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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.

Electrical stimulation may decrease cell death or promote sprouting to accelerate early recovery. Testosterone may affect the actual rate of axonal regeneration and produce acceleration in functional recovery. By targeting different stages of neural regeneration, the synergy of electrical stimulation and testosterone appears to have promise as a neurotherapeutic strategy for facial nerve injury.

Following crush injury to the facial nerve in Syrian hamsters, treatment with androgens enhances axonal regeneration rates and decreases time to recovery. It has been demonstrated in vitro that the ability of androgen to enhance neurite outgrowth in motoneurons is dependent on neuritin-a protein that is involved in the re-establisment of neuronal connectivity following traumatic damage to the central nervous system and that is under the control of several neurotrophic and neuroregenerative factors--and we have hypothesized that neuritin is a mediator of the ability of androgen to increase peripheral nerve regeneration rates in vivo. Testosterone treatment of facial nerve-axotomized hamsters resulted in an approximately 300% increase in neuritin mRNA levels 2 days post-injury. Simultaneous treatment with flutamide, an androgen receptor blocker that is known to prevent androgen enhancement of nerve regeneration, abolished the ability of testosterone to upregulate neuritin mRNA levels. In a corroborative in vitro experiment, the androgen dihydrotestosterone induced an approximately 100% increase in neuritin mRNA levels in motoneuron-neuroblastoma cells transfected with androgen receptors, but not in cells without androgen receptors. These data confirm that neuritin is under the control of androgens, and suggest that neuritin is an important effector of androgen in enhancing peripheral nerve regeneration following injury. Given that neuritin has now been shown to be involved in responses to both central and peripheral injuries, and appears to be a common effector molecule for several neurotrophic and neurotherapeutic agents, understanding the neuritin pathway is an important goal for the clinical management of traumatic nervous system injuries.

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Current research on the effects of gonadal steroids on the brain and spinal cord indicates that these agents have profound trophic effects on many aspects of neuronal functioning, including cell survival, growth and metabolism, elaboration of processes, synaptogenesis, and neurotransmission (Jones et al., 1985; Luine, 1985; Nordeen et al., 1985; Matsumoto et al., 1988a,b; Gould et al., 1990). Since many of the aspects of normal neuronal functioning altered by gonadal steroids are affected by injury to the nervous system, we initiated a series of experiments designed to exploit the trophic capabilities of steroids as therapeutic agents in neuronal injury and repair (Kujawa et al., 1989, 1991; Kujawa and Jones, 1990). Three steroid‐sensitive model systems were used for these studies: the hamster facial motoneuron, the rat sciatic motoneuron, and the hamster rubrospinal motoneuron. The results of our initial series of experiments suggest that androgens, and possibly estrogens, act either directly or indirectly on the injured motoneuron and enhance elements of the neuronal reparative response that are critical to successful recovery of function. Recently, we discovered that gonadal steroids may also modulate the central glia response to nerve damage. In this review, a summary of our data identifying a therapeutic role for androgens in enhancing the reparative response of motoneurons to injury is presented. This is followed by a discussion of the effects of androgens on the glial response to injury. © 1999 John Wiley & Sons, Inc. J Neurobiol 40: 560–573, 1999

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.

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