Range of brain diseases could be treated by single drug

By James Gallagher Health and science reporter, BBC News

Link:  http://www.bbc.co.uk/news/health-17952797

The author of this article sites a new study, recently published in Nature (abstract link below), which details a possible new therapy for neurodegenerative diseases.  If successful this drug could target numerous diseases including Parkinson’s, Alzheimer’s, Huntington’s, and prion diseases, such as the human form of mad cow disease.  This study utilized a mouse model of prion disease.  It is thought that the contributing factors to these diseases are accumulations of miss folded proteins.  They showed that as misfolded protein levels rise in the brain, cells respond by trying to shut down the production of all new proteins through phosphorylation of the α-subunit of eukaryotic translation initiation factor, eIF2.  Increased eIF2α-P levels are seen in neurodegenerative diseased patients.  It is theorized that cell death might result because this arm of protein synthesis is shut down leaving cells unable to rebuild and replenish themselves.  There data showed that increasing eIF2α-P levels, exacerbating neurotoxicity and significantly reducing survival in prion-diseased mice.  While reducing eIF2α-P levels decreased neuronal death and increased survivability of the mice.  Their results suggest that manipulation of common pathways such as translational control, rather than disease-specific approaches, may lead to new therapies preventing synaptic failure and neuronal loss across the spectrum of these disorders.

Certainly interesting work...  I would like to see more data on the longevity of these studies.  I wonder if other side effects would result due excessive protein buildup.  In numerous papers we have read they mention the inflammatory response due to excessive protein deposits.  Would this response be worsened, resulting in disease progression, if protein synthesis is not curbed?  I wonder if a combination of therapies could be utilized to lessen side effects while improving disease prognosis?

Nature abstract:  http://www.nature.com/nature/journal/vaop/ncurrent/full/nature11058.html

The magic of Botox

Botox has come a long way since starting as a treatment for lazy eye!!!

From treatments to reduce blepharospasm, torticollis, and facial spasms, to the not so neurological specific use of revitalizing the face (if you are one of those stars that can afford the $500/mL injections), botox has come a long way in proving its usefulness in a wide range of clinical environments.

More recently discovered is its possible function in the field of urology, more specifically, reducing bladder outlet obstruction (obstructive and irritating urination problems).

Article Link: http://www.biomedcentral.com/1471-2490/6/12

The research in this article found that botulinum toxin type A (commonly called botox), when injected into the bladder of male humans and dogs, induced prostate apoptosis in dogs, and reduced bladder outlet obstruction in males. This treatment has proven beneficial for the aging population, especially those with neurodegenerative diseases which aggravate the effects of bladder problems like Parkinson's disease. Botox typically doesn't last more than 3 months. It is different in everyone, as it depends on the sensitivity of the anchoring proteins in their presynaptic cleft that bind the vesicle to the wall. Some people may need a higher quantity injected to feel an effect, and some may be completely immune to the type a strain.

It would be interesting to conduct a study that looks at the effects of some of the other strains of neurotoxins, like dysport, myobloc, and xeomin, and see if they have similar results (the different strains are either more purified or act on different anchoring proteins).

Alzheimer’s Disease Basic Scientific Article

Fibrin deposition accelerates neurovascular damage and neuroinflammation in mouse models of Alzheimer’s disease.

Alzheimer’s disease (AD) is characterized by abnormal senile plaques and neurofibrillary tangle formations.  Amyloid-β peptide (AB) and precursor protein (AβPP) are the major components of these senile plaques.  Aβ is thought to be a major contributor to the neurodegenerative process, acting either through neurotoxic mechanisms or local inflammatory processes.  Interestingly one of the early hallmarks of AD is abnormal cerebral vasculature.  Neurovascular damage can allow fibrinogen access to the CNS.  Fibrinogen, classically known for its role in the clotting cascade, cannot normally cross the BBB.  Fibrin is found in the brains of AD patients, but the pathological significance is unknown.  Fibrin accumulation can be reduced genetically or pharmalogically. 

The aim of the experiment is to measure BBB permeability and fibrin deposition in three mouse models of AD.  Their results demonstrate BBB damage and the presence of fibrin in the brain of AD mice.  Furthermore the tPA/plasmin system, which likely aids in the clearance of Aβ, is down regulated in AD in accord with reductions in other naturally occurring Aβ-degrading proteases.  Also modulation of fibrin levels affects the pathology of AD mice, reducing fibrinolysis, thereby increases fibrin deposits, worsening the pathology, whereas fibrinogen depletion attenuates microgliosis and neurovascular damage.  Decreased clearance of fibrin is also thought to contribute to the progression of Aβ pathology.  The initial insult to the microvasculature likely arises from increased Aβ levels.  Fibrinogen binding elicits activation of NF-KB, caused increased expression of cytokine genes.  Thus fibrin may be an upstream effector of neuroinflammation .  Also fibrin-induced microgliosis could be toxic to endothelial cells.  Fibrin along with the mechanisms involved in its clearance, may present novel therapeutic targets for slowing the progression of AD.

The author’s utilized pharmacological methods to examine fibrin’s role, namely from platelets, in AD mouse models.  The aim was to reduce protein sources, which are linked to senile plaques, in order to prevent or lessen AD.  The data does suggest that this therapy is an effective way of modulating AD in mouse models.  However if this line of therapy was employed in human subjects significant side effects could result.  Humans are far more sensitive to reductions in platelet levels compared to mice.  If human platelet levels were reduced to those of the mice in these studies minor injuries could become life-threatening situations.

Source:  Justin Paul, Sidney Strickland, and Jerry P. Melchor:  Fibrin deposition accelerates neurovascular damage and neuroinflammation in mouse models of Alzheimer ’ s disease, Laboratory of Neurobiology and Genetics, The Rockefeller University, New York, NY 10065.

Love Drug?

Hey you guys I was just getting online today and I found this article on my msn.com homepage. I thought it would just be interesting to post on here even though its not really an inflammation issue. Its for a thing called the "love pill." Basically in this article it speaks of a new type of pill that scientists want to develop to hopefully prescribe to people in marriages who just aren't happy. In their paper entitled Neuroenhancement of Love and Marriage: The Chemicals Between Us, they speak of this pill to salvage failing marriages, and in today's world of constant divorce, i fell like if the broad lay community heard about this and believed it, it could have a huge selling as the top drug on the market. In this article they speak of the ingredients that this drug will have such as:
1) Pheromones
2) Testosterone
3) Oxytocin and Vasopressin, what they call "bonding chemicals"
4) Entactogens- "a drug found in MDMA pills like ecstasy"


Although this product is not yet in development, I found it interesting to note that I believe, if it works will cause some people to be in a relationship that otherwise they wouldn't be in. 


heres the link to the article on msn


http://living.msn.com/love-relationships/the-heart-beat-blog-post?post=71cbc378-6d27-4219-a464-df8e7645289a


and here is the original paper itself


Neuroenhancement of Love and Marriage: The Chemicals Between Us

Omega-3 Fatty Acids: what they do, and current research

Having gone through the anti-inflammatory articles we discussed on turmeric, it seems that many are looking to curcumin in hopes of providing a strong defense against chronic-inflammation diseases. Then after doing some thinking, I remembered that curcumin isn't the only anti-inflammatory that many people are pushing to consume because they believe it to be the magic cure all. Omega-3 fatty acids are just as equally pushed for their ability to reduce inflammation as well as assist in heart disease and stroke recovery, but what do we really know about Omega-3 fatty acids? Well, I was curious so I went and did some research on them and found some interesting information.

As it turns out, Omega-3 fatty acids are comprised of three different Essential Fatty Acids (EFA), that our bodies need to properly function. The three EFAs that make up Omega-3 fatty acids are decosahexaenoic acid (DHA), eicosapentaenoic acid (EPA) and alpha-linolenic acid (ALA). According to my sources these Omega-3 fatty acids are found predominately in fish-oil and certain plant and nut oils; DHA and EPA are found predominately in fish oil, whereas ALA is found predominately in nut and vegetable oils. Moreover each plays a unique role in what our bodies use them for; DHA for example is needed to maintain proper brain function as an adult, and is needed for the development of the nervous system and visual abilities during the first six months of life. EPA has been found to help lower risk of heart disease, and has been shown to have positive protective affects on coronary heart disease, high triglycerides, high blood pressure and inflammation. Finally, ALA is the interesting one, as its main contribution seems to be that, it can be converted into both EPA and DHA in our bodies.

Now, while reading about this is good I'm the kind of person who likes more detail, its cool to know that they can do these things but I also like knowing how they do these things. So I searched the boundless Internet in hopes of finding any research that had looked into this, and I did find scientific research articles looking at the mechanisms of each fatty acid. Unfortunately, I could only obtain the abstracts as the articles are owned by PubMed and they wouldn't let me obtain the full reports. However, just reading the abstracts gave me a better understanding of the research that was being undertaken in order to better understand the role each Omega-3 fatty acid plays in helping us to remain healthy.

The links below will take you to the places where I have obtained my information, links 2-4 are the same website, and it's defiantly more of an overview of information website than it is a detailed information website, but nonetheless contains useful information regarding the Omega-3 fatty acids. Links 5-7 are the research article abstracts I've found on each Omega-3 fatty acid, and while they are not the full articles they do provide an excellent summary of the contents of each paper. Also if someone who is familiar with PubMed could tell me how to access the full articles, I would be more than happy to edit this to take you to the full articles because the abstracts make me want to see the full thing. Finally, link 1 provides a nice overview of what the Omega-3 fatty acids are in general. Enjoy and leave any comments below.

 
http://www.mayoclinic.com/health/fish-oil/NS_patient-fishoil
http://www.umm.edu/altmed/articles/docosahexaenoic-acid-000300.htm
http://www.umm.edu/altmed/articles/eicosapentaenoic-acid-000301.htm
http://www.umm.edu/altmed/articles/alpha-linolenic-000284.htm
http://www.ncbi.nlm.nih.gov/pubmed/11724467
http://www.ncbi.nlm.nih.gov/pubmed/15881480
http://www.ncbi.nlm.nih.gov/pubmed/19641487

Neuro Review Article of Alzheimer’s disease

ALZHEIMER’S DISEASE AND INFLAMMATION:  A REVIEW OF CELLULAR AND THERAPEUTIC MECHANISMS

Alzheimer’s disease is the fourth leading cause of death in persons over the age of 65.  It is incurable and progressive and affects millions of people across the world.  Alzheimer’s disease (AD) is the most common neurodegenerative disease that causes dementia.  The three major pathological hallmarks of this disease are characterized as senile plaques, neurofibrillary tangles, and inflammation.  Senile plaques consist primarily of protein deposits, namely b-amyloid fragments.  These amyloid fragments seem to mediate inflammatory mechanisms by activating microglial cells via the complement pathway in a similar fashion to immunoglobulins.  Platelets are a major source of amyloid fragments thus therapies are proposed to curve platelet numbers and thus a source of protein fragments.  Also the use of NSAIDS to reduce the inflammatory microglial cell activation is discussed.

Inflammation of neuronal tissue can both be beneficial and detrimental depending on circumstances.  For example in brain injury the inflammatory response can:  aid in clearing out dead cells, debris, inhibit neuro toxic cytokines, and promote growth factors needed for recovery.  Conversely improper or chronic inflammation can cause severe damage and widespread death of neuronal cells worsening prognosis.  Possible drug interventions to curve these deleterious effects are proposed.  Evidence from RA patients who consume anti-inflammatory medications regularly does seem to show slowing of the progression of AD.  In conclusion the author’s call for future studies aimed at targeting the inflammatory process via NSAIDS and anti-platelet therapies. 

Source:  Glenda Halliday,* Stephen R Robinson,‡ Claire Shepherd* and Jillian Kril.  BRIEF REVIEW:  ALZHEIMER’S DISEASE AND INFLAMMATION: A REVIEW OF CELLULAR AND THERAPEUTIC MECHANISMS, Clinical and Experimental Pharmacology and Physiology (2000) 27, 1–8.

Being physically active may protect the brain from Alzheimer disease

This article was published in the April 2012 edition of Neurology.  The author’s study correlates the link between high levels of activity with reduced rates of Alzheimer’s disease.  716 subjects in this trial wore wrist monitors called actigraphies.  These monitors broadly assess the “activity” levels of these individuals.  Cognitive test were administered annually over the course of four years.  During this trial 71 patients developed Alzheimer’s disease.  It was concluded that the least physically active group was twice as likely to develop Alzheimer’s when compared to the most active.  In addition, the most vigorously active group was three times less likely to develop the disease. 

Although actigraphy cannot provide the exact physical activities subjects undertook it can provide a broad picture of overall activity levels.  For instance the devices were unable to determine whether subjects were playing cards or sprinting in a race.  The authors contend that this doesn’t really matter because they recorded total activity levels.  It is also stated that what is truly important is simply living a more active lifestyle and being less sedentary.  As long as the subjects engaged themselves in some type of activity the risk of developing Alzheimer’s disease was decreased.            

This brings up an interesting point.  Is it realty the vigor of physical activity that decreases risk?  Or is it rather some combination of increased mental stimulation and physical activity due to active lifestyles that decreases risk? 

Link to lay article http://www.foxnews.com/health/2012/04/18/active-lifestyle-cuts-risk-alzheimers-at-any-age-study-finds/

Link to actual article http://zp9vv3zm2k.ssscom.ezproxy2.library.arizona.edu/?url_ver=Z39.88-2004&rfr_id=info%3Asid%2Funiversityofarizona.worldcat.org%3Aworldcat&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&req_dat=%3Csessionid%3E&rfe_dat=%3Caccessionnumber%3E7893

How the manipulation of molecules in the heart may treat obesity!

During my weekly medGadget peruse I found this interesting article about a study just recently published in Cell.  
http://medgadget.com/2012/04/in-study-altering-heart-molecules-protects-against-obesity.html

In short, researchers at UT Southwestern found that a regulatory molecule in the heart, in this case mi-RNA-208a, that actually has an effect on the body's metabolism by effecting MED13 (mediator complex subunit 13), which is known to control transcription of thyroid hormone. micoRNA-208 has been shown to negatively regulate MED13 and in this particular study researchers show that cardiac-specific over-expression of MED13 OR pharmacologic inhibition of miRNA-208a provides mice with a resistance to high-fat diet induced obesity.

• I'll back track for a sec to explain what miRNAs  (micro RNAs) are: mi-RNA are short, single stranded RNA molecules usually around 20-25 nucleotides in length and are known to regulate gene expression.  Unlike mRNA, miRNAs don't actually encode for proteins but function by preventing translation of mRNA. So, in the case of miRNA-208a, we see prevention of MED13 translation.

The group also found that mice with a MED13 gene deletion, specific to the cardiomyocytes,  are prone to metabolic syndrome.  The hope is that in the future, miRNA-208a and MED13 can be targeted to help control metabolic disorders.

So, we've all learned that obesity, type 2 diabetes, and stroke are all inflammatory disorders; my  big question now is how does regulation of MED13 affect inflammation in the body??
Will we see prevention of chronic inflammation along with prevention of metabolic issues?
What would happen if an obese person with chronic inflammation was treated with miRNA-208a inhibition? -Would we see a reduction in that person's inflammation also??
If we do see a reduction in inflammation, would this treatment help in other inflammatory diseases??

There's lots more interesting research to be done!!

If you'd like to take a look at the journal article, search "A cardiac MicroRNA Governs Systemic Energy Homeostatis by Regulation of MED13" CE Grueter

Good control over blood glucose levels may lessen post-stroke damage?

There has been debate over the connection between blood glucose levels and severity of stroke, which is no surprise given the vast web of interconnecting inflammation in the body.  Dr. Bruno, a stroke specialist at the Medical College of Georgia, is investigating the use of insulin injections to help alleviate post-stroke damage.  Dr Bruno, who is also a clinical PI for the National Institute of Neurological Disorders and Stroke-funded study, believes that, upon admittance to the emergency room, every stroke patient should be given an insulin injection.  Generally, simple finger-prick tests are administered to check for diabetes anyway, so he believes that an insulin injection should be a standard as well, whether or not the patient is diabetic.  His rationale for this is that generally, stoke victims suffer more damage when blood glucose levels are high, so a quick dose of insulin should help lower glucose levels and therefore minimize damage.  In addition, he explains that low blood glucose levels can mimic stroke symptoms, so an insulin injection may lead to less false-positives. 

Does this theory sound promising?  Possibly.  Nearly 1400 physicians in the U.S. are claiming to subscribe to this easy treatments, but the exact method for success is not clear.  It is believed that stroke triggers the release of stress hormones, and they may interfere with the ability of cells to uptake glucose, leading to higher levels in blood.  So what causes the damage?  Dr. Bruno hypothesizes that free radicals released during stroke amplify the damage.  He is currently working a this trial, termed the SHINE Trial, in which stroke patients either receive insulin injections or, in tougher cases, IV insulin for three days.  Three months later, the patients' health is assessed. 

I thought this concept is interesting, and not too far-fetched.  Insulin injection, at proper doses, should be safe, and it makes sense that you would see elevated blood glucose levels post-stroke due to wide-spread effects of inflammation.  However, the article did not clarify how control over glucose levels would affect stroke damage, merely that there appears to be a connection.  This news article also did not link a scientific paper or study, possibly because this group has not yet published on the topic. So the bottom line is:  are elevated glucose levels partially responsible for more severe damage, or is this just an association?  The answer to this question could provide the link necessary to truly treat strokes more effectively.

Study seeks to improve stroke outcomes by optimizing blood glucose control