Featured Research

from universities, journals, and other organizations

Inflammation is controlled differently in brain and other tissues

Date:
October 21, 2011
Source:
The Scripps Research Institute
Summary:
Scientists have identified a new metabolic pathway for controlling brain inflammation, suggesting strategies for treating it.

A team led by scientists from The Scripps Research Institute has identified a new metabolic pathway for controlling brain inflammation, suggesting strategies for treating it.

Related Articles


The new report, which appears in the October 20, 2011 edition of Science Express, focuses on the type of inflammation normally treatable with non-steroidal anti-inflammatory drugs (NSAIDs), such as aspirin or ibuprofen. The study shows this type of inflammation is controlled by different enzymes in different parts of the body.

"Our findings open up the possibility of anti-inflammatory drugs that are more tissue-specific and don't have NSAIDs' side effects," said the study's senior author Benjamin F. Cravatt, chair of the Department of Chemical Physiology and member of the Skaggs Institute for Chemical Biology and the Dorris Neuroscience Center at Scripps Research.

A Serendipitous Discovery

The serendipitous discovery originated with an attempt by Cravatt and his colleagues to develop a new kind of pain-relieving drug targeting an enzyme known as monoacylglycerol lipase (MAGL). This enzyme normally breaks down a natural pain-relieving neurotransmitter known as 2-AG, a "cannabinoid" molecule whose actions are mimicked by certain compounds within marijuana. To reduce the rate of 2-AG breakdown, allowing 2-AG levels to rise and provide more pain relief, the Cravatt lab developed a powerful and selective MAGL-inhibiting compound, which the scientists described in 2009 and are still investigating as a possible pain drug.

In the course of this research, the scientists tested their MAGL inhibitor on mice and also engineered mice that genetically lack MAGL. "We noticed that the brains of the MAGL-inhibited mice showed reduced levels of arachidonic acid, a key precursor molecule for inflammatory lipids," said Daniel Nomura, a former member of the Cravatt lab who is currently assistant professor in the Department of Nutritional Science & Toxicology at the University of California, Berkeley. Nomura is the paper's co-corresponding author with Cravatt, and co-first author with Bradley E. Morrison of Scripps Research.

Arachidonic acid had been thought to originate similarly throughout the body, from a process involving fat molecules and phospholipase A2 enzymes. To their surprise, the researchers found that in the brain, arachidonic acid production is controlled chiefly by MAGL.

In effect, the enzyme takes pleasure-associated 2-AG, which is found in high concentrations in the brain, and turns it into arachidonic acid -- the precursor for pain- and inflammation-causing prostaglandin molecules. The researchers showed that blocking the activity of MAGL, or genetically eliminating it, shrinks the pool of arachidonic acid and prostaglandins in mouse brains, effectively limiting the possibility of brain inflammation.

Providing a Protective Effect

To further test this effect, the researchers set up two standard models of brain inflammation in lab mice. In one, they tried to induce inflammation with lipopolysaccharide, a highly pro-inflammatory molecule found in bacteria. In the other, they used the toxin MPTP, which induces brain inflammation and preferentially kills the same muscle-regulating neurons lost in Parkinson's disease.

"In both models, reducing MAGL -- genetically or with our MAGL-inhibitor -provided the animals with protection from neuroinflammation," said Nomura, who is continuing to research the system at UC Berkeley.

NSAIDs such as ibuprofen are already used to reduce the inflammation that originates from arachidonic acid. They work by inhibiting the cyclo-oxygenase enzymes that convert arachidonic acid into prostaglandins. But NSAIDs also inhibit cyclo-oxygenase enzymes that protect the lining of the gastrointestinal tract. They thus can cause gastrointestinal bleeding, among other adverse side effects. That greatly limits their potential usefulness. In the brain, where MAGL is the major controller of arachidonic acid levels, blocking the enzyme could be a better strategy. Alzheimer's disease, Parkinson's disease, multiple sclerosis, and traumatic brain injury all involve harmful but potentially treatable brain inflammation.

"In principle, with a MAGL inhibitor we could avoid the gastrointestinal toxicity that's associated with NSAIDs while still maintaining the anti-inflammatory effect," said Nomura.

Unexpected Elements

The new findings also are important from a basic science perspective because they advance the understanding of prostaglandin-mediated inflammation. Phospholipase A2 enzymes have long been considered the dominant producers of arachidonic acid, and thus a major element in prostaglandin-mediated inflammation throughout the body. Nomura, Cravatt, and their colleagues confirmed in their experiments that phospholipase A2 enzymes play a major role in arachidonic acid production in the gut and spleen. However, in the brain, the MAGL enzyme was the principal regulator, with phospholipase A2 enzymes making a more limited contribution. MAGL also regulated arachidonic acid and prostaglandins in liver and lungs.

"Biological pathways that we think we understand sometimes turn out to have these unexpected, tissue- or context-specific elements, which is why it's so important to follow up on clues such as the ones we found," Cravatt said.

In addition to Cravatt, Nomura, and Morrison, authors of the paper "Endocannabinoid hydrolysis generates brain prostaglandins that promote neuroinflammation" are Jacqueline L. Blankman,Jonathan Z. Long, Maria Cecilia G. Marcondes, Anna M. Ward, and Bruno Conti of Scripps Research; and Steven G. Kinsey, Yun Kyung Hahn, and Aron H. Lichtman of the Lichtman lab at Virginia Commonwealth University.

The research was supported by the National Institutes of Health, the Institute for Drug and Alcohol Studies at Virginia Commonwealth University, the Ellison Medical Foundation, and the Skaggs Institute for Chemical Biology at Scripps Research Institute.


Story Source:

The above story is based on materials provided by The Scripps Research Institute. Note: Materials may be edited for content and length.


Journal Reference:

  1. Daniel K. Nomura, Bradley E. Morrison, Jacqueline L. Blankman, Jonathan Z. Long, Steven G. Kinsey, Maria Cecilia G. Marcondes, Anna M. Ward, Aron H. Lichtman, Bruno Conti, and Benjamin F. Cravatt. Endocannabinoid Hydrolysis Generates Brain Prostaglandins That Promote Neuroinflammation. Science, 20 October 2011 DOI: 10.1126/science.1209200

Cite This Page:

The Scripps Research Institute. "Inflammation is controlled differently in brain and other tissues." ScienceDaily. ScienceDaily, 21 October 2011. <www.sciencedaily.com/releases/2011/10/111020084810.htm>.
The Scripps Research Institute. (2011, October 21). Inflammation is controlled differently in brain and other tissues. ScienceDaily. Retrieved November 24, 2014 from www.sciencedaily.com/releases/2011/10/111020084810.htm
The Scripps Research Institute. "Inflammation is controlled differently in brain and other tissues." ScienceDaily. www.sciencedaily.com/releases/2011/10/111020084810.htm (accessed November 24, 2014).

Share This


More From ScienceDaily



More Health & Medicine News

Monday, November 24, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

Winter Can Cause Depression — Here's How To Combat It

Winter Can Cause Depression — Here's How To Combat It

Newsy (Nov. 23, 2014) Millions of American suffer from seasonal depression every year. It can lead to adverse health effects, but there are ways to ease symptoms. Video provided by Newsy
Powered by NewsLook.com
Ebola-Hit Sierra Leone's Late Cocoa Leaves Bitter Taste

Ebola-Hit Sierra Leone's Late Cocoa Leaves Bitter Taste

AFP (Nov. 23, 2014) The arable district of Kenema in Sierra Leone -- at the centre of the Ebola outbreak in May -- has been under quarantine for three months as the cocoa harvest comes in. Duration: 01:32 Video provided by AFP
Powered by NewsLook.com
Don't Fall For Flu Shot Myths

Don't Fall For Flu Shot Myths

Newsy (Nov. 23, 2014) Misconceptions abound when it comes to your annual flu shot. Medical experts say most people older than 6 months should get the shot. Video provided by Newsy
Powered by NewsLook.com
WFP: Ebola Risks Heightened Among Women Throughout Africa

WFP: Ebola Risks Heightened Among Women Throughout Africa

AFP (Nov. 21, 2014) Having children has always been a frightening prospect in Sierra Leone, the world's most dangerous place to give birth, but Ebola has presented an alarming new threat for expectant mothers. Duration: 00:37 Video provided by AFP
Powered by NewsLook.com

Search ScienceDaily

Number of stories in archives: 140,361

Find with keyword(s):
Enter a keyword or phrase to search ScienceDaily for related topics and research stories.

Save/Print:
Share:

Breaking News:

Strange & Offbeat Stories


Health & Medicine

Mind & Brain

Living & Well

In Other News

... from NewsDaily.com

Science News

Health News

Environment News

Technology News



Save/Print:
Share:

Free Subscriptions


Get the latest science news with ScienceDaily's free email newsletters, updated daily and weekly. Or view hourly updated newsfeeds in your RSS reader:

Get Social & Mobile


Keep up to date with the latest news from ScienceDaily via social networks and mobile apps:

Have Feedback?


Tell us what you think of ScienceDaily -- we welcome both positive and negative comments. Have any problems using the site? Questions?
Mobile: iPhone Android Web
Follow: Facebook Twitter Google+
Subscribe: RSS Feeds Email Newsletters
Latest Headlines Health & Medicine Mind & Brain Space & Time Matter & Energy Computers & Math Plants & Animals Earth & Climate Fossils & Ruins