Two compounds developed by UC Irvine and Northwestern University scientists prevented cerebral palsy in preclinical animal trials, giving hope that a new drug for humans may be on the horizon.
Cerebral palsy is caused by an injury to the brain before, during or shortly after birth, although it typically is not diagnosed until after the age of 1. Approximately 750,000 children and adults in the U.S. have a form of cerebral palsy, and most were born with the condition. Caused by loss of function or structure in neurons, the disease affects body movement and muscle coordination.
In the study, published online Feb. 20 in the journal Annals of Neurology, animals predisposed to develop cerebral palsy were treated with the compounds. Results showed:
- Eighty-three percent of animals treated with one of the compounds were born with no cerebral palsy characteristics.
- Sixty-nine percent of animals treated with the other compound were born with no cerebral palsy characteristics.
- There was no sign of toxicity in the treated animals, and their blood pressure was normal.
The new compounds inhibit a brain cell enzyme that produces nitric oxide, thus lowering levels produced. At normal levels, nitric oxide is important to neuronal functioning, but at high levels it has been shown to damage brain tissue and is believed to play a role in cerebral palsy.
In developing the potential drugs, Thomas Poulos of UCI and Richard Silverman of Northwestern produced something pharmaceutical companies so far have not – highly selective compounds that inhibit the enzyme found in brain cells that produces nitric oxide but do not affect similar nitric oxide-producing enzymes found in other cells.
Poulos, Chancellor’s Professor of Molecular Biology & Biochemistry, and colleagues produced crystal structures that showed how the compounds synthesized by the Silverman lab block the formation of nitric oxide thereby preventing cerebral palsy.
“Thanks to the talents of Tom and his associate, Huiying Li, we could visualize for the first time why these compounds were selective and also see the difference between them,” said Silverman, the John Evans Professor of Chemistry at Northwestern who led the drug development effort.
“This is a great example of a multi-institutional collaboration that could not have been done without each of the parts – we each contributed something different,” Silverman said. “That’s the direction science is going these days.”
Scientists from the University of Texas, Charles University in Prague and the Medical College of Wisconsin also worked on the study, which was supported by the National Institutes of Health and the Robert A. Welch Foundation.