The immunophilin ligand FK506, but not GPI-1046, protects against neuronaldeath and inhibits c-Jun expression in the substantia nigra pars compacta following transection of the rat medial forebrain bundle

The immunophilin ligand FK506 (Tacrolimus) is used for prevention of graft rejection following organ transplantation. FK506 is a high-affinity ligand for FK506-binding proteins, an immunophilin subgroup of peptidyl-prolyl-cis /trans-rotamases abundant in the mammalian brain. Here, we demonstrate that FK506 is a potent survival factor that prevents neuronal cell death follow ing axotomy of central intrinsic neurons. Administration of FK506 (2 mg/kg, s.c., per day for two days pre-axotomy and for up to eight days post-axoto my) effectively delayed and reduced the death of axotomized neurons in the substantia nigra pars compacta following transection of the medial forebrai n bundle. In saline-treated controls, 75%, 89% and 92% of nigral neurons di ed after 25, 50 and 60 days post-axotomy, respectively. In contrast, applic ation of FK506 resulted in survival of 46%, 44% and 28% of the axotomized n igral neurons, and the majority of these surviving neurons showed continuou s expression of tyrosine hydroxylase, the pacemaker enzyme for dopamine syn thesis. Moreover, FK506 significantly reduced the expression of the inducib le transcription factor c-Jun and its N-terminal phosphorylation and preven ted the axotomy-induced suppression of the constitutive transcription facto r ATF-2 in neurons of the substantia nigra and mammillary body. The latter is also axotomized by the coincident transection of the mammillothalamic tr act, but the mammillary neurons survive the axotomy. In contradistinction t o FK506, the non-immunosuppressive FK506-binding protein ligand GPI-1046 (2 5 or 12.5 mg/kg, applied once or twice per day for two days pre-axotomy and for eight days post-axotomy) was completely ineffective for all these para meters investigated. Finally, FK506, but not GPI-1046, impressively acceler ated the recovery from surgery. Our data provide the first evidence that FK506 acts as a neuroprotective mo lecule that rescues axotomized otherwise degenerating central intrinsic neu rons in the adult mammalian brain by mechanisms that interfere with the tra nscriptional program of the axotomy-induced cell body response, such as act ivating transcription factor-2 suppression and c-Jun expression and phospho rylation. (C) 1999 IBRO. Published by Elsevier Science Ltd.