Stroke is the third leading cause of death in the United States and the most common cause of adult disability. An ischemic stroke occurs when a cerebral vessel occludes, obstructing blood flow to a portion of the brain. Currently, there is only one approved stroke therapy, tissue plasminogen activator, which targets the thrombus within the blood vessel. Because of the lack of available stroke treatments, neuroprotective agents have also generated as much interest as thrombolytic therapies.
The immunosuppressive drug FK506 (also known as Tacrolimus or Prograf®) 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 synthesized 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.
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