The immune system functions to protect an organism against microbial infections and may be involved in the reparative response to nerve injury. The goal of this study was to determine whether the immune system plays a role in regulating motoneuron survival after a peripheral nerve injury. After a right facial nerve axotomy, facial motoneuron (FMN) survival in C.B-17 (+/+) wild-type mice was found to be 87 +/- 3.0% of the unaxotomized left side control. In contrast, facial nerve axotomy in C.B-17 (-/-) severe combined immunodeficient (scid) mice, lacking functional T and B lymphocytes, resulted in an average FMN survival of 55 +/- 3.5% relative to the unaxotomized left side control. This represented an approximately 40% decrease in FMN survival compared with wild-type controls. The reconstitution of scid mice with wild-type splenocytes containing T and B lymphocytes restored FMN survival in these mice to the level of the wild-type controls. These results suggest that immune cells associated with acquired immunity play a role in regulating motoneuron survival after a peripheral nerve injury.

No 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.

Gonadal steroid hormones are known to influence the development of the cerebral cortex of mammals. Steroid hormone action involves hormone binding to cytoplasmic or nuclear receptors, followed by DNA binding and gene transcription. The goals of the present study were twofold: to determine whether androgen receptors are present during development in two known androgen sensitive regions of the rat cerebral cortex, the primary visual cortex (Oc1) and the anterior cingulate/frontal cortex (Cg1/Fr2); and to determine whether androgen receptor (AR) expression in these regions differs between developing males and females. We used immunocytochemistry to detect AR protein on postnatal days 0, 4, and 10, and in situ hybridization to detect AR mRNA on postnatal day 10 in male and female rats. The level of AR expression was specific to the cortical region, with higher AR immunoreactive cell density and more AR mRNA in Oc1 than in Cg1/Fr2. AR immunoreactive cell density increased with age in both regions. Finally, on postnatal day 10, males had a higher AR immunoreactive cell density and more AR mRNA in Oc1 than did females. Thus, the presence of ARs may allow androgens to directly influence the development the cerebral cortex.

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.