Skip to main content
. 2009 Feb 20;14(3):671–686. doi: 10.1111/j.1582-4934.2009.00715.x

Fig 4.

Fig 4

Mechanistic model of neuroprotection mediated by CsA and FK-506. Based upon results in facial motor neurons, the following model is proposed to explain the effects observed using CsA and FK-506. As indicated in this model, data from the present study suggest that the observed survival promoting and neurotrophic effects of these immunophilin ligands are mediated through distinct sets of molecular interactions. Evidence for exclusion of specific pathway is as indicated below. (1) CsA-mediated MPTP blockade is likely not the principle route of CsA-mediated neural rescue given that CsA and FK-506 treatment exhibit several similar mechanistic features, and co-administration of CsA and FK-506 did not enhance motor neuron survival over FK-506 treatment alone. (2) Administration of CsA or FK-506 did not act to reduce levels of reactive gliosis or infiltration of activated microglia; thus the enhanced survival of facial motor neurons was not due to repression of secondary injury responses. (3) Cypermethrin, an immunophilin-independent inhibitor of calcineurin, significantly enhanced motor neuron survival, hence highlighting calcineurin inhibition as a principal mechanism of regulating neuronal survival mediated by immunophilin ligands. (4) FK-506 and rapamycin both interact with FKBP-12, but only FK-506/FKBP-12 complexes inhibit calcineurin signalling. The failure of rapamycin to enhance motor neuron survival, following injury implicates calcineurin in the signalling pathway of motor neuron injury, and rules out mTOR-mediated effects. (5) Application of 17-AAG (a pharmacologic inhibitor of Hsp-90) failed to exhibit enhance motor neuron survival following injury, indicating that FK-506- and CsA-mediated enhancement in neuronal survival is distinct from the documented disruption in steroid receptor complex formation involved in enhancing neuritic outgrowth. (6) Inhibition of calcineurin-mediated Bad S112 dephosphorylation was observed at 20 hrs following axotomy for treatments with a single dose of either cypermethrin or FK-506, demonstrating a common mechanism by which cypermethrin, FK-506 and possibly CsA can enhance neuronal survival following injury.