Regulation of the expression of peripheral benzodiazepine receptors and their endogenous ligands during rat sciatic nerve degeneration and regeneration: a role for PBR in neurosteroidogenesis

Peripheral benzodiazepine receptors (PBR) and their endogenous ligands, the diazepam-binding inhibitor derived-peptides, are present in Schwann cells in the peripheral nervous system. The aim of this study was to determine th e influence of reversible (freeze-injury) and permanent (transection and li gature) nerve lesion on PBR density and on the levels of their endogenous l igands, by autoradiography (using [H-3]PK11195) and radioimmunoassay (using antisera directed against the octadecaneuropeptide (ODN), a diazepam-bindi ng inhibitor fragment). The potential role of PBR on peripheral nerve stero idogenesis, was studied by investigating the effect of specific PBR agonist s and antagonists on pregnenolone levels in the sciatic nerve. Sixteen to 3 0 days after nerve lesion, PBR density and ODN-LI level were highly increas ed. Their expression returned to normal level when regeneration was complet ed 60 days after freeze-injury, but remained elevated when regeneration did not occur in transected distal stumps. Reverse-phase HPLC analysis of ODN- LI showed that in control nerve extracts, the major immunoreactive peak co- elutes with triakontatetraneuropeptide (TTN). After freeze-injury, intermed iate molecular forms eluting between ODN and TTN were predominant and remai ned elevated at day 60. The greater accumulation of intermediate forms when regeneration is allowed to occur may indicate a particular role of these f orms in axonal elongation and myelination. Ro5-4864, a high affinity PBR ag onist increased pregnenolone concentration in the sciatic nerve. This effec t was antagonised by PK11195, a high affinity PBR antagonist, which had no effect on pregnenolone basal level, indicating a specific action of PBR in neurosteroid production. These results suggest a role for PBR and their end ogenous ligands in peripheral nerve regeneration A trophic effect could be exerted via stimulation of steroid synthesis. (C) 1999 Elsevier Science B.V . All rights reserved.