No abstract

In axotomized peripheral motoneurons capable of successful regeneration, one of the earliest morphological indicators of the injury response occurs within the nucleolus. In the initial part of this investigation, we mapped the nucleolar response of injured adult hamster facial motoneurons from a molecular perspective, utilizing in situ hybridization and ribosomal DNA probes complementary to stable rRNA. Recently, we have discovered that the gonadal steroid, testosterone propionate (TP), accelerates recovery from facial paralysis in the hamster by increasing the rate of regeneration of the fastest regrowing axons. In the second part of this study, the hypothesis that TP accomplishes these effects on facial nerve regeneration through an enhancement of the nerve cell body response to injury was tested using in situ hybridization and rDNA probes. Adult intact male hamsters were subjected to right facial nerve axotomies at the stylomastoid foramen. One-half of the axotomized animals received subcutaneous implants of TP, with the remainder sham implanted. In situ hybridization with tritiated rDNA probes was accomplished and levels of hybridizable rRNA assessed both qualitatively and quantitatively. Axotomy alone induced an upregulation in rRNA levels, with peak changes occurring by 24 hr postoperative and continuing through postoperative day 4. These molecular changes in the nucleolar response preceded, by a full day, any morphological signs of the nucleolar reactive pattern previously found in this cell type, and, as such, point to the usefulness of in situ hybridization as a tool to identify the earliest events associated with the axon reaction. A secondary smaller increase in rRNA levels was observed during the later stages of regeneration. TP significantly augmented the ribosomal response to injury, with levels of rRNA increased as early as 6 hr and the magnitude of the response greater than that occurring following axotomy alone. These results provide the first mechanistic step in the identification of the cellular processes underlying gonadal steroid augmentation of neuronal reparative processes. We conclude that TP accelerates the "switch" from a normal to a reparative state and suggest that this priming effect may be causally related to the differential effects of TP on the regenerative properties of this cell type.

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