Guillain-Barre Syndrome

The previous articles focus on inflammation and disease. In lecture I had remembered Zoe discussing about the Guillain-Barre syndrome (GBS) which is somewhat relevant to the articles. So now I am passing on the notes. GBS is an acute inflammatory demyelinating polyneuropathy. It is normally triggered by an acute infectious process and affects the peripheral nervous system.

The notes in lecture state that the Guillain-Barre syndrome is due to an immune response to foreign antigens (such as infectious agents or vaccines) but mistargeted to host nerve tissues instead (a form of antigenic mimicry). Gangliosides are thought to be the target of this immune attack. These gangliosides are complex glycosphingolipids existing in large quantities on human nerve tissues, specifically the nodes of Ranvier. Overall, the inflammation of myelin and conduction block caused by the autoimmune attack on the peripheral nerves leads to muscle paralysis. This end result might be accompanied by sensory or autonomic disturbances.

GBS is commonly severe and presents an ascending paralysis marked by weakness in the lower limbs and spreads to the upper limbs and the face coupled with complete loss of deep tendon reflexes. Treatments consist of administering intravenous immunoglobulins or plasmapheresis. After the acute phase, the patient may also need rehabilitation to regain lost functions.

Hippocampal and Olfactory Neurons Regenerate

Towards the end of our last discussion the question came up about neuron regeneration. There are actually two two different types of neurons that are able to regenerate. We have been taught and had the understanding for the longest time that neurons do not regenerate...thus don't go running around and getting too many concussions. However there has been research completed that says otherwise: that hippocampal and olfactory neurons DO regenerate. So I went looking for an article supporting some of this data and found that there happen to be multiple articles dated back to as early as 1999 that supports this. Here is a summary statement made by an article in 2007 with some of the latest developments towards research that is currently taking place based off of this idea.

Note: I posted only the statement because I had problems accessing the entire article, the citation is listed so if anyone can figure out how to locate a full version of the article for free, post it!

"It is now well documented that active neurogenesis does exist throughout the life span in the brain of various species including human. Two discrete brain regions contain progenitor cells that are capable of differentiating into neurons or glia, the subventricular zone and the dentate gyrus of the hippocampal formation. Recent studies have shown that neurogenesis can be modulated by a variety of factors, including stress and neurohormones, growth factors, neurotransmitters, drugs of abuse, and also strokes and traumatic brain injuries. In particular, the hippocampal neurogenesis may play a role in neuroadaptation associated with pathologies, such as cognitive disorders and depression. The increased neurogenesis at sites of injury may represent an attempt by the central nervous system to regenerate after damage. We herein review the most significant data on hippocampal neurogenesis in brain under various pathological conditions, with a special attention to mood disorders including depression and addiction."

2007 Oct;32(10):1762-71. Epub 2007 Apr 4.

PMID: 17406979 [PubMed - indexed for MEDLINE]

(here is a link to the old 1999 article)
http://www.princeton.edu/pr/pwb/99/0405/brain.htm

Attention: 495 to be held in the wine cellar next week

I am providing you with ample justification of the health benefits of alcohol consumption. The link provided is a study that investigated the effects of wine on inflammation. The blood concentration of inflammation markers C-reactive protein and fibrinogen were measured, however only fibrinogen levels decreased (...slightly) upon moderate wine consumption. The name 'C-reactive protein' sounds pretty nifty, so why would we want to lower it anyways?

http://alcalc.oxfordjournals.org/cgi/content/full/40/2/102

PS- Although it was a nice gesture for someone to bring cookies to class today, it encouraged obesity and subsequent development of type 2 diabetes, which would lead to a transient ischemic attack. If any of you were actually interested in joining the fight against inflammation, you would bring in a bottle of red next week.

question

Hi class. I was just wondering how ischemia causes damage to the blood brain barrier, which in turn allows leukocytes and neutrophils access to the infarction site. I understand how the microglia change metabolically and chemically to become phagocytic during ischemia; does this possible have something to do with the breakdown of the B.B.B. at the site?

NO in cerebral ischaemia: hate it or love it

In the article, Nitric Oxide, ischaemia and brain inflammation, nitric oxide and nitric oxide synthase (NOS) isoforms are shown to be implicated in stroke pathophysiology. In a cell, nitric oxide can mutate DNA, inhibit the electron transport chain, and either promote or protect the cell from apoptosis. There are three isoforms of NOS: neuronal NOS-1, inducible NOS-2, and endothelial NOS-3. All isoforms have been shown to increase with cerebral ischaemia. The article focuses on NOS-2 and explains that it has been shown to increase after ischaemia, because cytokines like IL-1beta and TNF-alpha induce NOS-2 transcription. An interesting find in the article, is that NO from NOS-1 and NOS-2 has been shown to be detrimental, however NO from NOS-3 has been shown to be beneficial. Therefore, it is important to try to find treatments to protect the brain from NOS-2 after a stroke. When looking at medications that inhibit NOS, it was found that selective inhibitors were more beneficial than non-selective inhibitors to lessen the deleterious effects of cerebral ischaemia. Other therapeutic options may include pharmaceutical NO donors, which are still under investigative study, preconditioning neurons to help them withstand the effects of ischaemia, and administration of estrogen and/or progesterone, which have shown to reduce lesion volume and improve cognitive function after ischaemia. What I found to be really interesting and cool is that new neurons can differentiate after having a stroke and NO donors have shown to increase neurogenesis. This helps the brain recover from a stroke, which usually have very damaging effects on the brain.

Stroke, and E-selectin tolerance...

As mentioned in our readings, stroke is one of the more common causes of death or disability. It is characterized as damage to the brain due to loss of blood flow by way of one of the two causes mentioned in the previous post. Either a blockage develops in the arteries of the brain (ischemia), or a rupture occurs, leading to a hemorrhage.

Several elements related to inflammation are involved in this event, but one in particular was of interest to me during the reading of the review article: “The Inflammatory Response in Stroke.” J Neuroimmunol. March 2007. Selectins were mentioned as molecules which assist leukocyte entry into the brain. Leukocytes then release proinflammatory mediators which can cause further damage to salvageable tissue. E-selectin is one of these molecules, which promotes rolling and adhesion of leukocytes on the capillary endothelium. E-selectin is also mentioned to be “exclusively upregulated in stimulated epithelium.” The interesting point brought up by this article, is that exposure to E-selectin through the nose, can create an immune tolerance to it. This tolerance can then lower the chances of leukocyte entry into the brain, reducing damage after a stroke, or could potentially prevent one! A little extra research turned up only a few excerpts and news briefs that this research has shown promising signs of reducing the occurrence of stroke in rats, with long term prevention seen with continual treatment. I had some trouble locating the article which presents these findings. If anyone may know of where I can find this, please let me know. It will be interesting to see if this proves effective with future research, and also if a tolerance to P-selectin (related to E-selectin in its function) could show similar results.

A STROKE WILL KILL YOU

 Hello class, to give everyone a little background strokes are categorized into two different types: ischemic and hemorrhage.  Ischemic strokes are caused by either a thrombosis or an embolism.  Hemorrhage strokes are either intracranial or intracerebral.  And if you are wondering what kind of stroke you can look forward to dying from and at what percent, then I am glad to inform you that you are probably going to die of a ischemic stroke at betting line of ~80%.   The public access paper only talks about ischemic strokes, and I will try to summarize it for you: INFLAMMATION IS BAD FOR THE BRAIN.  If that is a good enough explanation for you, by all means stop reading, if you crave more info you can read on.  Other then food and oxygen the brain really hates help from the body.  In the case of a stroke, the body sends leukocytes in the form of neutrophils followed by lymphocytes to the brain.  Both leukocytes have deleterious roles and also tissue-damaging properties within the brain leading to permanent brain damage.  These inflammatory cells also release cytotoxic agents inducing more cell damage as well as disruptions in the blood brain barrier.  Studies have found that inhibition of neutrophil infiltration will significantly reduce the infarct volume within the brain.  Other studies have found that inhibition of certain adhesion molecules: selectins, immunoglobulins and integrins show higher recovery of rates for brain tissue following brain ischemia.  Also interesting is the relation between diabetes and stroke due to TNF-alpha.  While it has been shown that stroke is exacerbated in diabetic rats, TNF-A is a double-edged sword in stroke.  Studies have shown that TNF-A appears to be involved in two different pathways due to the signaling of the TNF-A receptor 1 (TNFR1).  TNFR1 is thought to have a bifurcation in its signaling pathway which leads to cell life or death.  One route leads to the Fasassociated death domain (FADD) and apoptosis.  The other route TNFR1 to TNFR associating factor 2 may lead to anti-inflammatory and anti-apoptotic function, i.e. ischemic tolerance.

Contradictory evidence regarding the effects of exercise induced IL-6.

Here is the passage i read at the end of our last discussion...
"Interleukin-6 (IL-6) could mediate some of the health beneficial effects of exercise. In resting muscle, the IL-6 gene is silent, but it is rapidly activated by contractions. The transcription rate is very fast and the fold changes of IL-6 mRNA is marked. IL-6 is released from working muscles into the circulation in high amounts. The IL-6 production is modulated by the glycogen content in muscles, and IL-6 thus works as an energy sensor. IL-6 exerts its effect on adipose tissue, inducing lipolysis and gene transcription in abdominal subcutaneous fat and increases whole body lipid oxidation. Furthermore, IL-6 inhibits low-grade TNF-a-production and may thereby inhibit TNF-a-induced insulin resistance and atherosclerosis development."

As we've investigated the causes of diabetes mellitus, obesity, and the resulting atherosclerosis over the last two weeks, every article has listed IL-6 as a statistically significant factor to these inflammation related health problems. With this study were seeing a different perspective on ways to regulate IL-6 in the body through exercise. Muscle-derived IL-6 is shown to be a strong mediator of the anti-inflammatory effects of exercise, and to have beneficial health effects on vascular compartments. The first thing that i thought upon reading this, is that lap band surgery really can be avoided if these results are true, and that diet and exercise to a large degree can offer protection against cardiovascular disease , type 2 diabetes, ischemic heart disease, heart failure, athersclerosis, blood pressure and obesity. What is everyone's response to this contradiction between the importance and effects of muscle derived IL-6 versus elevated IL-6 in adipose tissue?

IL-6 and Cardiovascular Disease

So this is just a question I wanted to throw out there for anyone to answer. While I was reading the article that discussed the relationship of body fat mass and distribution to markers of chronic inflammation, it was stated that IL-6 has been shown to predict cardiovascular disease. I've heard this before, but I was wondering if anyone knew how this correlation was found and how this prediction works. I know that IL-6 is a proinflammatory cytokine, but Im still unclear on its relationship to cardiovascular disease.

(More?) Pigs Brain

Last week we talked about how the human brain doesn't have an immune response and white cells can recognize the brain as "foreign" so just came across this article and thought it was interesting...

http://www.nytimes.com/2008/02/05/health/05pork.html?pagewanted=1&_r=1&hp