Study advances new target for CNS drug development

Jan 15, 2010

A breakthrough discovery by scientists at the University of Kentucky could someday lead to new treatments for a variety of diseases of the brain, spinal cord and the eye.

Researchers led by Royce Mohan, associate professor of ophthalmology and visual science in the UK College of Medicine, found that the small molecule withaferin A can simultaneously target two key proteins — vimentin and glial fibrillary acidic protein (GFAP) — implicated in a damaging biological process called reactive gliosis.

Both vimentin and GFAP, members of a family of proteins called intermediate filaments, are important factors in the stress response of the (CNS). But pathology in the CNS from a or neurodegenerative disease can cause overexpression of vimentin and GFAP and lead to reactive gliosis.

During gliosis, astrocyte cells that express vimentin and GFAP accumulate into dense, fibrous patches called glial scars, which interfere with normal functioning of the CNS. Gliosis is a significant feature of many disorders of the CNS, including multiple sclerosis, Alzheimer's disease, stroke, and traumatic brain and spinal cord injury, and it is also central to major retinal diseases such as age-related macular degeneration, and glaucoma.

Mohan's lab discovered that withaferin A binds to both vimentin and GFAP within an unique pocket when these proteins are in their soluble, tetrameric form. This finding makes withaferin A an appealing therapeutic lead for drug-development research, Mohan said, and he owes great credit to the interdisciplinary team of collaborators who contributed to extending this finding.

Mohan describes the discovery as serendipitous. Originally, his team was investigating withaferin A as an , a type of drug used to slow the development and growth of new blood vessels. Such drugs are useful in treating cancers and various conditions of the eye, such as corneal neovascularization, wet-stage macular degeneration and glaucoma.

Using an approach called reverse chemical genetics, Mohan's lab started with the identification of withaferin A as a vimentin probe, and then looked for CNS pathological indications where the related type III intermediate filament GFAP is critically involved.

"It was fortuitous that we looked at the retina of injured mice," Mohan said. "This drug was causing simultaneous inhibition of both corneal angiogenesis and retinal gliosis, a finding that is relevant to combat ocular trauma from the alarming incidence of blast injuries. Rarely does one get the opportunity to make an important discovery that advances on two drug targets at once."

Explore further: Metabolism may have started in our early oceans before the origin of life

More information: The study, "Withaferin A Targets Intermediate Filaments GFAP and Vimentin in a Model of Retinal Gliosis," was published online Jan. 4 in the Journal of Biological Chemistry.

Provided by University of Kentucky

4.7 /5 (3 votes)
add to favorites email to friend print save as pdf

Related Stories

Neuronal survival and axonal regrowth obtained in vitro

Jul 24, 2009

While repair of the central nervous system has long been considered impossible, French researchers from Inserm, the CNRS and the UPMC have just developed a strategy that could promote neuronal regeneration after injury. The ...

Scientists increases understanding of two types of blindness

Feb 07, 2009

Though based on mouse studies, the research bolsters the idea that humans suffering from these and other eye conditions may be able to help preserve function by adding antioxidants to their diet, and explains why this would ...

Recommended for you

New method to analyse how cancer cells die

22 hours ago

(Phys.org) —A team from The University of Manchester – part of the Manchester Cancer Research Centre - have found a new method to more efficiently manufacture a chemical used to monitor cancer cells.

The anti-inflammatory factory

Apr 22, 2014

Russian scientists, in collaboration with their colleagues from Pittsburgh University, have discovered how lipid mediators are produced. The relevant paper was published in Nature Chemistry. Lipid mediators are molecules that p ...

User comments : 0

More news stories

Computer program could help solve arson cases

Sifting through the chemical clues left behind by arson is delicate, time-consuming work, but University of Alberta researchers teaming with RCMP scientists in Canada, have found a way to speed the process.

Google+ boss leaving the company

The executive credited with bringing the Google+ social network to life is leaving the Internet colossus after playing a key role there for nearly eight years.

Facebook woos journalists with 'FB Newswire'

Facebook launched Thursday FB Newswire, billed as an online trove of real-time information for journalists and newsrooms to mine while reporting on events or crafting stories.