Gonadal Steroid Attenuation of Developing Hamster Facial Motoneuron Loss by Axotomy: Equal Efficacy of Testosterone, Dihydrotestosterone, and 17-β Estradiol

Abstract

In the hamster facial nerve injury paradigm, we have established that androgens enhance both functional recovery from facial nerve paralysis and the rate of regeneration in the adult, through intrinsic effects on the nerve cell body response to injury and via an androgen receptor (AR)-mediated mechanism. Whether these therapeutic effects of gonadal steroids encompass neuroprotection from axotomyinduced cell death is the focus of the present study. Virtually 100% of adult hamster facial motoneurons (FMNs) survive axotomy at the stylomastoid foramen (SMF), whereas, before postnatal day 15 (P15), developing FMNs undergo substantial axotomy-induced cell death. The first part of the present study focuses on determining when ARs are first expressed in developing hamster FMNs. Using AR immunocytochemistry, it was found that males express ARs by P2 and females by P4, which is the earliest demonstration of AR expression in mammalian motoneurons reported thus far in the literature. The second half examines the neuroprotective effects of testosterone propionate, 17-␤ estradiol, and dihydrotestosterone on FMNs of P7 hamsters after facial nerve transection at the SMF. The results demonstrate that androgens and estrogens are equally able to rescue ϳ20% of FMNs from axotomy-induced cell death, with the effects permanent. This study is the first to investigate the effects of both androgens and estrogens on axotomy-induced cell death in one system and, with our previously published work, to validate the hamster FMN injury paradigm as a model of choice in the investigation of both neurotherapeutic and neuroprotective actions of gonadal steroids.

Androgenic, but not estrogenic, protection of motoneurons from somal and dendritic atrophy induced by the death of neighboring motoneurons

“…Androgens are already known to prevent or reduce motoneuron death in several experimental paradigms (Ahlbom et al, 2001;Hammond et al, 2001;Pike, 2001;Ramsden et al, 2003;Huppenbauer et al, 2005). In addition, the present results suggest that androgens are also capable of attenuating secondary atrophy in surviving nearby motoneurons.…”

“…Furthermore, saporin injection resulted in a laterally specific depletion of SNB motoneurons-motoneuron number in the nearby contralateral SNB did not differ from normal following saporin injection. In some model preparations, steroid hormones prevent injuryinduced neuron death (Ahlbom et al, 2001;Hammond et al, 2001;Pike, 2001;Ramsden et al, 2003;Huppenbauer et al, 2005). It was therefore important to establish that saporin injection killed approximately the same number of motoneurons in the untreated and steroid-treated groups.…”

“…Thus, the SNB stands in contrast to some other areas in the nervous system, where estradiol has powerful neuroprotective effects (Woolley and Cohen, 2002). For example, estradiol protects cortical and hippocampal neurons from cell death induced by ischemia (Hoffman et al, 2006) and promotes cell survival (Huppenbauer et al, 2005) and axonal regeneration (Tanzer and Jones, 1997) in brain stem motoneurons following peripheral axotomy.…”

“…Estrogens also exert neurotherapeutic effects. For example, estradiol controls dendritic spine density in the hippocampus (Woolley and McEwen, 1994) and prevents axotomy-induced motoneuron death (Huppenbauer et al, 2005). …”

Androgen regulation of axon growth and neurite extension in motoneurons

“…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).…”