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Stem cells in Parkinson's Disease

Page history last edited by ellen wagner 15 years, 3 months ago

 

Stem Cells in Parkinson's Disease


 

Primary authors:

                                            David DeMar

                                   Kevin Kim

                                   Christina Ortolan

                                   Ellen Wagner

 

Motivation

 

Each year, 60,000 Americans are diagnosed with Parkinson’s disease.  This is in addition to the one and a half million who have already been diagnosed.  Parkinson’s disease, over time, progressively degrades the patient's quality of life.  In the worst stages of the disease, Parkinson’s leaves the patient unable to walk, or even stand.  They will be in need of continuous assistance and care; they will not be able to live alone.  They will be afflicted by tremors in the hands, feet and face, rigidity in the neck and extremities, and may also become emaciated.  The disease is undeniably life-altering, and while 85% of new cases are in patients over the age of 50, the rest are even younger.  For all patients, they still have the rest of their lives ahead of them.  While there currently are medications being used to ease the symptoms, there is a clear incentive to research more effective methods to relieve patients and potentially reverse the effects of the disease.  One of these methods that is still being developed is the use of stem cells to reinnervate the damaged region of the brain that causes Parkinson’s disease. [1] One other method is neural grafting, or the implantation of grafts consisting of dopaminergic neurons.  Optimally, these grafts will result in regeneration of the damaged dopamine-producing cells.  For the patient's convenience, grafts will hopefully supply sustained relief, especially in comparison with the short-lived relief from medications.

 

 

The Basics of Parkinson's Disease

 

Parkinson’s disease is resultant of cells in the substantia nigra dying or becoming damaged.  The substantia nigra is located in the mesencephalon, in the mid brain region, and is responsible for the production of dopamine (DA). 

 

 

                         

Figure 1

Left: Shown here is an image that displays the location of the substantia nigra in a horizontal cross section of the brain.  The substantia nigra is the region of the brain that causes symptoms of Parkinson's disease when the cells are damaged or dead.

Right: A closer view of the substantia nigra shows the visible difference between healthy and diseased substantia nigra.

Images [2]

  

Dopamine is a compound that helps control body movements and aids in regulating mood, as well as several other functions.  When about 80% of these dopamine-producing cells lose their production abilities, the symptoms of Parkinson’s disease become apparent.  Some of the symptoms include:

 

o   Shaking 

o   Stiffness 

o   Slow movement 

o   Inability to balance 

o   Depression 

o   Fatigue [1]

 

Those listed above are considered primary symptoms.  Secondary symptoms may include:

 

o   Decreased ability to respond quickly to questions 

o   Extreme sweating, salivating 

o   Excessive coughing or drooling 

o   Dry skin 

o   Constipation 

o   Issues with control of bladder or bowels 

o   Trouble with swallowing

 

There is no single defined method of diagnosing the disease.  For some illnesses, specific lab tests may be conducted to determine what the patient actually has.  For Parkinson’s disease, most tests that are performed are used to rule out the possibility of other problems.  Simpler tests that allow the doctor to analyze the level of coordination, balance, and other motor skills will be able to help determine if the patient has Parkinson’s. [3]

  

The Unified Parkinson's Disease Rating Scale is used by doctors, among others, in order to have a common scale to rate the severity of patients' symptoms.  The scale can be seen here:                    UPDRS

 

Medications for Symptomatic Relief 

 

The medication that a person might use for treatment for Parkinson’s disease is different for each person.  There isn’t a “wonder drug” that has therapeutic effects for everyone.  The variety of medications that are in use today each have a slightly different function, and each provide symptomatic relief to a different extent.  Some of the medications used are designed to replace the missing dopamine in the brain, and others work to increase the availability of dopamine by other methods.

  

Levodopa (L-Dopa):   Levodopa works by being taken up by the surviving dopamine-producing cells in the brain, and is converted by these cells into dopamine.

  

Levodopa is one of the most effective treatments for reducing the symptoms of Parkinson’s disease. Levodopa was first used to treat patients in 1961.  In the 1970s, research showed that adding carbidopa, or some other kind of dopa decarboxylase inhibitor, helped with the side effects of levodopa (dyskinesias, which is defined as “spasmodic or repetitive motions or lack of coordination” [dictionary.reference.com] and motor fluctuations) and also improved the efficiency of the drug.  The carbidopa ensures that the levodopa reaches the brain without being broken down by inhibiting enzymes in the blood that break down the levodopa. [4]  The addition of carbidopa means that less levodopa needs to be administered, since smaller doses will be more effective.  Smaller doses help decrease side effects of levodopa, like nausea and dizziness. [5]   In 1975 the first levodopa+carbidopa combination was presented for wide use. [4] The amount of time that the levodopa is in effect can be controlled by adjusting how quickly the gastrointestinal tract is able to intake the levodopa. [1]

 

Dopamine Agonists:  These are used in place of dopamine. They are synthetically made dopamine and thus it is not necessary for the brain to convert the drug into dopamine like in the case with levodopa.

  

Dopamine agonists were developed as alternatives, or additions to, levodopa treatments. Dopamine agonists cause a wider variety of side effects, although motor fluctuations are less frequent than with the use of levodopa.  This is important to consider when prescribing a drug.  The number of agonists available means that if a specific drug is not working the best for a patient, they can try a different one in hopes of better results.

  

Amantadine:   Amantadine was originally meant to be an antiviral drug but was found, by accident, to reduce some Parkinson’s symptoms.   

  

Amantadine works well alone or with either of the above two treatments.  It addresses fatigue, tremor, motor fluctuations, and dyskinesias.  [1]  Its most common side effects are nausea, dizziness and insomnia and it is less effective than levodopa.  The overall function is to cause increased release of dopamine. [6]

  

Anticholinergic medications: This group of drugs was the first medication used to treat the symptoms of Parkinson’s disease.  It works to decrease the activity of acetylcholine. The behavior of acetylcholine (involved in nerve impulse transmission across the synapse) is more noticeable when dopamine levels are low. [7] The medication deals with the imbalance of chemicals between two neurological pathways. [8]

  

Like with amantadine, anticholinergic medications can be used alone or with levodopa.  The symptoms reduced with use of these drugs are tremors and stiffness.  A main side effect is increased confusion; these types of drugs are not often used for older patients [1]  Other side effects include memory loss, hallucinations and blurred vision. Once again, this class of drug is less effective than levodopa and is only effective for a short time. [7]

 

Selegiline: Selegiline is an enzyme inhibitor and a mild antidepressant.

 

Seligiline inhibits an enzyme called monoamine oxidase B (MAO-B).  This enzyme is involved in breaking down dopamine. [1]  Side effects of the drug include upset stomach, appetite loss, nausea, heartburn, dry mouth, dizziness, and lightheadedness.  Too large of a dose can reduce the selectivity of selegiline and it will begin to inhibit MAO-A.  Among other things, MAO-A breaks down serotonin.  Serotonin affects almost all brain cells in relation to mood, behavior, memory, learning capacity and various other vital human functions.  Inaccurate dosage of this drug is very dangerous. [9]  Selegiline produces several other positive results besides the primary desired effect of increasing dopamine availability.  Research indicates that memory is improved. [10]  Use of selegiline could put off the need for the use of levodopa by up to three months and may even be capable of reviving damaged neurons. [11] 

 

COMT (Catechol-O-methyltranferase) inhibitors: COMT breaks down levodopa; hence inhibition of this enzyme provides more levodopa for transformation into dopamine. [11]

  

COMT inhibitors increase the amount of levodopa, and even dopamine itself, available to brain cells.  This means that patients will require lower dosage of levodopa, reducing the risk of the related side effects.  COMT inhibitors have side effects of their own. [12] Dyskinesias, nausea, and dizziness are some common symptoms, and sometimes liver function is affected. [11]

  

Deep Brain Stimulation

 

Deep Brain Stimulation (DBS) is a surgical procedure that is used to treat a variety of symptoms that cannot be controlled with medications, such as tremors, rigidity, stiffness, slowed movements, and walking problems. Patients can turn the device on or off with a simple magnet after having the device implanted. It is not like a pace-maker where the patient will always have it on. It is used like a medication: when symptoms are so severe that medications cannot provide relief, the device can be activated. [13]

  

DBS uses a battery-operated medical device called a neuro-stimulator, which is similar to a heart pacemaker and is the size of a watch. It does not last a life-time since a battery will inevitably need to be replaced. Fortunately, it is easy to replace the battery; this must be done every three to five years. The device sends signals to targeted places in the brain that control movement. For the thalamus the electrode would be put in place to alleviate tremors, or multiple sclerosis. The thalamus is responsible for motor controls; it receives auditory, somatosensory and visual sensory signals, and it relays sensory signals to the cerebral cortex. The electrodes would be most likely be put in the globus pallidus for patients with Parkinson’s disease. The globus pallidus regulates voluntary movements at a subconscious level. [14]

 

  YouTube plugin error

  

Figure 2: This video shows how the Deep Brain Stimulation works and what it does. In this video the wires are connected to the thalamus. Research shows that both the thalamus and globus pallidus are the two places that the stimulators are connected for patients with Parkinson's disease. This video also shows the electrodes going into the globus pallidus. [15]

 

 

Figure 3: This picture shows where the globus pallidus and the thalamus are located in the brain. Both of these regions in the brain control major voluntary muscle movements. [16]

  

One research paper from Detante et al. involved a study on the stimulation of the globus pallidus on patients with dystonia. Dystonia is a disease that is similar to Parkinson’s disease. Six patients with dystonia and eight control patients were used. After the patients received the implant they were tested on their motor tasks through a joystick. Times were recorded to see how fast they would react with the stimulator on or off. The results show that all six patients improved their reaction time when the stimulator was on. More of this research can be found:  http://brain.oxfordjournals.org/cgi/content/full/127/8/1899#SEC3 [17]

 

Another research paper from Andrés et al. focused on a positron emission in the thalamus to see if more blood flow would go to the brain if it was stimulated. Six patients with Parkinson’s disease were used for this test. They all had DBS inserted in their thalamus. The six patients were then tested on their motor functions by checking how fast they could react with or without the stimulator on. The results prove that the stimulator worked, and also that there was more blood flow to the brain. More of this research can be found:  http://archneur.ama-assn.org/cgi/reprint/56/8/997 [18]

 

One advantage to this system is that it does not destroy any brain tissue. Other surgeries usually lead to the death or removal of sections of the brain to stop tremors. DBS electrodes are sent to a certain area of the brain to turn on electrical signals, to either turn off the section of the brain or to try to stimulate that part of the brain. Therefore this does not block any further future treatment that a patient might be able to recieve, such as neural graft surgery which is covered in detail below. Other advantages are that the device is removable and adjustable, making it comfortable for the patient and able to be removed if needed. [14]

 

Some disadvantages to deep brain stimulation are that the battery must be replaced every three to five years. Also because of multiple surgeries and the fact that there is a foreign substance in the body, there is a higher chance of infection. Also there seems to be a lot of discomfort when the stimulator is on.  [14]

 

Neural Grafts from Human Embryonic Mesencephalic Tissue into the Striatum 

 

The cell replacement strategy using neural grafts is based upon the idea that regeneration of dopamine releasing cells in the striatum can lead to long term recovery of functionality. There have been many drugs available since the 1960’s but they are only a temporary solution to the problem. The neural grafts are composed of dopaminergic neurons up to five donors. The grafts can contain from 7000 to 135,000 dopaminergic neurons depending on the size and number of donors. The dopaminergic cells are not the only cells in the graft; the other 90% are non-dopaminergic mesencephalic cells, whose role in the success or failure is still unknown. The first human trials began in 1987, with over 350 patients receiving the graft since. It was first unknown what the effects would be from a neural graft. There were many questions surrounding the ability for the grafts to work successfully including i) can the grafted neurons survive and form viable neural connections, ii) can the patient’s brain integrate and use the grafted neurons, and iii) can the grafts induce a measurable clinical improvement.

 

Figure 4

FIgure 4: This model of the brain shows the parts of the Striatum where the the neural grafts will be placed.

 

It has been seen that grafted dopamine neurons can survive between 6 and 10 years post surgery. In over 40 of the patients there was a significant increase in fluorodopa, [18F], and using histopathological studies the implanted neurons extended connections up to 7mm within the putamen, where as the patients’ own dopamine cells decreased [18F] intake, the [18F] intake remained the same in the grafter neurons indicating that they were still surviving. This continued even through drug treatment and lack of immunosuppressant drugs. In 4 separate studies, where patients received grafts from 5 different donors, patients were examined 10-24 months post operation to see how they have improved. There was an increase in [18F] intake by 60% and a decrease to 45% of the daily L-dopa required. Fig D2 illustrates the difference in [18F] uptake in those who recieved the graft and those who did not. However, the results indicated that there was a lot of room for improvement with the overall relief between 30 and 40% [19].

 

Figure 5 [1]

Figure5: This graph is a grafted verses non-grafted putamen of Fluoradopa. This shows that the grafted putamen shows more uptake after a one year period post operation. This shows that the grafted is taken up by the body by almost six folds after ten years after transplantation. 

 

In a double-blind sham surgery-controlled study, more moderate results were seen. Using the United Parkinson’s Disease Rating Scale (UPDRS), there was only an 18% reduction of the UPDRS motor score while “off medication”. However, there was a 34% improvement with patients under the age of 60 [20].  This is important because it was the first demonstration that the improvement is actually caused by the cell and not a placebo effect. However, because the results continued to vary there are many factors to be concerned. The length of survival of the dopaminergic cells varied between six and ten years. The time it took to see positive results also varied greatly as well as the degree of improvement. One of the most important factors is normalizing the composition of the neural grafts. Because grafts can be from up to five donors, the consistency varies between grafts and causes varied results. Furthermore, it is not known what percentage of dopaminergic cells produces the most improvement. Moreover, in about 15% of patients severe dyskinesias was reported [19]. Finally, the source of the neural grafts has raised an ethical dilemma. Is it okay to take cells form a fetus, or should they only be taken from consenting adults. If the neural grafts are to become a viable future option, these problems will need to be solved.

 

Generation of Dopaminergic Neurons Using Stem Cells

 

Methods of Stem Cell Therapy and Stem Cell Sources

 

There are two basic approaches to stem cell therapy for Parkinson's disease (PD). The first, more accessible approach involves the differentiation of stem cells into the desired neurons in vitro, then the implantation of those neurons into the damaged brain tissue. (see Figure 6) This method would allow neuron preparation to be standardized and quality controlled, while providing an almost limitless source of neurons from the continually cultured stem cells. However, trauma from implantation may be detrimental to the neurons. In the second approach, undifferentiated stem cells or neuronal precursor cells are directly implanted into the brain, after which they are free to differentiate into the needed dopaminergic neurons. This method may result in better neural integration and pathway reconstruction, but requires that the mechanisms to trigger differentiation are present in the diseased brain. [19] 

 

 

Figure 6: Stem cell differentiation into DA neurons in vivo and in vitro. ES cells differentate in vivo via a series of precursor cells. Cells taken from any of these stages can be expanded in vitro and stimulated into DA neurons, which can then be transplanted. [21]

 

Stem cells are present in a variety of tissues, adult and fetal, although not all stem cells have the same potential for neuronal differentiation. Stem cells capable of differentiating into neurons have been harvested from the embryos of fertilized eggs as well as adult tissues, theoretically the patient's own. Stem cells from the adult brain have the potential to form DA neurons, but so far no such neurons have been generated. Additionally, using stem cells from the patient's brain would require extra surgery to remove the cells, and may not be effective if the cells are functionally impared due to age or disease. Stem cells from other adult tissues, such as dermis and bone marrow, have been successfully differentiated into neurons, although implantation did not lead to any release of DA. Neural stem cells have also been harvested from the embryonic brain, successfully differentiated and implanted, although with a very low yield. To date, the mose effective stem cells are embryonic stem cells harvested from the fertilized egg. These stem cells have been successfully differentiated into DA neurons in vitro or via direct implantation, and the implanted neurons survived, proliferated, and actively extended processes. [19]  

  

Directed Differentiation of Rodent Embryonic Stem Cells

 

Stem cells are unique in that they not only have the ability to self-replicate, but also to differentiate into more specialized cells. Embryonic stem (ES) cells are pluripotent, meaning they have the ability to give rise to all types of cells in the human body. [22] The generation of the desired dopaminergic (DA) neurons from ES cells is not a single-step process; a very specific sequence of chemical triggers must be used to not only stimluate the ES cell to differentiate, but also to direct the differentiation to produce the desired neuron. [23] An efficient synthesis of DA neurons is currently achieved by a five-stage culturing process. [24] (see Figure 7)

 

 

Figure 7: Directed differentiaion of ES cells into DA neurons or insulin-secreting clusters. [23]

 

Stage one of this method involves the proliferation of undifferentiated ES cells in culture dishes, with a growth media containg fetal calf serum and supplemental amino acids. These conditions keep the ES cells in an undifferentated state. In the second stage, the cells are induced to form embryoid bodies (clusters of stem cells) by plating them at high densities on a surface that promotes aggregation. In stage three, the embryoid bodies are replated on a growth medium lacking fetal calf serum. This selects for cells that express nestin, a protein present in nerve cells. After 6-10 days in this medium, the cells are dissociated and replated onto a new medium supplemented with laminin and fibroblast growth factor (FGF), which induces proliferation. After stage four, the cells express genes such as Pax-2, Pax-5, Wnt-1, En-1, and Nurr-1 that, in vivo, trigger the develoment of DA neurons. [23] In the final stage, the basic growth factor is removed to stop cell division, and ascorbic acid (AA), the sonic hedgehog gene (SHH), and the more specific growth factor FGF-8 are used to induce differentiation into neurons. [22] To determine if the new neurons are capable of synthesizing dopamine, the expression of tyrosine hydroxylase (TH), the rate-limiting enzyme in the production of dopamine, can be measured. [23]

 

More recently, overexpression of transcription factor Nurr-1 has been shown to increase the amount of TH+ neurons generated via the 5-stage method from 5% to 50%. (see Figure 8-a) The ability of the TH+ neurons to release dopamine was measured via liquid chromatography, and showed a pronounced increase in dopamine secretion from the Nurr-1 overexpressed ES derived neurons. (see Figure 8-b) [24]

 

 

Figure 8: Yield of TH+ neurons and synthesis of dopamine. a) Nurr-1 ES cells differentiate into more TH+ neurons than wild-type ES cells. b) Release of dopamine from Nurr-1 ES-derived neurons is much higher than in wild-type neurons. [24]

  

From this data, it has been shown that true DA neurons can be generated from stem cells. The next step is to pair this technology with the current method of neuronal grafts, which have been shown to reduce the symptoms of Parkinson's disease. [19]

  

Human Stem Cells

  

The majority of the research pertaining to the generation of DA neurons from ES cells, and the subsequent success of the transplants, has been done on rodent models. [22, 23, 24] However, in 2007 researchers injected undifferentiated human neural stem cells into primate Parkinson's models, and found that the treated monkeys improved significantly compared to the untreated and sham-operated monkeys. [25] (see Figure 9) This recent research gives hope to a possible treatment of Parkinson's disease using human stem cells.

 

 

Figure 9: Behavioral recovery of severe Parkinsonion monkeys after human neural stem cell injections. Postoperative groups show a significant behavorial difference between injected monkeys and sham operated monkeys. [25]

 

Conclusion 

 

Although the capacity exists to use stem cells to regenerate neurons, issues still remain with the practical application of the technology. Survival and proliferation of the neurons after transplantation currently limits the effectiveness of the grafts, and in many experiments it is unclear if the stem-cell generated neurons have the same functionality as the mature DA neurons found naturally. Also, as this treatment is still in the research phase, the majority of the literature pertains to mouse ES cells, and human ES cells may perform differently. Currently, no clinically useful cell therapy for Parkinson’s disease exists, but neural grafts are a current technology that has been proven successful.  

  

Citations

 

[1] “National Parkinson Foundation.” ©2007 The National Parkinson Foundation, Inc. [Cited 9-10 December 2008] Available at <http://www.parkinson.org/NETCOMMUNITY/Page.aspx?pid=201&srcid=227>

 

[2] “Substantia Nigra and Parkinson’s Disease.”  A.D.A.M. Editorial Team. 5 May 2006. [Cited 10 December 2008] Available at <http://medicalimages.allrefer.com/large/substantia-nigra-and-parkinsons-disease.jpg>

 

[3] Belmonte, Joelle. “Parkinson’s Disease and Dimensia.” August 2008. [Cited 10 October 2008] Avaiable at <http://www.helpguide.org/elder/parkinsons_disease.htm>

 

[4] “History of levodopa and dopamine agonists in Parkinson’s disease treatment.” Neurology. 1998 Jun;50(6 Suppl 6):S2-10; discussion S44-8. [Cited 10 December 2008] Available at <http://www.rasagiline.com/history.htm>

  

[5] “GENERIC NAME: levodopa-carbidopa.” © 2008 MedicineNet, Inc. [Cited 10 December 2008] Available at <http://www.medicinenet.com/levodopa-carbidopa/article.htm>

 

[6] “Amantadine: Brand name: Symmetrel.”©2008 Phillip W. Long, M.D. [Cited 10 December 2008] Available at <http://www.mentalhealth.com/drug/p30-s05.html>

 

[7] Schoenstadt, Arthur. “Anticholinergics for Parkinson’s Disease.” 30 May 2008. [Cited 10 December 2008] Available at <http://parkinsons-disease.emedtv.com/parkinson's-disease/parkinson's-disease-medications-p4.html>

 

[8] Brocks, Dion R. “Anticholinergic Drugs Used In Parkinson's Disease: An Overlooked Class Of Drugs From A Pharmacokinetic Perspective.” © 199 The Canadian Society for Pharmaceutical Sciences. [Cited 10 December 2008] Available at <http://www.ualberta.ca/~csps/JPPS2(2)/D.Brocks2/anticholinergic.htm>

 

[9] Bouchez, Colette. “Serotonin: 9 Questions and Answers.” © 2008 WebMD, LLC. [Cited 10 December 2008] Available at <http://www.webmd.com/depression/features/serotonin-9-questions-and-answers>

 

[10] Dixit SN, Behari M, Ahuja GK. "Effect of selegiline on cognitive functions in Parkinson's disease." 1999 Aug;47(8):784-6. [Cited 10 December 2008] Available at <http://www.selegiline.com/park.html>

 

[11] Hain, Timothy C. “Parkinson’s Disease” [Cited 10 December 2008] Available at <http://www.tchain.com/otoneurology/disorders/central/movement/parkinsons.html>

 

[12] Waters, Cheryl. “The Use of COMT Inhibitors in Older Patients.” © 2008 Geriatric Times. [Cited 10 December 2008] Available at <http://www.cmellc.com/geriatrictimes/g010324.html>

 

[13] NINDS Deep Brain Stimulation for Parkinson’s Disease Information Page. http://www.ninds.nih.gov/disorders/deep_brain_stimulation/deep_brain_stimulation.htm. Dec. 2007.

 

[14] Haines, Cynthia M.D. Parkinson’s Disease: Deep Brain Stimulation. http://www.webmd.com/parkinsons-disease/deep-brain-stimulation. June 2005

 

[15] Deep Brain Stimulation. http://www.youtube.com/watch?v=B6sqV7bEPo0. Cleveland clinic. December 2008.

 

[16] Lavelle, Peter. Parkinson’s Disease. www.abc.net.au/health/library/ff_parkinsons.htm. August 2002.

 

[17] Detante et al. “Globus pallidus internus stimulation in primary generalized dystonia: a H215O PET study.” Brain. August 2004.

 

[18] Andrés et al. “A Positron Emission Tomographic Study of Subthalamic Nucleus Stimulation in Parkinson Disease.” Arch Neurol. August 1999.

 

[19] Lindvall, O. Stem cells for cell therapy in Parkinson's disease. Pharmacological Research 47, 279-287 (2003)

 

[20] Freed CR, Greene PE, Breeze RE, Tsia W-Y, DuMouchel W, Kao R, et al. Transplantation of embryonic dopamine neurons for severe Parkinson's disease. N Engl J Med 2001; 344:710-9

 

[21] "Stem cell differentiation into DA neurons in vivo and in vitro." [Illustration]. Neurosurg Focus 13(5), 2002. © 2002 American Association of Neurological Surgeons [cited Wednesday, December 10, 2008] Available at <http://www.medscape.com/content/2002/00/44/61/446195/art-nf446195.fig4.gif>

 

[22] Lee, S., Lumelsky, N., Studer, L., Auerbach, J., McKay, R. Efficient generation of midbrain and hindbrain neurons from mouse embryonic stem cells. Nature Biotechnology 18, 675-679 (2000)

 

[23] Appendix B: Mouse Embryonic Stem Cell Cultures . In Stem Cell Information [World Wide Web site]. Bethesda, MD: National Institutes of Health, U.S. Department of Health and Human Services, 2006 [cited Wednesday, December 10, 2008] Available at <http://stemcells.nih.gov/info/scireport/appendixb>

 

[24] Kim, J., Auerbach, J., Rodriguez-Gomez, I. et al. Dopamine neurons derived from embryonic stem cells function in an animal model of Parkinson's disease. Nature 418, 50-56 (2002)

 

[25] Redmond, D., Bjugstad, K., Teng, Y., et al. Behavioral improvement in a primate Parkinson's model is associated with multiple homeostatic effects of human neural stem cells. PNAS 104, 12175-12180 (2007)

 

Comments (6)

nathan.d.cook@... said

at 4:25 pm on Dec 10, 2008

Do we know why the adult stem cells did not lead to the release of DA?

Chen Tao said

at 11:00 pm on Dec 10, 2008

I like your figures and diagrams a lot. They are visually refreshing and informative. Keep up the good work!

Sarah Haeger said

at 12:31 am on Dec 12, 2008

Your page looks very organized and thought through. The figures add a lot to your writing!

Anonymous said

at 10:10 pm on Dec 15, 2008

This was very well put together and the video/visuals helped alot. I also liked that it's broken down into managable chunks instead of one or two information thick paragraphs.

Anonymous said

at 12:02 am on Dec 16, 2008

This is really interesting and you set up your page really well, I like that videos and lots of visuals were included as well as the flow of everything, it's really good!

Anonymous said

at 12:23 am on Dec 16, 2008

this is really good! you might want to check more into your research about how dopamine works...i did that as part of my ochem paper, its the reduced number of dopamine receptors, not dopamine itself that decreases the motor movement

heres part of my paper...

The D1 family consists of D1 and D5 sub-receptors and are considered the “excitatory” receptors due to their activation of adenylyl cyclase, controlling neuronal growth and development, behavioral responses, release of calcium, and modulation of D2 receptor events. D1 receptors are involved with cognition, emotion, and sporadic memory. The D2 family consists of the D2, D3, and D4 sub-receptors known as the “inhibitory” receptors because they inhibit the adenylate cyclase enzyme, inhibiting the formation of cAMP.

The amounts of dopamine receptors and concentration of dopamine in the brain are responsible for positive symptoms (hallucinations, delusions, and thinking disturbances) due to excessive amounts of dopamine, and negative symptoms (inattention, poor speech, voice tone, motor movement, and indifference) caused by reduced number of D1, D3, and D4 receptors in the prefrontal cortex. The negative symptoms are caused by the inability of the receptors to send chemical signals due to the lack of receptors and concentration of dopamine. Excessive amounts of dopamine and receptors cause statements, events, and objects to have a heightened significance, even if there is no rational basis for their significance. A schizophrenic’s attempt to account for the significance leads to suspicion, paranoia, and irrational actions, accounting for the positive symptoms associated with schizophrenia.

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