In the study, researchers from Professor Raymond Swanson's team at the University of California, San Francisco examined the use of a PARP inhibitor, PJ34, in a rat model of cerebral ischemia-reperfusion. Ischemia is a restriction in blood supply to a tissue, whereas reperfusion injury refers to tissue damage caused when blood supply is returned to that tissue. Rats were subjected to 10 minutes of cerebral ischemia and then treated with PJ34 or placebo (saline) for seven days beginning eight hours after the onset of reperfusion.
Researchers measured the activation of brain macrophages, known as microglial cells, at several time-points between 0 and 14 days following ischemia. Microglial activation is an important component of the brain's inflammatory response and precedes neuronal death. Rats treated with PJ34 exhibited near-complete suppression of microglial response after 5 days, and similar responses were also observed at other timepoints. At 7 days post-ischemia, neuronal survival was evaluated. PJ-34 reduced neuronal death in the CA1 hippocampus region by 84% in treated rats relative to control rats.
"We now have support for PARP inhibition as a potential method of suppressing brain inflammation and preventing injury following ischemia-reperfusion," said Andrew Salzman, M.D., President and Chief Executive Officer of Inotek. "These results support our earlier preclinical data which suggested that PARP inhibition therapy had activity when introduced late in the course of ischemia reperfusion to the animal brain. This may have particular relevance to the clinical setting where it is often impossible to treat patients early in the course of acute stroke."
These data were published by Professor Raymond A. Swanson of the University of California, San Francisco and the Veterans Affairs Medical Center, San Francisco in the February 2007 issue of Stroke (Vol. 38 (part 2), pages 632-6).
About PARP Inhibitors
Poly (ADP-ribose) polymerase (PARP) is an abundant nuclear enzyme that mediates the repair of DNA single strand breaks through the activation and recruitment of DNA repair enzymes. PARP's role in the inflammatory response may result from its ability to potentiate the activity of key inflammatory transcription factors (NF-kappaB and AP-1). PARP inhibitors have shown promise in a variety of inflammatory and ischemia/reperfusion diseases, including those related to acute cardiovascular conditions. PARP inhibitors may also have potential application in cancer, and are being studied to ascertain their ability to block one of the key defense mechanisms that cancer cells rely upon to resist standard chemotherapy. By blocking tumor defenses, PARP therapy may increase the susceptibility of tumors to standard chemotherapy or even reverse tumor resistance.
About Inotek Pharmaceuticals
Inotek Pharmaceuticals Corporation (www.inotekcorp.com) is a Phase 2, drug-development company with a deep pipeline of small molecule compounds targeting the key biological processes involved in cell survival and tissue injury. Inotek's three platform programs have resulted in six novel molecules in various stages of preclinical and clinical development that target: 1) PARP, a nuclear enzyme that is fundamental to DNA repair and inflammation; 2) peroxynitrite, a highly toxic oxidative and nitro sative species produced by cells in response to injury; and 3) the purinergic receptor family, with a specific focus on adenosine receptors.
Inotek was founded in 1996 and currently has 140 employees, located in its corporate headquarters and main research laboratories in Beverly, Massachusetts and its clinical operations and GMP production facilities in Israel. Inotek has developed integrated capabilities from early discovery through Phase 2 clinical development.
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