Inflammation controlled differently in brain and other tissues, study finds
October 20, 2011 in Medical researchA team led by scientists from The Scripps Research Institute has identified a new metabolic pathway for controlling brain inflammation, suggesting strategies for treating it.
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 acidthe 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.
More information: "Endocannabinoid hydrolysis generates brain prostaglandins that promote neuroinflammation" Science Express, October 20, 2011.
Provided by
The Scripps Research Institute
-
Researchers define new painkilling chemical pathway
Nov 23, 2008 |
not rated yet |
0
-
Study puts a new spin on ibuprofen's actions
Sep 25, 2011 |
not rated yet |
0
-
New study sheds light on painkilling system in brain
Aug 24, 2010 |
not rated yet |
0
-
Scientists find cancer cells co-opt fat metabolism pathway to become more malignant
Jan 12, 2010 |
not rated yet |
0
-
Lack of omega-6 fatty acid linked to severe dermatitis
Apr 12, 2010 |
not rated yet |
0
-
Of mice and mental models: Neuroscientific implications of risk-optimized behavior in the mouse
May 25, 2012 |
not rated yet |
0
-
Limits to growth: Scientists identify key metastasis-enabling enzyme
May 22, 2012 |
5 / 5 (4) |
0
-
Seeing is as seeing does: Spatially-structured retinal input in early development of cortical maps
Apr 26, 2012 |
5 / 5 (4) |
1
-
Dreamless nights: Brain activity during nonrapid eye movement sleep
Apr 09, 2012 |
4.4 / 5 (12) |
0
-
Take your time: Neurobiology sheds light on the superiority of spaced vs. massed learning
Mar 28, 2012 |
4.5 / 5 (21) |
3
-
Potential Breakthrough in Seizure Control
7 hours ago
-
Popping/Cracked sternum.
12 hours ago
-
Which Mental Illness Encompasses This Problem?
12 hours ago
-
A question about drug tolerance
May 23, 2012
-
Poor nutrition leading to overeating?
May 23, 2012
-
Math and dyslexia?
May 21, 2012
- More from Physics Forums - Medical Sciences
More news stories
Implantable pain disk may help those with cancer
An estimated 3.5 million cancer patients around the globe are in severe pain from their disease, but many get no relief.
Medical research
May 25, 2012 |
not rated yet |
0
|
Energy levels link sleep control mechanisms
Sleep, or lack of it, can determine level of cognitive performance which is linked with accidents as well as increased risk of serious health problems. Links between cell energy levels, gene transcription ...
Medical research
May 25, 2012 |
not rated yet |
0
Researchers identify key brain cell in antidepressant action
(Medical Xpress) -- Antidepressant medications such as Prozac have helped improve mood and lessen anxiety in millions of people with major depression. But scientists know surprisingly little about how these drugs work.
Medical research
May 25, 2012 |
4.7 / 5 (3) |
0
|
Rockefeller scientists pioneer new method to determine mechanisms of drug action
(Medical Xpress) -- Knowing that a drug works is great. Knowing how it works is a luxury. And until now, determining a drugs mechanism of action has been a tedious and difficult process for scientists.
Medical research
May 25, 2012 |
not rated yet |
0
|
Like curry? New biological role identified for compound used in ancient medicine
Scientists have just identified a new reason why some curry dishes, made with spices humans have used for thousands of years, might be good for you.
Medical research
May 25, 2012 |
4.5 / 5 (12) |
2
|
Travel to high altitudes tied to Crohn's, colitis flare-ups
(HealthDay) -- People with inflammatory bowel disease, which includes Crohn's disease and colitis, may be at increased risk for flare-ups when they fly or travel to high altitudes for skiing or mountain climbing, ...
Family history of Alzheimer's affects functional connectivity
(HealthDay) -- Cognitively normal individuals with a family history of late-onset Alzheimer's disease (AD) may display lower resting state functional connectivity in the default mode network (DMN) of the brain, ...
Transvaginal mesh op restores pelvic organ prolapse at price
(HealthDay) -- Transvaginal mesh (TVM) procedures are effective for anatomical restoration of pelvic organ prolapse (POP), but patients report a worsening of sexual function following surgery, according to ...
Skp2 activates cancer-promoting, glucose-processing Akt
HER2 and its epidermal growth factor receptor cousins mobilize a specialized protein to activate a major player in cancer development and sugar metabolism, scientists report in the May 25 issue of Cell.
Tongue analysis software uses ancient Chinese medicine to warn of disease
For 5,000 years, the Chinese have used a system of medicine based on the flow and balance of positive and negative energies in the body. In this system, the appearance of the tongue is one of the measures used to classify ...
Early physical therapist treatment associated with reduced risk of healthcare utilization and reduced overall healthcare
A new study published in Spine shows that early treatment by a physical therapist for low back pain (LBP), as compared to delayed treatment, was associated with reduced risk of subsequent healthcare utilization and lower ...
Oct 20, 2011
Rank: 5 / 5 (1)