Prostaglandins and Inflammation

In the article I am presenting tomorrow in class, prostaglandins are frequently mentioned. However, the article does not provide a good explanation for the role of prostaglandins in inflammation. They also focus solely on its negative effects. Hopefully, some of you have the chance to read this post before tomorrow, so that you can come in with a better understanding of the action of prostaglandins.

Prostaglandins are derived from arachidonic acid. They play a role in sustaining homeostatic functions and they also help to mediate pathogenic mechanisms (inflammation for example). They are made from arachidonate with the help of cyclooxygenase enzymes (COX-1 and COX-2). Their synthesis is blocked by non-steroidal anti-inflammatory drugs. Prostaglandins promote inflammation and also help to resolve it.

PGE2 is one of the most abundant prostaglandins in the body. It helps to mediate "immune responses, blood pressure, gastrointestinal integrity, and fertility", among other things. The dysregulation of PGE2 can actually cause certain types of pathology.

PGE2 leads to the classical signs of inflammation: redness, pain, and swelling. Redness and swelling are caused by increased blood flow, which is mediated by vasodilation caused in part by PGE2. Pain is caused by PGE2 acting on peripheral sensory neurons and on other sites in the brain and spinal cord.

PGE2 can have pro-inflammatory as well as anti-inflammatory effects, depending on the receptor type that it is bound to. It can regulate the function of many cells including macrophages, dendritic cells, T cells, and B cells. As a pro-inflammatory mediator, it can act on T cells to bias a Th1 or Th2 response. As an anti-inflammatory mediator, it can act on neutrophils, natural killer cells, and monocytes.



Ricciotti, Emanuela, and Garret A. FitzGerald. "Prostaglandins and Inflammation."Prostaglandins and Inflammation. American Heart Association, 2011. Web. 08 Dec. 2013.

Capsaicin Treatment

I was interested in the mechanism behind how capsaicin can provide some pain relief. I found a variety of articles and studies that have been conducted to test the effects of capsaicin on inflammatory conditions.

In an article titled, "Vascular and Sensory Responses of Human Skin to Mild Injury After Topical Treatment with Capsaicin", a general mechanism of action is discussed. The authors state that substance P causes vasodilation (also known as flare). As you may remember, I mentioned substance P in conjunction with calcitonin gene related peptide in my discussion of the anti-inflammatory actions of acupuncture. The authors also state that substance P is released from "central terminals of nociceptive afferent fibers." It is proposed that vasodilation after injury is partially caused by the release of substance P from these fibers.

The authors propose that treatment with capsaicin helps to decreases the levels of substance P that are released in the skin. Treatment with capsaicin is also thought to decrease the activity of some inflammatory agents.

Topical capsaicin may "deplete the skin nerve terminals of substance P." Substance P may also be "the agent that causes axon reflex flare."

However, I am still somewhat skeptical about the actions of capsaicin. The authors seem to feel similarly. They state that capsaicin has been shown to decrease the amount of dilator peptide (other than substance P) in the spinal cord. Over an extended period of time, capsaicin can actually "reduce the excitability of cutaneous nociceptors." This could lead to hypoalgesia and decreased flare, however that authors call this a toxic action.

It seems that capsaicin could have some concerning negative effects when used over a long period of time. Perhaps capsaicin is best used on a short time scale, for minor strains and sore muscles. After reading this article, I am curious as to how acupuncture can mimic the effects of capsaicin. It makes me wonder if there is any potential harm in having acupuncture over an extended period of time. Although, I have not heard of any data stating this.



Carpenter, Sandra E., and Bruce Lynn. "Vascular and Sensory Response of Human Skin to Mild Injury After Topical Treatment With Capsaicin." British Journal of Pharmacology 73.3 (2012): 755-58. 

Pain - It is its own disease

           I thought this video was interesting because in class we talked about NSAIDs, and how they can have side affects, which is why it is important to have knowledge of COX-1 Cox-2 inhibitors. Dr. Elliot Krane's TedTalk, discusses how chronic pain becomes its own disease because it can persist for months or oftentimes years.The sensation that many of his patients experience when they visit him is as he describes, even when an object as light as a feather touches the arm, to these patients it may feel like something as excruciating as a hot blow torch. Dr. Krane, mentions ibuprofen, and that how many times these NSAIDs can be ineffective when attempting to help patients with their chronic pain even though they are prescribed anyway. He then continues on to talk about the huge role the nervous system and a positive feedback loop have when an individual is experiencing chronic pain.

         I felt as if one of the main take home points from this video is that there are other approaches we should incorporate into our treatment of pain including chronic pain. Dr. Krane, mentions that his belief is that the future holds the promise that new drugs will be developed that are not symtom-modyfing drugs that "simply mask the problem", but that will be "disease-modifying drugs", that will actually go right to the root of the problem and attack glial cells. It sounds like a fantastic idea, but I wonder the possible side effects of such medications.

http://www.ted.com/talks/elliot_krane_the_mystery_of_chronic_pain.html

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Resveratrol: the Good and the Bad

Resveratrol is a polyphenol compound found in a variety of edible fruits, red wine, nuts, berries, grapes, and certain plants that is characterized for its cardioprotective, antioxidant, anticarcinogenic, antiinflammatory properties. A study at Yonsei University in South Korea (one of the studies we will be discussing on Monday) was carried out through which the effects of resveratrol on obesity were studied. The results gathered from this experiment ssuggested that with resveratrol supplementation to high-fat diets, the amount of weight gained over a 10 week period in mice was significantly reduced. Resveratrol significantly reduced the size of adipocytes, and was able t improve obesity-induced inflammation. Here, resveratrol showed to have positive anti-obesity effects.

However, after researching more on resveratrol and its effects on the body, I came across another study from University of Copenhagen in which they found that resveratrol actually blunts the positive effects of training on cardiovascular health in aged men. By comparing the effects of only exercising and the effects of resveratrol supplementation with exercise, it was found that resveratrol supplementation combined with training abolished reduction of blood pressure and blood lipid levels and led to a significantly lower increase in maximal oxygen uptake with training. What confused me was that in the study from Yonsei University, it mentioned that resveratrol had cardioprotective characteristics, but in the Copenhagen study, they concluded the opposite. Is resveratrol supplementation only beneficial without exercise? And if that's the case, is that a proper way to deal with obesity?

Lasse Gliemann, et al. Resveratrol blunts the positive effects of exercise training on cardiovascular health in aged men. The Journal of Physiology (2013). doi: 10.1113/jphysiol.2013.258061
(http://jp.physoc.org/content/early/2013/07/19/jphysiol.2013.258061.full.pdf+html)

What are NSAIDs?

The topic up for discussion for the next two weeks is antiinflammatories. My article, in particular, is about the use of nonsteroidal antiinflammatory drugs, or NSAIDs.

What exactly are NSAIDs?

NSAIDs are medications that are prescribed to provide relief from pain and fever. They work by reducing the production of prostaglandins by blocking the enzyme cyclooxygenase (COX). Prostaglandins are a family of chemicals that promote inflammation, pain, and fever, and are produced by the two types of COX enzymes. COX-1 enzyme is present in most tissues and is responsible for functions like protecting the lining of the stomach from stomach acid and is involved in kidney and platelet function. While COX-1 is constantly expressed in most tissues, COX-2 is only expressed when induced by inflammation. The main function of COX-2 enzyme is to cause pain and inflammation in the body. Thus, since NSAIDs essentially block the function of the COX enzymes, the protective functions of COX-1 and inflammation-inducing functions of COX-2 are inhibited.

There are two types of NSAIDs: selective and non-selective. Selective NSAIDs inhibit only COX-2 enzymes, while non-selective NSAIDs inhibit both COX-1 and COX-2 enzymes. Thus, while non-selective NSAIDs have the ability to inhibit inflammation and pain effects, they are associated with an increased risk of gastric ulceration and direct irritation of the stomach lining. That is why selective NSAIDs are more often used; inflammation and pain effects are blocked while prostaglandins that protect the stomach are still produced.

However, this doesn't mean that the use of selective COX-2 inhibitors is the best solution to relieving pain or fever. There are some serious cardiovascular risks associated with COX-2 selectivity of NSAIDs. What we will discuss later in class is how the degree of selectivity of COX-1 or COX-2 enzymes of the NSAID is related to cardiovascular and gastrointestinal risks.

If these COX inhibitors come with so many serious risks, is it even worth using to ease pain? Why try to relieve pain in one area when the pain relievers can in fact cause even more damage to your body?

References:
http://www.medicinenet.com/nonsteroidal_antiinflammatory_drugs/article.htm
http://www.virtualmedicalcentre.com/treatment/nsaids-non-steroidal-anti-inflammatory-drugs/78
http://www.medicalnewstoday.com/articles/179211.php

Tentative Link of Brain Trauma and Neurodegenerative Disease

As most of us know, tonight is the annual rivalry football game between the Arizona State Sun Devils and the Arizona Wildcats.  In addition to our very intense rivalry game, there are tons of significant rivalry games across the US today.  That being said, there's always a lot of clammer leading up to a rivalry game including phrases from team to team that hint at wanting to "kill" the opponent or at least "knock their heads off their shoulders".  All of this rivalry talk got me thinking about the significance of head injuries to neurodegenerative diseases.  The findings were not too surprising:

I came across a Cambridge University study that inadvertently focused on the significance of brain injury and Alzheimer's that was published just two weeks ago!  The researchers used a very simple cultured-cell model to examine the activity of a specific protein called Tubulin Associated Protein Unit (Tau).  They noted that many post-death brain examinations of Alzheimer's patients yield the discovery of high amounts of abnormally-clumped Tau protein throughout the brain.  The researchers introduced the Tau protein to the cell culture (raised to behave like brain and nervous cells) and observed a new phenomenon.  They saw that when Tau is introduced to the outside of the cells, they immediately begin to endocytose the extracellular Tau protein.  As the protein was endocytosed it clumped very quickly inside of the cells; they very significantly noted that Tau already in the cell before endocytosis also began to clump abnormally even if it did not come into contact with the extracellular Tau.

The researchers go on to note that in the human model, they would expect Tau escaping from brain tissues to leak and cause similar behavior.  They note that one very likely method for Tau to leak comes from damage incurred from significant head trauma.  The researchers do, however, admit that this is a very preliminary model and that they will use it to evolve future studies.  They will focus on the source of extracellular Tau and where it meets normal Tau as it is endocytosed.

Now I'm really rootin' for a Wildcats' victory today, but after reading this, I can honestly say that I hope for no Sun Devil's head to be knocked from their shoulders.  It will be interesting to see new studies emerging from these preliminary findings, perhaps a study including American football players (or other contact sports) and their prevalence of Alzheimer's Disease.

Go 'Cats!

Sources:
-Medical News Today:  http://www.medicalnewstoday.com/articles/269460.php
-Cambridge Press Release:  http://www.cam.ac.uk/research/news/protein-released-from-cells-triggers-chain-reactions-that-could-cause-alzheimers-disease
--The published study:  http://www.jbc.org/content/early/2013/11/14/jbc.M113.515445.full.pdf

Meditation Aids in Slowing of Progression of Alzheimer's?

Meditation is known to cause changes in the brain, but the effects of those changes have not been thoroughly studied. Researchers collected data from 14 individuals ages 55-90 that had been diagnosed with mild cognitive impairment, a stage typically before progression to Alzheimer's disease. The participants were randomly placed in two different groups: one that participated in Mindfulness-Based Stress Reduction (MBSR) and another that did not. MBSR is a combination of meditation and yoga. The participants in the MBSR group met for 2 hours each week to participate in the activity for eight weeks.

In order to study the effects of meditation on the brain, researchers compared functional MRI (fMRI) images from baseline and then after eight weeks for both groups. The results of the fMRI images showed that the group that participated in MBSR had significantly improved functional connectivity in the areas of the default mode network. The default mode network is the part of the brain that is engaged when remembering past events or envisioning the future, typically connectivity decreases in this part of the brain during the pathophysiology of Alzheimer's disease. They also found that both groups experienced atrophy in the hippocampus, as expected, but those that had practiced MBSR experienced less atrophy.

I like this study because I feel like meditation or MBSR are manageable activities for senior citizens. I think it could also be easy for assisted living or senior centers to incorporate classes that enable seniors to participate in these activities. Additionally, it is not a large time commitment. While the results of this study are promising, I do think that more research is needed on this topic to further examine if MBSR has long term cognitive benefits for Alzheimer’s disease because the researchers did not directly test cognitive function and this study only had a small sample with 14 participants.

Sources:

Lawman, Kelly. "Stress Reduction through Meditation May Aid in Slowing the Progression of Alzheimer's Disease." Beth Israel Deaconess Medical Center, 19 Nov. 2013. Web. 27 Nov. 2013. <http://www.bidmc.org/News/In-Research/2013/November/Wells-Meditation.aspx>.