Local administration of thyroid hormones in silicone chamber increases regeneration of rat transected sciatic nerve.

Conflicting actions of the exogenous thyroid hormone on regenerating peripheral nerve have been reported. These contradictory results were probably due to daily intraperitoneal injections which induce a high concentration of thyroid hormone after administration. In our present study we adapted a technique which allows a local administration of thyroid hormones in a closed system. The effect of a single and local treatment with triiodothyronine (T3) on axonal growth across a gap between sectioned ends of sciatic nerve within silicone chambers was examined in Wistar rats. After nerve transection and surgical implantation, silicone chambers were filled with either a neutral pH solution of triiodothyronine dissolved in NaOH or with sterile solvent as control. Regeneration of the nerves was examined 2 to 8 weeks following the surgery. Early regeneration (4 weeks) was studied by morphological analysis of nerves which showed a significant difference between T3-treated and control groups. Morphometric analysis revealed: (1) a significant difference in the mean diameter of myelinated axons between T3-treated nerve (phi 3.80 +/- 0.22 microns) and control (phi 3.07 +/- 0.44 microns); (2) that T3 increased significantly (1.4-fold) the number of myelinated axons that grew into the middle and distal ends of regeneration chambers; (3) that ultrastructural analysis showed significantly higher percentage of myelinated axons per total axon population in T3-treated groups (38.8 +/- 5.9%) as compared to control (16.0 +/- 2.3%); and (4) that the myelinated axons had thicker myelin sheaths. The beneficial effects of T3 on regeneration, observed at 4 weeks, were sustained over a prolonged period of time. Thus, at 8 weeks of regeneration, the number, the mean diameter of myelinated axons, and the thickness of myelin sheaths remained significantly greater in T3-treated groups. Therefore, a single and local administration of thyroid hormone at the level of the transected sciatic nerve is sufficient to rapidly set off several mechanisms which, in turn, produce a stimulating and lasting effect on peripheral nerve regeneration. The beneficial effects of T3 upon injured peripheral nerve may have considerable therapeutic potential.

Differential distribution of thyroid hormone receptor isoform in rat dorsal root ganglia and sciatic nerve in vivo and in vitro.

Using autoradiographic techniques carried out under precise conditions we previously demonstrated that both sensory neurons and peripheral glial cells in dorsal root ganglia (DRG) or sciatic nerve, possess specific [125I]-labeled T3 binding sites. Thyroid hormone receptors (TR) include several isoforms (TR alpha(1), TR alpha(2), TR beta(1), TR beta(2...)) The present study demonstrates that while sensory neurons and peripheral glial cells both possess functional TR, they express a differential expression of TR isoforms. Using a panel of antisera to specific for the TR alpha-common (alpha(1) and alpha(2)), TR alpha-1 or TR beta-1 isoforms, we detected TRs isoform localization at the cellular level during DRG and sciatic nerve development and regeneration. Immunohistochemical analysis revealed that during embryonic life, sensory neurons express TR alpha-common and TR beta-1 rather than TR alpha-1. The number of TR alpha-common and TR beta-1 positive neurons as well as the intensity of labeling increased during the first two postnatal weeks and remained more or less stable in adult life. TR alpha-1 immunoreactivity, which was undetectable in embryonic sensory neurons, became discreetly visible in neurons after birth. In developing DRG and sciatic nerves, Schwann cells exhibited TR alpha-common and TR alpha-1 rather than TR beta-1 immunolabeling. The appearance of TR alpha-common and alpha-1 isoform immunoreactivity in the sciatic nerve was restricted to a short period ranging from E17 up to two postnatal weeks. By comparing TR alpha-common and TR alpha-1 immunostaining we can deduce that Schwann cells primarily express TR alpha-1. Afterwards, in adult rat sciatic nerve TR alpha isoforms was no more detected. However transection of sciatic nerve caused a reexpression of TR alpha isoforms in degenerating nerve. The prevalence of TR alpha in Schwann cells in vivo was correlated with in vitro results. The differential expression of TR alpha and beta by sensory neurons and Schwann cells indicates that the feedback regulation of circulating thyroid hormone could occur by binding to either the alpha or beta TR isoforms. Moreover, the presence of multiple receptor isoforms in developing sensory neurons suggests that thyroid hormone uses multiple signaling pathways to regulate DRG and sciatic nerve development.