The research appears as the "Paper of the Week" in the May 26 issue of the Journal of Biological Chemistry. The immunosuppressive drug FK506 is often administered to patients receiving transplants to prevent organ rejection. Dervatives of the drug are also commonly used in the treatment of autoimmune diseases. FK506 inhibits T-cell activation by binding to members of the FK506-binding protein (FKBP) family. Interestingly, FK506, and several molecules with similar structures, also demonstrate neuroprotective and neuroregenerative effects in a wide range of animal models mimicking Parkinson's disease, dementia, stroke, and nerve damage.
Gunter Fischer and his colleagues at the Max-Planck Research Unit for Enzymology of Protein Folding in Germany have now determined that neuroprotective FK506 derivatives specifically target a receptor called FKBP38. "High FKBP38 activity in neuronal cells triggers mechanisms leading to programmed cell death," explains Fischer. "Inhibition of FKBP38 makes cells more predisposed to survive."
The scientists also synthesised a molecule that specifically inhibits FKBP38 and administered it to rats that were experiencing stroke symptoms. "We developed a lead compound that strongly inhibits FKBP38 leaving other brain FKBP almost untouched under certain conditions," said Fischer. "A strong neuroprotective effect became obvious in an animal model of stroke when the animals were treated with this lead compound."
Fischer and his colleagues found that their compound protected the rats' neurons and also caused neural stem cell proliferation and neuronal differentiation. Diseased animals with motor behavior deficits also showed improvement when they were given the synthetic drug.
These results suggest a potential therapeutic application specific FKBP38 inhibitors in the treatment of neurodegeneration following stroke and a number of other diseases.
MEDICA.de; Source: Journal of Biological Chemistry