Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

UK Study Advances New Target for CNS Drug Development

18.01.2010
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 central nervous system (CNS). But pathology in the CNS from a traumatic injury 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, diabetic retinopathy 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 angiogenesis inhibitor, 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."

This research was supported by grants from the National Institutes of Health, the RPB Foundation and the Kentucky Science and Technology Corporation. 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, with senior scientist Paola Bargagna-Mohan as lead author. Additional authors are: Riya R. Paranthan, Adel Hamza, Neviana Dimova, Beatrice Trucchi, Cidambi Srinivasan, Gregory I. Elliott, Chang-Guo Zhan, Daniel L. Lau, Haiyan Zhu, Kousuke Kasahara, Masaki Inagaki, Franca Cambi and Royce Mohan.

Keith Hautala | EurekAlert!
Further information:
http://www.uky.edu

Further reports about: CNS Drug Delivery End User Development GFAP Gliosis Kentucky Target blood vessel key protein

More articles from Life Sciences:

nachricht Show me your leaves - Health check for urban trees
12.12.2017 | Gesellschaft für Ökologie e.V.

nachricht Liver Cancer: Lipid Synthesis Promotes Tumor Formation
12.12.2017 | Universität Basel

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Long-lived storage of a photonic qubit for worldwide teleportation

MPQ scientists achieve long storage times for photonic quantum bits which break the lower bound for direct teleportation in a global quantum network.

Concerning the development of quantum memories for the realization of global quantum networks, scientists of the Quantum Dynamics Division led by Professor...

Im Focus: Electromagnetic water cloak eliminates drag and wake

Detailed calculations show water cloaks are feasible with today's technology

Researchers have developed a water cloaking concept based on electromagnetic forces that could eliminate an object's wake, greatly reducing its drag while...

Im Focus: Scientists channel graphene to understand filtration and ion transport into cells

Tiny pores at a cell's entryway act as miniature bouncers, letting in some electrically charged atoms--ions--but blocking others. Operating as exquisitely sensitive filters, these "ion channels" play a critical role in biological functions such as muscle contraction and the firing of brain cells.

To rapidly transport the right ions through the cell membrane, the tiny channels rely on a complex interplay between the ions and surrounding molecules,...

Im Focus: Towards data storage at the single molecule level

The miniaturization of the current technology of storage media is hindered by fundamental limits of quantum mechanics. A new approach consists in using so-called spin-crossover molecules as the smallest possible storage unit. Similar to normal hard drives, these special molecules can save information via their magnetic state. A research team from Kiel University has now managed to successfully place a new class of spin-crossover molecules onto a surface and to improve the molecule’s storage capacity. The storage density of conventional hard drives could therefore theoretically be increased by more than one hundred fold. The study has been published in the scientific journal Nano Letters.

Over the past few years, the building blocks of storage media have gotten ever smaller. But further miniaturization of the current technology is hindered by...

Im Focus: Successful Mechanical Testing of Nanowires

With innovative experiments, researchers at the Helmholtz-Zentrums Geesthacht and the Technical University Hamburg unravel why tiny metallic structures are extremely strong

Light-weight and simultaneously strong – porous metallic nanomaterials promise interesting applications as, for instance, for future aeroplanes with enhanced...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

See, understand and experience the work of the future

11.12.2017 | Event News

Innovative strategies to tackle parasitic worms

08.12.2017 | Event News

AKL’18: The opportunities and challenges of digitalization in the laser industry

07.12.2017 | Event News

 
Latest News

Long-lived storage of a photonic qubit for worldwide teleportation

12.12.2017 | Physics and Astronomy

Multi-year submarine-canyon study challenges textbook theories about turbidity currents

12.12.2017 | Earth Sciences

Electromagnetic water cloak eliminates drag and wake

12.12.2017 | Power and Electrical Engineering

VideoLinks
B2B-VideoLinks
More VideoLinks >>>