Cytrx’s study offers a better perception of arimoclomol's mechanism of action in induced animal stroke

Aug 25 2009

CytRx Corporation (NASDAQ: CYTR), a biopharmaceutical research and development company engaged in the development of high-value human therapeutics, today announced that study results demonstrated that arimoclomol exhibited both statistically significant neuroprotective and neuroregenerative effects in brain cells of animals induced with stroke, offering important insights into this drug candidate’s mechanism of action. Orally administered arimoclomol is a molecular chaperone amplifier that is believed to help reduce the accumulation of damaged proteins that may play a role in multiple diseases and disorders.

“These results help explain how arimoclomol achieved the dramatic improvements in functional recovery that we observed in our previously announced rat stroke studies,” said CytRx President and CEO Steven A. Kriegsman. “This better understanding of arimoclomol’s mechanism of action is an important piece of information that we expect will be valuable in attracting potential pharmaceutical or biotechnology partners for further development of this exciting drug candidate. Currently, t-PA is the only FDA-approved treatment for stroke and must be administered within three hours of the initiation of stroke. We believe that arimoclomol has the potential to reach a much larger market, as our animal studies have shown statistically significant results even when animals are treated ten hours or more after stroke onset. In addition, clinical testing of arimoclomol for stroke recovery could be less expensive, as more patients could be treated at fewer sites due to the expanded therapeutic window.”

The study was conducted under the direction of world-renowned stroke expert Dr. Michael Chopp of the Department of Neurology in the Henry Ford Health System, Detroit, Michigan and the Department of Physics, Oakland University, Rochester, Michigan. Detailed cellular analysis in the brains of rats treated with arimoclomol following stroke inducement showed significantly increased molecular chaperone expression, decreases in both the number of cells undergoing programmed cell death (apoptosis) and the number of microglial cells that cause inflammation, and, most importantly, increases in the number of developing neurons sprouting new projections, called neurites, which are indicative of neuroregeneration.

Stroke is the result of oxygen deprivation to regions of the brain through diminished blood flow, usually due to a blood clot. Stroke affects about 700,000 Americans each year. On average, every 40 seconds someone in the United States has a stroke, and stroke is the leading cause of serious, long-term disability, according to the American Heart Association.

In the study, stroke was induced in rats by introducing blood clots into the middle cerebral artery, causing cerebral oxygen deprivation. These stroke-induced rats in groups of 10 received an oral dose of arimoclomol or a control substance daily for 28 days with the initial dose administered either six, 10, 24 or 48 hours after stroke. Sections of brain tissue were then evaluated for each of the following: 1) chaperone protein HSP70; 2) the number of cells with the characteristic DNA cleavage caused by apoptosis; 3) the microglial cell marker IB4-receptor; or 4) a marker for newly developing brain cells called doublecortin. HSP70 and doublecortin were detected with specific antibodies to the respective proteins, DNA cleavage was detected by a standard assay called TUNEL, and IB4-receptor was measured by binding to IB4-ligand.

The results showed that arimoclomol treatment in all groups tended to increase the number of cells expressing HSP70 compared to controls in the zone surrounding the lesion, reaching statistical significance (p<0.05) in those animals initially dosed either six or 10 hours following the stroke event. Moreover, all arimoclomol-treated groups tended to have a reduction in the number of apoptotic cells and microglial cells compared to controls in the zone surrounding the lesion, again reaching statistical significance (p<0.05) in those animals initially treated either six or 10 hours after stroke. Importantly, treatment with arimoclomol initiated at all four time points following the stroke event significantly increased the number of newly developing neurons in both the zone surrounding the lesion, as well as in an area called the subventricular zone of the lateral ventricle – the typical origin of these cells prior to their migration to the damaged tissue.

“We expected arimoclomol to increase chaperone expression and therefore probably prevent cells from undergoing apoptosis; however, we were elated to discover that it also controlled the proliferation of these inflammatory microglial cells and stimulated neuroregeneration as well,” said Jack Barber, Ph.D., CytRx Chief Scientific Officer. “These latter effects may explain arimoclomol’s ability to restore brain function even when administered well after the stroke event, because the negative effects of inflammatory cells and the positive effects of neuroregeneration occur much later than the initial damage.”