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Showing entries tagged neurodegeneration.  Show all entries

December 3, 2011

Deep Brain Stimulation - A Different Approach

Let's talk about Parkinson's Disease (PD). PD is one of the most prevalent neurodegenerative disorders in the world for people over the age of fifty; as the population has aged and people have started living longer, PD diagnosis has increased significantly. Some of the symptoms include tremor (shaking), akinesia (inability to initiate movement), muscle rigidity, and later in the progression of the disease, slowed speech, blank staring, and dementia. So there are motor and cognitive problems associated with PD, but this post will deal with the reduction of the earlier-onset motor symptoms.

There are two main types of treatment for PD motor symptoms: drugs and deep brain stimulation (DBS). The drugs usually have a compound called L-Dopa, which is a precursor in the formation of the neurotransmitter dopamine, the lack of which has been implicated in inducing the motor symptoms of PD.

The other treatment, DBS, can only be used on some patients, namely those for whom the drugs have had little to no effect and who are also healthy enough to undergo surgery and stay alive for longer than a few years. What they do is create an open-loop (i.e. not a closed circuit) by surgically inserting an electrode into a specific region of the brain, which is connected to a pacemaker-type device called a pulse generator (IPG) that they insert below the neck. Doctors then set the IPG to a certain frequency, so the electrode will send out electrical signals into the brain every so often, and this has been shown to reduce the motor symptoms of PD.

The whole process takes up to a year, with the surgery and adjustments to the properties of the stimulation being continuously modulated until the motor symptoms are reduced and the side effects of the stimulation are not too severe. But, since PD is a progressive disease, the motor symptoms will continue getting worse and the DBS stimulation will continue to need adjustments more and more frequently as the disease progresses.

The issue with this is that no one really knows why DBS works, so all of the adjustments are guesses (systematic guesses, but guesses nonetheless) and patients need to keep coming into the hospital, which costs a lot of money, time, and frustration when their symptoms are not relieved. This is where research in the "closed-loop," or real-time adaptive, DBS comes in. This potential form of DBS also involves a chip that is used to record when natural electrical signaling occurs in the brain region the DBS electrode is in. The recording then sets the properties of the DBS stimulation on the IPG and sets a timer for when the electrode will deliver that stimulation, producing a feedback loop, and decreasing the need for the constant hospital visits.

One study found that given some specific criteria for the wait-time and the number of stimulations, some PD symptoms were reduced (namely akinesia) to a greater extent than with open-loop DBS. However, the study also found many problems with using closed-loop rather than open-loop DBS to alleviate motor symptoms, but these problems have to do with what actually causes the motor problems associated with PD. As such, the study concludes that with more research on the efficacy of closed-loop DBS and on the details of the cause of PD motor symptoms, closed-loop DBS could be used as a potential treatment for PD that will produce not only a more significant reduction of motor problems, but will also enhance the long-term efficacy of using DBS as PD progresses.

Rosin, B., Slovik, M., Mitelman, R., Rivlin-Etzion, M., Haber, S. N., Israel, Z., . . . Bergman, H. (2011). Closed-loop deep brain stimulation is superior in ameliorating Parkinsonism. Neuron, 72(2), 370-384. doi:10.1016/j.neuron.2011.08.023 Retrieved from
Posted by      Anna G. at 11:58 AM MST

October 24, 2011

Restoration of Bovine Sanity and a Cure for Neurodegeneration

Mad cow disease. This deadly, presently incurable, brain-eating disease has been the cause of many a steak-lover's trepidation. After all, who wants his brain looking like swiss cheese? It is caused by the consumption or spontaneous generation and accumulation of PrPSc - the misfolded form of cellular prion protein (PrP) - and is responsible for several forms of "swiss cheese brain" besides bovine spongiform encephalopathy (affectionately known as mad cow disease), including the sheep-transmitted scrapie and the human form known as Creutzfeldt-Jakob syndrome, among others. Unfortunately for its victims, PrPSc is much more stable than the properly folded form of the protein and is thus resistant to normal methods of protein digestion (i.e. with protease) and is only known to be degradable via incineration of the infected victim. Clearly, this is an undesirable outcome for the individual who has been unfortunate enough to come into contact with such a protein.

As the misfolded PrPSc aggregates, it forms amyloid fibrils, essentially converting the normally folded PrP to the dark side and eventually causing neuronal cell death and ultimately the death of the organism. However, a recent study of methods to stabilize mouse PrPSc species, published in the Journal of Neuroscience, has shown that prion activity can be reduced by trapping partially digested PrP(27-30) with thienyl pyrimidine compounds.

The process of PrP conversion to the abnormally β-sheet-rich PrPSc form is autocatalytic, that is, it happens spontaneously and independently of other types of molecules. In their study, the researchers discovered that the formation of amyloid fibrils may actually be the "result of a protective process to sequester more dangerous soluble oligomers". As a result, rather than attempting to break the prions apart into smaller, supposedly more easily digested pieces, they decided to attempt to isolate them to avoid increasing the infectivity. Using mouse neuroblastoma cell cultures, they performed various drug assays and blotting techniques, including incubation of fibrils with thienyl pyrimidine compound. When all was said and done, they only observed a minimal decrease in the rate of infectivity, but it was a decrease, nonetheless. They concluded that the binding of thienyl pyrimidine-based drugs diverted dimers and trimers of misfolded protein from their pathological aggregation pathway, trapping them thermodynamically in an energy valley where they could no longer fold into their mortality-causing fibril-forming shape.

Though the study was largely inconclusive, it is clear that meaningful advances were made in discovering that the treatment of prion diseases is not as hopeless as we have believed up to this point. Indeed, the thought of finding a cure seems a daunting task, as the mad cow protein only seems to become more stable under most reaction conditions. However, this study has shown that sometime in the not-so-distant future, the mechanism of misfolding will likely be discovered, a cure for a once incurable disease developed, and we will no longer have to fear prions as much as we have in the past. Also, not only does this research have significant implications for those of us who enjoy a good steak or lamb chop, it may also have far-reaching influence on the treatment of other "prionopathies", including Alzheimer's, Parkinson's and Huntington's Diseases. Since these are diseases which affect a significant fraction of the aging population, research in this vein is critical for the progress of gerontological studies as well.
Posted by      Clarinda H. at 12:03 AM MDT

October 23, 2011

Jalapenos...a treatment for arthritis?

We've all bitten into a jalapeno and experienced the slow burning pain that is associated with it. And whether you love it or hate it you've probably wondered why some people have a higher tolerance for spicy foods than others. The answer to that is two-fold.

To understand why we must first understand the mechanism through which capsaicin (the oily substance found in peppers which gives them their signature 'kick') works. Capsaicin targets a subgroup of sensory neurons called nociceptors. Prior research has shown that capsaicin excites these neurons by increasing the permeability of the plasma membrane to cations (K+, Na+ and Ca++ in particular) although it was unknown whether this was through direct disruption of the plasma membrane (capsaicin is hydrophobic and could thus perturb the phospholipids of the membrane)or though a ligand-system in which the molecule binds to specific receptors on the surface of the cell. The latter possibility was ruled more likely as capsaicin derivatives operate in dose-dependent manners highly characteristic of receptor activation via ligand binding. This was further supported through the use of resiniferatoxin, an extremely potent capsaicin analog derived from the plant genus Eurphorbia. This neurotoxin's extreme potency, eliciting responses at nanomolar concentrations, allowed scientists to assume that it bound with great affinity to the proposed capsaicin receptor. Using this, the molecule was radio labeled and researchers were able to visualize its binding to cell-surface receptors.

This provides the first the leg of the answer. The density of these receptors on an individual's nociceptors can influence the affect spicy food has. More receptors, more binding, greater response evoked.
An interesting side note...why do spicy foods produce a burning sensation? The specific receptors that capsaicin binds to are heat-gated receptors. These are analogous to our very well known voltage-gated channels but open is response to changes in ambient temperature and apparently capsaicin binding. This produces pain and the burning sensation that I for one love.

The second leg to our answer comes with a remarkably interesting point of immense pharmacological importance. Exposure to capsaicin initially excites a neuron leading to the pain response. However prolonged exposure (in this paper just a few hours) can cause cell death. Examination of dead cells revealed no evidence of DNA fragmentation meaning that no apoptotic events occurred. The actual cause of death was cytotoxicity caused by excessive ion influx, similar to the excitiotoxicity observed in TBI.
So as you can imagine eating spicy foods can actually kill these neurons, desensitizing your mouth to the pain a jalapeno can produce.

I did mention a pharmacological importance that is briefly covered by the authors, although they do not go into any sort of detail about it. In the opening paragraph they say that this nociceptor desensitization has lead to use of capsaicin as an analgesic agent in the treatment of n analgesic agent in the treatment of disorders ranging from viral and diabetic neuropathies to rheumatoid arthritis. While they do not elaborate on the mechanisms of this we can assume that these diseases cause pain through stimulation of these same nociceptors.
Posted by      Zach I. at 2:03 PM MDT
  Christina Uhlir  says:

I am curious as to whether or not there was a discussion about the clinical uses of different peppers based on their Scoville scale heat, and the fact that they could induce excitotoxicity.
Posted on Sun, 23 Oct 2011 6:04 PM MDT by Christina U.

The Better to Remember You With, My Dear...

We've all heard those reports on "super fruit" or the next magical food to prevent this disease or to cure that disease during slow news days. While these stories are lovely fluff pieces, they often lack substantial support. Fortunately, a group of neuroscientists took it upon themselves to perform a legitimate study and to pull information from reliable research in order to identify certain foods that may be helpful in fighting the curse of aging, as well as pinpoint the beneficial effects of these dietary components.

The studies revolved around prevention and possible therapeutic techniques for neurodegenerative diseases and the aging of the brain in general. The first substance of focus was polyphenol, found most often in berry fruits. During experimentation on rat subjects, there proved to be a significant improvement in motor abilities in the group receiving a diet rich in polyphenol while the abilities of the control group either
deteriorated or maintained. In the experimental group, there was also an improvement in various aspects of memory, including LTP, fear conditioning, and both hippocampal-dependent and striatum-dependent memory. It is believed that the reasons for these enhancements are not only the antioxidant activity of the fruit, but also the positive effects on neuronal communication, a neuron's ability to buffer against calcium, and lessening of stress signals. Polyunsaturated fatty acids found mainly in walnuts have been found to improve age related motor and cognitive declines, too.

The article makes it clear that two important factors of the negative effects of aging are oxidative stressors and inflammatory issues. While not much is known about the specific mechanisms that these compounds work on, it is inferred that one of the reasons that they are so beneficial is because of their ability to reduce oxidative stress. Oxidative stress could cause disruptions in the balance of cellular calcium and could cause issues in neuronal signaling. Furthermore, high levels of oxidative stress can ultimately cause gene expression to be changed which could have drastic effects on the dynamics of individual cells, as well as the function and interaction of large groups of neurons. Docosahaenoic acid, or DHA, contained in walnuts and fish oil also plays a large role in the positive activities of these foods. DHA has been linked to anti-inflammatory properties that work to prevent Alzheimer's Disease. It seems that DHA is able to reduce Aβ oligomer production which in turn reduces toxicity levels within cells.

The disadvantages of the use of these foods are heavily outweighed by the advantages. The principal disadvantage stated in the article is the fact that relying on these foods to prevent neurodegenerative diseases could be hard to stick to because of the lack of variety. That is obviously dwarfed by the advantages brought up in the study, a few of the obvious being "safety, broad spectrum utility, low cost, and suitability for prevention." Giving up variety in order to delay ailments such as Alzheimer's Disease and Parkinson's Disease is a minor drawback.


Joseph, James, et. al. Nutrition, Brain Aging, and Neurodegeneration. The Journal of Neuroscience. 29(41): 12795-12801. < >
Posted by      Breanna S. at 12:19 PM MDT
  Christina Uhlir  says:
So sweet, and not just the fruit. But thank you for posting such an uplifting blog, sometimes it's easy to forget about all of the advances in light of all the studies that have negative or inconclusive results.
Posted on Mon, 24 Oct 2011 6:20 PM MDT by Christina U.

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