Navigation Links
Stunning finding: Compounds protect against cerebral palsy
Date:2/25/2009

Two compounds developed by Northwestern University chemists have been shown to be effective in pre-clinical trials in protecting against cerebral palsy, a condition caused by neurodegeneration that affects body movement and muscle coordination.

"The results were just stunning, absolutely amazing," said Richard B. Silverman, John Evans Professor of Chemistry in the Weinberg College of Arts and Sciences at Northwestern, who led the drug development effort. "There was a remarkable difference between animals treated with a small dose of one of our compounds and those that were not."

The findings, which are published online by the journal Annals of Neurology, suggest that a preventive strategy for cerebral palsy may be feasible for humans in the future. (The paper also will appear in the journal's February issue, in print the week of March 2.)

None of the fetuses born to animals treated with the two compounds died; more than half of those born to untreated animals died. Eighty-three percent of animals treated with one of the compounds were born normal, with no cerebral palsy characteristics. Sixty-nine percent of animals treated with the other compound were born normal. There was no sign of toxicity in the treated animals, and their blood pressure was normal.

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 one. Approximately 750,000 children and adults in the United States have a form of cerebral palsy, with the majority having been born with the condition.

The new compounds Silverman and his team developed inhibit an enzyme found in brain cells that produces nitric oxide, thus lowering nitric oxide levels. At normal levels, nitric oxide acts as a neurotransmitter and is important to neuronal functioning, but at high levels it has been shown to damage brain tissue. An overabundance of nitric oxide is believed to play a role in cerebral palsy.

After a lengthy drug development process, Silverman went to his collaborator Sidhartha Tan, M.D., a neonatologist from NorthShore University HealthSystem, to test the two best compounds on Tan's cerebral palsy animal model. A diminished supply of oxygen (hypoxia) from mother to fetus causes an increase in nitric oxide levels in the brain, which leads to brain damage and newborns with cerebral palsy characteristics.

Silverman and Tan wanted to see if they could prevent brain damage in the fetuses by administering one of the compounds to the mother before the hypoxic event. They expected some degree of success but were surprised by how effective the treatment was. The researchers attribute the protection from cerebral palsy to the decrease in the brain enzyme and the nitric oxide that is produced.

"We still have to bring the phenomenon to humans, which would be very exciting," said Tan, who has been investigating the impact of nitric oxide on neuronal damage. "There is such a dire need. If we could safely give the drug early to mothers in at-risk situations, we could prevent the fetal brain injury that results in cerebral palsy."

In developing the potential drugs, Silverman and his team were able to produce something that pharmaceutical companies so far have not: highly selective compounds that inhibit the enzyme found in brain cells that produces nitric oxide but that do not affect similar nitric oxide-producing enzymes found in endothelial and macrophage cells.

Endothelial cells regulate blood pressure, and macrophage cells play an important role in the immune system. Reducing their production of nitric oxide would have deleterious effects on an animal, such as increasing blood pressure or compromising the immune system.

"The challenge was to lower only the nitric oxide in the brain and not in the other cells where the nitric oxide is very important," said Silverman, a member of Northwestern's Center for Drug Discovery and Chemical Biology.

"Early compounds developed by drug companies to target the brain enzyme actually bound to all three nitric oxide enzymes," he said. "This made me think that the three enzymes must be very similar in structure. We decided to look for differences away from the normal binding site to get selectivity for only the brain enzyme."

This approach paid off. Silverman and his team started with a molecule that showed good selectivity of the brain enzyme over the macrophage enzyme but with no selectivity over the endothelial enzyme. The researchers then made modifications to the molecule and built a library of 185 different compounds that could be tested for the selectivity they wanted. They found 10 good ones. More modifications were made until they had a few compounds that were very selective and very potent for the brain enzyme.

Silverman then started collaborating with Thomas Poulos, Chancellor's Professor of Molecular Biology and Biochemistry and a crystallographer from University of California, Irvine, who had been working on the structure of the neuronal brain enzyme. Silverman sent him several potent and selective compounds, and Poulos produced crystal structures showing each compound bound to the brain enzyme.

"Thanks to the talents of Tom and his associate Huiying Li we could, for the first time, see visually why these compounds were selective and also see the difference between them," said Silverman.

Haitao Ji, a postdoctoral fellow who is an expert in structure-based design, joined Silverman's team. Ji took the crystal structures of their molecules bound to the enzyme and, using computer modeling, designed new structures with even better properties.

These compounds were more potent and much more selective than earlier ones. Poulos produced crystal structures of the new compounds. These are the compounds that Tan tested on his cerebral palsy animal model with such promising results, as reported by the research team in the Annals of Neurology paper.

"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," said Silverman. "Science is going in that direction these days."

The researchers caution that taking the compounds to human clinical trials is a lengthy and complicated process. Silverman says they next plan to make the compounds even more potent, selective and bioavailable and then envision partnering with a company that would want to develop the drugs further.


'/>"/>

Contact: Megan Fellman
fellman@northwestern.edu
847-491-3115
Northwestern University
Source:Eurekalert

Related medicine news :

1. AstraZeneca Licenses Novel Antidepressant Compounds Discovered by Mayo Clinic and Virginia Tech Collaboration
2. New platinum-phosphate compounds kill ovarian cancer cells
3. Scientists exploring new compounds to target muscular dystrophy
4. University of Illinois - Chicago Study: Raisins Contain Compounds that May Inhibit Cavity-causing Bacteria
5. InNexus Biotechnology Announces Third Antibody and Expands Pipeline of Anticancer Compounds
6. USPTO Issues Patent Embodying Methodologies for Abating a Broad Range of Allergens, Pathogens, Viruses, Bacteria, Odors and Volatile Organic Compounds.
7. Study Finds Spice-Rich Marinades Can Reduce Harmful Compounds When Grilling
8. ChromaDex Licenses Green Chemistry Technology to Manufacture a New Class of Super Fruit Compounds
9. Drugs With Marijuana Compounds Dont Boost Adverse Events
10. UCR chemists use green chemistry to produce amines, chemical compounds used widely in industry
11. Telik Announces Patents on Compounds Related to TELINTRA
Post Your Comments:
*Name:
*Comment:
*Email:
(Date:6/25/2016)... FL (PRWEB) , ... June 25, 2016 , ... The temporary closing of Bruton Memorial ... Plant City Observer , brings up a new, often overlooked aspect of head lice: the ... closing for fumigation is not a common occurrence, but a necessary one in the event ...
(Date:6/25/2016)... ... June 25, 2016 , ... First Choice Emergency Room ... Dr. Sesan Ogunleye, as the Medical Director of its new Mesquite-Samuell Farm facility. ... of our new Mesquite location,” said Dr. James M. Muzzarelli, Executive Medical Director of ...
(Date:6/25/2016)... ... June 25, 2016 , ... ... non-athletes recover from injury. Recently, he has implemented orthobiologic procedures as a method ... —Johnson is one of the first doctors to perform the treatment. Orthobiologics are ...
(Date:6/25/2016)... ... June 25, 2016 , ... Conventional wisdom preaches the benefits of moderation, ... the latter, setting the bar too high can result in disappointment, perhaps even self-loathing. ... toward their goal. , Research from PsychTests.com reveals that behind the ...
(Date:6/24/2016)... ... ... Those who have experienced traumatic events may suffer from a complex set of ... or alcohol abuse, as a coping mechanism. To avoid this pain and suffering, Serenity ... event. , Trauma sufferers tend to feel a range of emotions, from depression, guilt, ...
Breaking Medicine News(10 mins):
(Date:6/26/2016)... Jazz Pharmaceuticals plc (Nasdaq: JAZZ ... Antitrust Improvements Act of 1976, as amended ("HSR"), with ... ("Celator"; Nasdaq: CPXX ) expired effective June ... As previously announced on May 31, 2016, Jazz ... under which Jazz Pharmaceuticals has commenced a tender offer ...
(Date:6/26/2016)... 2016 Story Highlights: ... within the health care industry is causing providers to ... , Deloitte offers a suite of solutions for health ... efficient cost optimization: labor resource analysis, revenue cycle optimization ... better outcomes and better economics ...
(Date:6/24/2016)... 24, 2016  Collagen Matrix, Inc., ("Collagen Matrix") ... manufacturing of collagen and mineral based medical devices ... Bill Messer has joined the company ... leverage the growing portfolio of oral surgery, neurosurgery, ... Bill joins the Collagen Matrix executive team as ...
Breaking Medicine Technology: