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A T9 laminectomy was performed to expose the underlying thoracic spinal cord segment(s), and animals received a severe (a 10-g weight dropped from a height of 25 mm) contusion injury by using an NYU impactor. Gonadal steroid hormones provide protection from many of the pathophysiological changes seen after SCI, for example, by reducing the inflammation and free radical generation that contribute to progressive secondary injury. In the United States, more than 10,000 people per year survive a spinal cord injury (SCI); 45% suffer from spinal motoneuron lesions, and this number rises to 95% for those with lumbar or sacral injuries (Doherty et al., 2002). Soma volume, motoneuron number, lesion volume, and tissue sparing were also assessed, as were muscle weight, fiber cross-sectional area, and motor endplate size and density. In vitro experiments indicate that testosterone acts as a neuroprotectant, with activation of the MAPK pathway playing a key role.
Together, these findings suggest that neuroprotective effects on motoneurons can be mediated by either androgenic or estrogenic hormones and require action via steroid hormone receptors, further supporting a role for hormones as neurotherapeutic agents in the injured nervous system. The mechanism by which steroidal enhancement of the regenerative properties of injured motoneurons occurs may involve pre-existing androgen receptors, heat shock proteins, and modulation of the cellular stress response. Thus, axotomy-induced down-regulation of androgen receptors does not underlie the inability of SNB motoneurons to respond to androgen treatment several months after pudendal nerve cut in development. Sciatic nerve cells coexpress progesterone receptor (PR) and steroid receptor coactivator-2 (SRC-2) in female rats.
This lack of effect with testosterone treatment is similar to that observed by Kachadroka et al. (2010), wherein the percentage of white matter sparing at the lesion epicenter as a consequence of treatment with estradiol was not affected by the presence or absence of endogenous androgens. More importantly, such atrophy could be almost completely restored after testosterone treatment, indicating a protective role of testosterone on prevention of motoneuron dendritic degeneration after SCI. Testosterone treatment protects motoneurons from injury-induced atrophy (Fargo et al., 2009a). Following contusion injury, quadriceps motoneurons underwent marked dendritic atrophy (Fig. 2). In sham animals, the number of motoneurons within the identified quadriceps range averaged 1,054.75 (± 202.96).
Such findings highlight the hormone’s neuroprotective capabilities even amidst aging. Interestingly, some research indicates testosterone therapy can improve memory in testosterone-deficient older men. Studies show older men with low testosterone have higher risk of Alzheimer’s disease and impaired cognitive function. Low testosterone may increase susceptibility to neurodegeneration and hinder recovery from TBI. The treatment has shown real promise in animal models.
Together, these mechanisms illustrate testosterone’s multifaceted approach to promoting neuron survival, reducing secondary injury, and improving functional recovery after TBI. The treatment group also showed increased activity of antioxidant enzymes like glutathione peroxidase. The findings indicate testosterone reduced secondary injury from oxidative stress. Lipid peroxidation is the oxidative degradation of lipids which damages cell membranes.
These muscles are innervated by motoneurons located in column 3 of the lateral motor column in the L2 spinal segment (Nicolopoulos-Stournaras and Iles, 1983; Brushart and Seiler, 1987; Al-Majed et al., 2000) and project via the femoral nerve to the four muscles of the quadriceps. In the presence of ligand, bound receptors translocate to the nucleus, interact with specific hormone response elements on genomic DNA, and increase or decrease transcription of steroid-regulated genes (Kumar and Thompson, 1999; Aranda and Pascual, 2001). Both of these testosterone metabolites have been shown to have neuroprotective/neurotherapeutic effects (e.g., Garcia-Segura et al., 2000; Garcia-Segura et al., 2003; Huppenbauer et al., 2005; Barreto et al., 2007; Tanzer and Jones, 1997). Our previous experiments have demonstrated that testosterone is indeed neuroprotective following motoneuron loss.
Counts of labeled quadriceps motoneurons were made under brightfield illumination, whereby somata could be visualized and cytoplasmic inclusion of BHRP reaction product confirmed. By using similar methods, the number of BHRP-labeled motoneurons was assessed in all sections of the reacted series through the entire rostrocaudal extent of their distribution for all animals. Forty-eight hours after BHRP injection, a period that ensures optimal labeling of motoneurons (Gold-stein et al., 1990; Kurz et al., 1986), animals were weighed and received a lethal dose of Nembutal (60 mg/kg, i.p.), and were then perfused intracardially with saline followed by cold fixative (1% paraformaldehyde/1.25% glutaraldehyde).

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