Illinois Medicine

STOPPING THE PAIN R Study on sickle cell disease funded with $2 million NIH grant ESEARCHERS AT THE UNIVERSITY OF ILLINOIS at Chicago will use a $2 million grant from the National Heart, Lung and Blood Institute, one of the Na- tional Institutes of Health, to investigate why patients with sickle cell disease experience chronic pain—and to develop drugs to treat it. The neurobiology of pain in sickle cell disease is poorly understood, says Z. Jim Wang, PhD, associate professor of pharmacology and pharmaceu- tics and lead researcher on the four-year study. Affecting more than 70,000 Americans, sickle cell disease causes red blood cells to become hard and pointed instead of soft and round, and the disease can damage lung tissue and cause excruciating pain and stroke. The blockage of blood flow caused by sickled cells also causes damage to most organs, including the spleen, kidneys and liver. About 2.5 million Americans have the sickle cell trait. Research has been conducted on pain associated with the disease using several animal models, but the findings were limited. In preliminary studies conducted at UIC for the NIH grant, Wang and his team observed that CaMKII, an enzyme called a protein kinase that plays an important role in the generation and maintenance of opioid addiction, is a critical component leading to persistent pain. Several pain tests—some that are employed in ongoing human studies of sickle cell disease using quantitative sensory testing— will be used on mouse models, according to Wang. UIC researchers will examine the expression and activity of CaMKII in mice carrying human sickle mutations and test the hypothesis that spinal CaMKII is a "molecular mechanism that promotes and maintains the manifestation of chronic pain in sickle cell disease," Wang says. Following the initial studies, the research team, includ- Sickle cell disease causes red blood cells to become hard and pointed instead of soft and round, and the disease can damage lung tissue and cause excruciating pain and stroke. ing Diana Wilkie, PhD, RN, professor of biobehavioral health science, Robert Molokie, MD, instructor in medicine, and Joseph Desimone, PhD, director of the UIC Sickle Cell Center, will conduct pharmacological studies using an FDA-approved oral antipsychotic prescription medication. The medication—trifluoperazine—is found to be a CaMKII inhib- itor that reduces inflammatory and neuropathic pain. The phase I work will be performed in humans with sickle cell disease. A NEW PURPOSE A Diabetes drug shows promise against multiple sclerosis DRUG CURRENTLY FDA-APPROVED for use in diabetes shows some protective effects in the brains of patients with relapsing remitting multiple sclerosis, researchers at the College of Medicine reported in a study in the Journal of Neuroimmunology last year. In a small, double-blind clinical trial, patients with relapsing remitting multiple sclerosis were assigned to take pioglitazone (a drug commercially known as Actos, used to treat type 2 diabetes) or a placebo. Patients taking pioglitazone showed significantly less loss of gray matter over the course of the one-year trial than patients taking a placebo. Of the 21 patients who finished the study, those taking pioglitazone had no adverse reactions and, further, found taking pioglitazone, which is administered in an oral tablet, easy. "This is very encouraging," says Douglas Feinstein, PhD, research professor of anesthesiology at UIC. "Gray matter in the brain is the part that is rich in neurons. These preliminary results suggest that the drug has important effects on neuronal survival." Feinstein's lab has been interested in the class of drugs called thiazolidinediones, or TZDs. Several TZDs have been approved for use in the treatment of type 2 diabetes because of the drugs' effect on the body's re- sponse to insulin. The lab tested pioglitazone in an animal model of MS. They and other researchers have shown that pioglitazone and other TZDs "can significantly reduce the clinical signs in mice with an MS-type disease," Feinstein says. "More importantly, when mice who are already ill are treated with pioglitazone, the clinical signs of the disease go away. We were able to induce almost complete remis- sions in a number of mice." The researchers focused on pioglitazone because of its known anti-inflammatory effects, Feinstein says. They used primary cultures of brain cells to show that piogli- tazone reduced the production of toxic chemicals called cytokines and reactive oxygen species. These molecules are believed to be important in the development of symp- toms in MS. "We are now working to determine the mechanisms to explain the protective effect on neurons that we see in our studies," Feinstein says. "We hope to expand into a larger trial to confirm these preliminary results." 6 | SPRING 2 010 PHOTO: SUSAN REICH

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