DOI, a psychedelic drug with exceptional potency inhibiting TNF-a

DOI is a psychedelic drug commonly used in research as a 5HT-2A agonist, but is known to bind to all 3 isoforms of the 5HT-2 receptor (A, B, and C). 5HT-2A receptors are present in the CNS as well as the periphery, but little was known about its role in inflammatory processes. To investigate the effects on proinflammatory markers, rat aortic muscle was isolated, and grown in a petri dish. The cells were then pretreated with DOI or other 5HT-2A agonists such as LSD, 2C-BCB, and LA-SS-Az (an analogue of LSD). After 24 hours, TNF-a was added, and the expression of inflammatory mediators was measured. These inflammatory processes measured were ICAM-1, VCAM-1, IL-6, NO synthase, and NF-kB.

DOI was found to inhibit ICAM-1, VCAM-1, and IL-6 with an EC50 (effective concentration to inhibit 50% of the activity induced by TNF-a) of 10-20 pM; some 300-fold more potent than currently used anti-inflammatory drugs. DOI was also found to inhibit NOS activity and NF-kB translocation to the nucleus. This effect was found to be 5HT-2A dependent by using specific inhibitors for each of the 5HT-2 receptor subtypes. And while LSD, 2C-BCB, and LA-SS-Az were also found to inhibit TNF-a mediated increases in inflammatory molecules, none were nearly as potent as DOI.

When DOI was added at the same time as TNF-a, it was still found to completely block proinflammatory markers. Even when DOI was added 4 hours after TNF-a addition, it blocked 50% of the increase in inflammatory molecules. To investigate this mechanism further, the researchers looked at PKC, which is known to activate ICAM-1 expression. They found that an inhibitor of PKC inhibited TNF-a stimulation of all the proinflammatory markers tested.

This discovery represents a novel way to treat inflammation. While the drugs tested in this experiment are all psychoactive, there may be development of 5HT-2A agonists that are not psychoactive, or cannot cross the BBB.

Full paper here:
http://www.ncbi.nlm.nih.gov/pubmed/18708586

SBrookshire; PSIO495K

Stroke Risk Factors and Symptoms

When it comes to the treatment of a stroke patient timing is key. The longer the brain cells go without oxygen the more severe the damage will be. The only approved treatment used on stroke patients is tissue plasminogen activator (t-PA), which works to dissolve the clot causing the ischemic stroke. This treatment is extremely time-sensitive, so it is extremely important to know the risk factors and warning signs of a stroke.

An ischemic stroke is more likely to occur in someone over the age of 55, it is also more likely to occur in men. African Americans are more likely to experience a stroke due to sickle cell anemia, which can narrow arteries. All of these risk factors are uncontrollable, however just like many other diseases, there are certain life style factors that can be controlled to reduce your risk. One of the biggest controllable risk factors is hypertension; this can be treated through diet, exercise and medication if needed. Quitting smoking can reduce your risk because atherosclerosis is seen in the carotid artery of many smokers. Other treatable risk factors include; diabetes, high cholesterol, physical inactivity and obesity.

Once the aforementioned risk factors have been assessed its important to have the ability to recognize the symptoms of an ischemic attack. On Monday an article was discussed that mentioned transient ischemic attacks (TIAs) or mini strokes, these events can consist of numbness, dizziness, fatigue or a short-lived intense headache. These mild ischemic events can appear suddenly and are highly indicative of a stroke. Other stroke symptoms include; weakness on one side of the face or body, slurred speech, trouble understanding and difficulty hearing. It is important to note that these symptoms will appear very suddenly. The knowledge of your risk factors combined with the ability to recognize the signs of a stroke will increase your chances of receiving proper treatment and therefore minimize damage to the brain.

http://www.stroke.org/site/PageServer?pagename=SYMP

http://www.mayoclinic.com/health/stroke/DS00150/DSECTION=risk-factors

http://www.webmd.com/stroke/guide/stroke-treatment-overview

Are Normal Aging Symptoms Normal?

It is not a surprise when an elderly person is showing typical signs of aging. However, recent studies have shown that many typical aging symptoms, including shaky hands, can be associated with small brain lesions. These small brain lesions would most likely arise from transient ischemic attacks (mini strokes), which might have no immediate symptoms associated with it. The study incorporated 1100 nuns and priests, whom were examined every year starting in 1994. When they passed away, their brains were donated to the study for further examination. The study found that 30% of the 418 people that died showed small lesions or thrombosis in their brains. However, the subjects didn’t show any signs of brain disease or stroke when alive. And while alive, the subjects with the hardest time walking and other aging symptoms, showed more lesions.

This conclusion does coincide with possible causes of stroke, which are more likely to develop with aging. Two risk factors for a stroke are hemodynamic impairment (HDI) and micro embolic signals (MES), which can be associated with arthrosclerosis, internal carotid artery disease, plaque formation, and other common developments with aging. Another study demonstrated the correlation between these risk factors and transient ischemic attacks, which concluded that HDI and MES can independently and collectively promote watershed infarcts. This demonstrates that these risk factors, which are prevalent among the elderly, can lead to brain ischemia.

By recognizing these “aging symptoms” as a result of a preceding mini stroke, these patients could be informed they are at a higher risk of a worse stroke. These patients could take action by lowering cholesterol levels, increasing physical activity, as well as taking prescription medications, including anticoagulants. With the results from these two studies it is evident that normal aging symptoms could be considered not so normal after all.

Sources:

Below are links to the abstract and an article posted on NPR. The final source demonstrates the link between hemodynamic impairment and micro embolic signals with transient ischemic attacks.

http://www.ncbi.nlm.nih.gov/pubmed/21885844

http://www.npr.org/blogs/health/2011/09/02/140146620/tiny-strokes-may-cause-the-shuffling-gait-of-old-age?sc=ipad&f=1001

http://www.ncbi.nlm.nih.gov/pubmed/20508190

Caffeine and Inflammation - Especially Neuroinflammation

Since I missed our discussion last week I wanted to create a more in-depth post and this block of discussion has provided me an opportunity to talk about a pet theory of mine. Years ago I stumbled past a folk remedy book about recovering from sports injuries that talked about avoiding caffeine. At roughly the same time, I read an article in Outside magazine that suggested a link between caffeine and post-injury pain reduction. (I couldn’t find online references for either, sorry about that.)

My own antecdotal evidence suggested that caffeine actually slowed recovery after a major injury, but it wasn't until I found several papers on the subject that I realized the issue was one of Ca2+ mobilization and that caffeine interferes with bone remodeling and repair in the early stages [1,2.] I also wonder if there is a link between caffeine modulating inflammatory responses and lesser phagocytosis of damaged tissue resulting in prolonged tissue recovery times. I've been unable to locate any hard research on this. Either way, I think I can make a strong case that caffeine has positive effects with regard to CNS inflammation and generally negative effects with regard to peripheral inflammation.

Caffeine exerts its effects on inflammation by antagonistically binding adenosine receptors (Especially A1 and A2A, but others with lesser affinity.) This has several consequences downstream from the CNS, as well as within the CNS. In brain, caffeine antagonism of A1 and A2A receptors blocks the activity of adenosine, which acts to reduce the exocytosis of glutamate. Glutamate plays a central role in neuro-inflammation and studies that sought to modulate its release showed protective effects for diseases including Parkinson’s, Dimentia, and Alzheimer’s [3,4,5,6.] This activity also serves to excite neural cells resulting in a signal being received by the pituitary implying that some sort of “fight or flight” situation must be unfolding; it, in turn, tells the adrenal glands to begin releasing epinephrine. Epinephrine has serious consequences on inflammation, as those who have taken Neuroendocrine Physiology will probably remember. Among other things, it inhibits leukocyte vascular adhesion, reverses stimulus for TNF-alpha production, and increases IL-6 production. All of which would have demonstrable consequences for peripheral inflammation.

The reason I bring this up now is that some of the most promising research regarding caffeine and inflammation modulation seems to be centered around its possible neuro-protective effects. Indeed, plenty of research has been done on caffeine in relation to diabetes and other inflammatory disorders to little current avail. The current state of research for caffeine and Alzheimer’s, for example, suggests that caffeine may not just play a preventative role but might also function as a useful therapy [5.] Additionally, several studies have noted an improvement in motor symptoms and a slowing of disease course in Parkinson’s when patients are regular caffeine users, including the study referenced here [4.] Since caffeine is such a part of many American’s daily lives and it seems to have a definable place in control of neuro-inflammation, I wanted to make sure it got mentioned. Thanks for reading!

1. 1. Lu, Pin-Zhen (May 2008.) “Caffeine Induces Cell Death via Activation of Apoptotic Signal and Inactivation of Survival Signal in Human Osteoblasts.” Int J Mol Sci. 2008 May; 9(5): 698–718. PMC2635715.
2. 2. Duarte, PM (August 2009.) “The effects of caffeine administration on the early stage of bone healing and bone density: A histometric study in rats.” Arch Oral Biol. 2009 Aug;54(8):717-22. PMC19482261.
3. 3. Brothers, Holly M (August 2010.) “Caffeine attenuates lipopolysaccharide-induced neuroinflammation.” Neurosci Lett. 2010 August 16; 480(2): 97–100. PMC2905864.
4. 4. Ross, GW (2001.) “Current evidence for neuroprotective effects of nicotine and caffeine against Parkinson's disease.” Drugs Aging. 2001;18(11):797-806. PMC11772120.
5. 5. Marques, S (2011.) “Modulating Alzheimer's disease through caffeine: a putative link to epigenetics.” J Alzheimers Dis. 2011;24 Suppl 2:161-71. PMC21427489
6. 6. Gelber, RP (2011.) “Coffee intake in midlife and risk of dementia and its neuropathologic correlates.” J Alzheimers Dis. 2011;23(4):607-15. PMC21157028.

An apple a day?

New research out of the Netherlands has shown that consumption of high levels of white fruits and vegetables may reduce stroke risk. Food consumption was recorded using a food frequency questionaire for ~20,000 subjects (male and female). Fruits and vegetables were separated into 4 color categories by the color of the main edible portion of the fruit or vegetable: green, yellow/orange, red/purple, and white. Consumption of white fruits and vegetables were found to be inversely proportional to incidence of stroke. No relationship was found between other color categories and stroke risk.

This seems to contradict previous studies on the health benefits of pigmented bioactive compounds found in grapes and dark leafy greens. Red grapes have been shown to reduce inflammation, which might transiently reduce the risk of stroke. It is plausible to suggest that perhaps the compounds present in white fruits and vegetables are better at reducing chronic low levels of inflammation than fruits and vegetables of other colors. Perhaps an apple a day really does keep the doctor away?


Chuang CC, Martinez K, Xie G, Kennedy A, Bumrungpert A, Overman A, Jia W, McIntosh MK. Quercetin is equally or more effective than resveratrol in attenuating tumor necrosis factor-{alpha}-mediated inflammation and insulin resistance in primary human adipocytes. Am J Clin Nutr. 2010 Dec;92(6):1511-21. Epub 2010 Oct 13. http://www.ncbi.nlm.nih.gov/pubmed/20943792

Oude Griep LM, Verschuren WM, Kromhout D, Ocké MC, Geleijnse JM. Colors of Fruit and Vegetables and 10-Year Incidence of Stroke. Stroke. 2011 Sep 15. http://www.ncbi.nlm.nih.gov/pubmed/21921279

A Nobel Prize for Immunology

Today the winners of the 2011 Nobel Prize in Medicine were announced, awarding Ralph Steinman, Bruce A. Beutler, and Jules A. Hoffmann for their discoveries concerning the immune system.  Beutler and Hoffmann were cited for their discoveries in the 1990s of receptor proteins that can recognize bacteria and other microorganisms as they enter the body, and activate innate immunity.  Steinman was honored for his discovery in 1973 of dendritic cells, which activate T-cells and help regulate adaptive immunity.

Sadly, Ralph Steinman passed away on Friday, presenting a unique quandary for the Nobel committee, whose rules prohibit awarding a prize posthumously unless the winner dies after the award is announced.  Steinman was diagnosed with pancreatic cancer four years ago and his life was extended using a dendritic-cell based immunotherapy he designed.  Steinman's research also contributed to the launch last year of the first vaccine designed to kill tumors.  Regardless of the Nobel committee's decision, Steinman will always be remembered for his major contributions to the field of immunology.

http://www.nobelprize.org/nobel_prizes/medicine/laureates/2011/press.pdf



 

Inflammation and Stroke

The relationship between inflammation and stroke seems to be multi-layered. First, it is important to look at inflammation as a risk factor for stroke. Secondly, it is important to investigate the role of inflammation in the severity and spread of infarct and damage during and after stroke. And thirdly, it is important to look at the role of inflammation in the recovery process after stroke.

1. According to the National Stroke Association, certain controllable and non-controllable risk factors increase the chances of a person having a stroke. Non-controllable risk factors include: age, gender and race. Controllable risk factors include: hypertension, hypercholesterolemia, diabetes, atherosclerosis, circulation problems, physical inactivity, and obesity. Chronic low-levels of inflammation have been linked to these controllable risk factors, and therefore can be linked to stroke as well. It seems to me that these risk factors and chronic inflammation should be linked more to thrombotic stroke than to hemorrhagic stroke, with the possible exception of hypertension. What are your thoughts on this? Has anyone seen any data to support or discount this?

2. In patients with ischemic stroke, increased levels of proinflammatory cytokines are related to larger cerebral infact and poorer clinical outcome (Vila et al. 'Levels of anti-inflammatory cytokines and neurological worsening in acute ischemic stroke'. Stroke (2003) pp. 671-675). Furthermore, administration of IL-10, an anti-inflammatory molecule, has been shown to reduce infarct size (Vila et al.) and SCID mice have reduced lesion size with middle cerebral artery occlusion compared to wild-type mice (Hurn, et al. 'T- and B-cell-deficient mice with experimental stroke have reduced lesion size and inflammation'. Journal of Cerebral Blood Flow and Metabolism (2007) 27, pp. 1798-1805). However, both of these studies have focused on the short term effect of inflammation during ischemic stroke. What about the long term?

3. What are the long term effects of inflammation during ischemic stroke? Even though inflammation has been shown to increase infart size, isn't inflammation critical during the healing processes? It is very difficult to analyze the role of inflammation during and after stroke. More research needs to be done to evaluate the full spatial and temporal relationship between the two.

As a side note to this post... Worried about having a stroke? Use this scorecard to evaluate your risk! http://www.stroke.org/site/DocServer/scorecard_risk.pdf?docID=601