Motoneuron Injury and Repair: New Perspectives on Gonadal Steroids as Neurotherapeutics

Abstract

In this review, we will summarize recent work from our laboratory on the role of gonadal steroids as neuroprotective agents in motoneuron viability following cell stress. Three motoneuron models will be discussed: developing axotomized hamster facial motoneurons (FMNs); adult axotomized mouse FMNs; and immortalized, cultured mouse spinal motoneurons subjected to heat shock. New work on two relevant motoneuron proteins, the survival of motor neuron protein, and neuritin or candidate plasticity-related gene 15, indicates differential steroid regulation of these two proteins after axotomy. The concept of gonadal steroids as cellular stress correction factors and the implications of this for acute neurological injury situations will be presented as well.

Androgen regulation of axon growth and neurite extension in motoneurons

“…Post hoc analysis indicated that neuritin mRNA levels were significantly higher in testosteronetreated animals two days post-axotomy than in any other group (Fisher's LSD, ps < .001), increasing by approximately 300% above the uninjured control side. In contrast, no such increase occurred in untreated animals (Tetzlaff et al, 2006). Because testosterone treatment increases the rate of axon regeneration in injured hamster facial motoneurons (Kujawa et al, 1991), these data demonstrate a relationship between neuritin expression and androgenenhanced axon regeneration in vivo.…”

“…Androgen treatment also accelerates functional recovery from facial nerve crush in mice (Tetzlaff et al, 2006). Early studies by Yu and colleagues demonstrated a sex difference in the rates of axonal regeneration (males regenerating faster) following axotomy of the hypoglossal nerve in rats (Yu, 1982), and that androgen treatment enhances axonal regeneration rates in both male (Yu, 1982;Yu and Yu, 1983) and female (Yu and Srinivasan, 1981) rats.…”

“…In vivo, androgens also promote the survival of motoneurons in both the spinal cord (SNB motoneurons; Breedlove and Arnold, 1983a,b;Nordeen et al, 1985) and brainstem (facial motoneurons; Huppenbauer et al, 2005;Tetzlaff et al, 2006). While the androgen-dependent survival of SNB motoneurons during development is traditionally thought of as being mediated by their target muscles (Kurz et al, 1992;Johansen et al, 2004), androgens are capable of preventing the death of facial motoneurons that have been disconnected from their target muscles by axotomy (Huppenbauer et al, 2005;Tetzlaff et al, 2006). Furthermore, in vitro studies of NSC34/mAR cells have indicated that androgens can act directly on motoneurons to drive process outgrowth, and that this effect is AR-mediated (Marron et al, 2005).…”

Molecular Changes at the Post-Synapse and Improved Motor Function Suggest Accelerated Recovery with SARM Treatment in an Androgen-Depleted Animal Model of Nerve Injury

“…The factors that determine the regenerative ability of an injured neuron are known to include severity and proximity of the injury to the cell body [39], and their interplay with therapeutic agents can augment re-innervation. Androgens have been shown to be effective agents at enhancing nerve regeneration/innervation, though the specific nerve injuries and resultant methods of defining regeneration by androgens (e.g., function, molecular, innervation) show varied effectiveness [10,[12][13][14]40]. Likewise, the mechanism(s) by which androgen's positive effects are driven are not completely understood.…”

“…Moreover, androgens have been shown to protect against motorneuron death, and display capacity to enhance nerve regeneration following injury [10]. Initial nerve regeneration studies were performed using rodent facial nerve axotomy model [11,12], where androgens exerted dramatic positive effects on the speed of functional recovery [12,13].…”