDNF receptor, trkB, is regulated by testosterone. This finding suggests that maintenance of BDNF’s receptors with testosterone may be necessary to permit the effects of BDNF in supporting dendritic morphology after nerve damage.
Subsequent research will address questions about the time course and dose-dependency of testosterone treatment, measures of functional recovery after damage and treatment with testosterone, and potential mechanisms of testosterone’s neurotherapeutic effects.
Motor neuron loss is a significant medical problem, and can result from disease processes or from traumatic injuries. For example, amyotrophic lateral sclerosis (ALS) is a fatal disease characterized by the rapidly progressive loss of motor neurons, affecting 4-8 people per 100,000 population per year, with approximately 5000 new diagnoses made every year in the United States alone. Traumatic spinal cord injuries are even more prevalent: in the United States, more than 10,000 people per year survive a spinal cord injury. After injury or disease, surviving motor neurons respond with marked atrophy, and this atrophy is responsible for some of the movement deficits that accompany degenerative movement disorders and spinal cord trauma. Given that we currently lack the technology to replace dead motor neurons, developing the ability to protect or repair surviving motor neurons is an important goal. Gonadal steroids exhibit a wide array of neuroprotective and neurotherapeutic effects, and the therapeutic effects of testosterone we observed could potentially have a major impact on the restoration of motor function after injury or disease.