Getwellbean

another difficult day in the Davey household. Kathleen looked much better in the morning and afternoon but coughed vigorously most of the evening. Thankfully she was coughing it out on her own for the most part though. Kathleen will likely remain in room 628 at Kaiser past Mother's Day. :(


Perhaps a very significant breakthrough for treating the brain. Lets hope so. Perhaps stem cells and epo together with this?

Mike, I tried emailing this to you previously, but I'm not sure if it made it through. The most hopeful news is from www.neuronova.com - I hope this helps.

Please let me know which email address I should use now, and I will email you the term paper as an attachment.

Lots of prayers coming your way. We hope Bean is feeling better soon & that you are encouraged and uplifted.
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Plausibility of Neurogenesis Following Anoxic-Ischemia
And Other Brain Injuries

Barbara Bower Jandu
Psych. 7: Physiological Psychology
April 27, 2006


Plausibility of Neurogenesis Following Anoxic-Ischemia
And Other Brain Injuries
When an ischemic brain injury occurs, the brain is deprived of oxygen and nutrients that normally provide for healthy neural functioning. Such events could be: a stroke, hypoxic/anoxic ischemic encephalopathy, a cerebrovascular accident, or any other injury that might prevent blood flow to the brain. Infants, children, young adults, as well as older people can all be at risk of such an injury, as noted in: www.myspace.com/globalischemia. When a person’s brain is deprived of oxygen for any substantial length of time, it can result in the death of many neurons.
Until just recently, it was widely assumed among the scientific community that neurogenesis (generation of neurons) in the brain was impossible. This theory, first documented by Santiago Ramón y Cajal in the late 1800’s, indicated that brain cells do not divide, and are never regenerated. Yet, in the early 1960s, Joseph Altman of MIT reported that he found new neurons being produced in the brains of adult lab rats.
In the spring of 1998, Elizabeth Gould, professor of psychology at Princeton University, was the first recent scientist to document evidence of neurogenesis in the adult primate brain -- in the hippocampal area.
Additionally, in 1999, a neuroscientist by the name of Dr. Jonas Frisén published that he and his team could identify stem cells within the brain. Since stem cells are what divide to create new brain cells, this was also an interesting revelation to the scientific community.
Perhaps most significant is that Gould’s work is what has caused other researchers to dig deeper. For example, in 2005, researchers Bjornebekk, Mathe & Brene determined that voluntary exercise may promote the survival of neurons attempting to regenerate in the hippocampus. And in 2002, Lee, et al, linked the negative affects of chronic stress and depression to the decrease in the proliferation of neural cells in this region. Continuing to build upon this work, Ronald S. Duman of the Laboratory of Molecular Psychiatry at Yale University realized that depression and stress might not only be killing neurons, but could actually be preventing these new cells from being born. Additionally, in recent years, there have been a number of surprising discoveries which may lead us to a place of hope, rather than resignation. So what was once lost may perhaps grow again. In the remainder of this paper, we shall investigate just a few of these amazing findings.

Methods
After the brain has suffered such an injury, scar tissue often develops that prevents neurons from re-growing via a certain type of protein molecule contained within it. Dr. James Fawcett (University of Cambridge, UK) and his team conducted studies whereby they inhibited the proteins. Fawcett and his team gave laboratory rats an enzyme that blocked the scar tissue molecules that inhibit neuron re-growth from forming; their purpose was to see whether or not regeneration could occur.
Steven Goldman, M.D., Ph.D., from the University of Rochester Medical Center, a neurologist, and his research team, introduced a gene called telomerase, which caused the spinal “progenitor” cells to continually divide, but still only produce a certain type of neuron.
Duman, et al has been studying the effect of anti-depressant treatment in lab rodents for more than 15 years now. His lab team has focused primarily on the cellular actions of these drugs, and observing how the signals between cell pathways control neural functioning.
In 1993, David Schaffer published that the protein Sonic Hedgehog (so named after a video game hero), could play a meaningful role in cell division. Although the Sonic Hedgehog is used by various tissues within the body, Schaeffer focuses his energies on how this protein works in the brain.
These neurons could now become a healthy supply from which the brain could replace dying neurons, and potentially have an impact on the recovery from brain trauma and injury. Schaffer and his team studied the Sonic Hedgehog protein in culture dishes, and then added it to other proteins. Then they observed the protein at work in lab mice. In the mice, the protein broke down too quickly. In order to counteract this, Schaffer injected the gene which encodes for the Sonic protein. By using this approach, they were able to replicate the positive results they’d observed in the culture dishes, and tripled the number of stem cells within the brains of the mice.
Hiroki Toda and Jun Takahashi of the Department of Neurosurgery, Clinical Neuroscience at Kyoto University Graduate School of Medicine, along with Noboru Iwakami and his research team from Research Laboratories, Toyama Chemical Company Ltd. In Japan set out to determine the possibility of neural stem cells being used to therapeutically benefit the damaged central nervous system. They grafted neural stem cells taken from the hippocampal area of adult lab rats that had experienced transient global ischemia.
Frisén founded a biotech firm called NeuroNova in 1998 in Stockholm, Sweden. The purpose of this company is to pursue drugs which stimulate neurogenesis. Even as embryonic brain tissue transplantation was being attempted as a treatment for Parkinson’s disease, with disappointing results, NeuroNova forged ahead by screening thousands upon thousands of possible drug compounds to treat this disease. In November, 2005, Frisén’s company, NeuroNova injected a drug called sNN0031 into lab rats with Parkinson’s disease.
Results
The research team led by Dr. Fawcett in the UK found that by inhibiting those proteins within the scar tissue, one could actually encourage the re-growth of nerve cells. Not only did the neurons re-grow, but they grew back along the same pathways of their previous locations (which would indicate that the specific nerves re-grown might actually be able to re-obtain their original functions).
When Gould’s associate, Kozorovitskiy, put marmosets in a plain laboratory cage, their brains were also “plain”. The marmosets showed a reduced level of neurogenesis and fewer neural interconnections. When these same adult marmosets were put into an enriched environment, their brains recovered quickly. In less than four weeks, there was an significant and observable level of increased density in interconnections and protein level in their synaptic activity.
Steven Goldman’s team was able to devise a virtually immortal line of progenitor cells, which would be capable of continually producing human spinal neurons. (These progenitor cells do not possess the ability to transform themselves into any type of cell. They are instead rather “decisive” in terms of being only a certain type of neuron.) The way they proved this was available was by propagating the progenitor cells for an entire two years. Then a team led by professor of Neurosurgery, Maiken Nedergaard, M.D., Ph.D., injected the new progenitor cells into lab rats. What they found was that the rats were able to re-grow small sections of damaged spinal cord.
Gould’s team discovered in the middle-aged and younger monkeys that there were a large number of cells that incorporated the bromodeoxyuridine. Those cells were able to exhibit morphological characteristics of both mature and immature neurons. Also, new cells located by process of using markers, were found in the dentate gyrus, as well as mature granule neurons (including neuron-specific enolase, the calcium-binding protein calbindin, and neuronal nuclei). Some evidence of neurogenesis was also seen in the older monkeys, but not as strong. Overall, this evidence showed that the brains of adult Old World monkeys can produce new neurons in the hippocampal region. This evidence led Gould to continue her studies, using adult macaque monkeys as the test subjects, wherein she was able to additionally prove the occurrence of neurogenesis, and study the affects of stress and environment.
The most effective treatments Duman explored were electroconvulsive therapy which increased hippocampal neurogenesis by 75% and Fluoxetine, (Prozac), which increased neurogenesis in the hippocampus by 50%.
Additional studies showed that chronic antidepressant treatment increased the proliferation of neural cells in the hippocampus, as evidenced by triple labeling for BrdU and neuronal-specific or glial-specific markers.
The research teams of Toda et al and Iwakami et al noted that in the hippocampal CA1 region, up to 3% of the grafted neural stem cells survived. Between 3-9% of those expressed neuronal marker NeuN. Rats that had over 120 NeuN-positive cells exhibited some improvement in their spatial learning, as evidenced by performance in a water maze test.
Elizabeth Gould and her team investigated the potential of neurogenesis by injecting eleven lab monkeys (of varying ages between 5 to 23 years), with the thymidine analog bromodeoxyuridine. Then, by using neuronal and glial markers, they observed the outcome of the cells they had labeled at different survival rates.
Genia Kozorovitskiy is a graduate student who started working with Gould as a undergrad at Princeton. She has studied how environment affects their marmosets, by comparing their brains when taken from a plain environment to an enriched environment. The enriched environment included such things as toys that were rotated out every so often, hidden food, and lifelike branches.
Frisén’s results were astounding. These rats were formerly hardly able to walk at all. After only five weeks of treatment with sNN0031, their symptoms were gone, and normal bodily movement was restored.
In December, 2005 the US government granted NeuroNova Patent No. 6,969,702 to use pharmaceutical substances to treat central nervous system diseases.
Discussion
Dr. Fawcett indicates:
"Although there is still no treatment for spinal cord injury, there are now several methods to promote nerve fiber regeneration that have been successful in animal models, and "The amount of regeneration in these various experiments--up to four centimeters--is sufficient to bring a useful return of function to a patient with a spinal cord injury, although not complete recovery''
Dr. Goldman noted that human testing for progenitor cells is also quite a ways off; however, progenitor cells do possess a great advantage in treating diseases that have damage to a specific type of cell. For example, a patient suffering from Parkinson’s might only need the type of neuron that produces dopamine, whereas a person with Multiple Sclerosis would only need myelin-producing cells.
Usually progenitor cells can only divide for only a certain number of times. Goldman’s team introduced the gene for telomerase at precisely the best moment in the cell’s life cycle (at which point, it had “decided” to commit to becoming a spinal cord type of cell). This caused the cells to continue to divide and become that specific type of neuron indefinitely. Of course, the spinal cord is comprised of more than just one type of neuron, so Goldman’s team is in the process of devising other cells, using the same process, which would be able to repair the tissues of the spinal cord. Certainly, his research shows the potential for application within the brain as well.
The hippocampus is part of the limbic brain that is involved in learning, memory, mood and emotion, and neurogenesis in this area could be a possible explanation for the plasticity of these functions.
"In humans, brain imaging studies demonstrate that in patients with depression or post traumatic stress syndrome there is a decrease in volume of the hippocampus that is thought to be related to the neuronal atrophy and loss," Duman said. "The results of our study demonstrate that anti-depressants can reverse or block further loss of neurons in the hippocampus by increasing neurogenesis (new cell growth)."
While the results from Toda, et al, and Iwakami et al suggest that neural stem cells grafted into an ischemic brain can differentiate into neurons and thus improve spatial recognition, Schaffer cautions that since the stem cell field is so new, it may take over a decade before these cells are able to repair tissue.
Gould is optimistic that the brain should be able to heal itself. “My hunch is that a lot of these abnormalities [caused by stress] can be fixed in adulthood,” she states. “I think that there’s a lot of evidence for the resiliency of the brain.”
This year, NeuroNova plans to begin testing sNN0031 on primates with Parkinson’s disease. This drug is already being used in humans for an unrelated condition, so human clinical trials should begin shortly.



Works Cited


Depression and the Birth and Death of Brain Cells, Source: American Scientist
Date: July-August 2000, http://www.biopsychiatry.com/newbraincell/index.html
Enzyme Promotes Nerve Regrowth in Rats, New York, Reuters Health: Nature Neuroscience 2001;4:465-466. http://www.spinalrehab.com.au/Updates/Enzymepromotenervegrowth.htm
Gould, E., Reeves, A.J., Fallah, M., Tanapat, P., Gross, C.G., and Fuchs, E., (1999), Department of Psychology, Princeton University and German Primate Center, Hippocampal neurogenesis in adult Old World primates Neurobiology, Vol. 96, Issue 9, 5263-5267
Gould, E., et al. 1998. Proliferation of granule cell precursors in the dentate gyrus of adult monkeys is diminished by stress. Proceedings of the National Academy of Sciences 95 (March 16):3168.
Malberg, J., Eisch, A.J., Nestler, E.J., and Duman, R.S., Yale University (2000), Laboratory of Molecular Psychiatry, Departments of Psychiatry and Pharmacology, Yale University School of Medicine, Connecticut Mental Health Center, New Haven, (December 15, 2000), Sustained use of anti-depressants increases cell growth and protects cells in the brain, The Journal of Neuroscience, 20(24):9104-9110
Reinvention of the Self, The; Mind-altering idea reveals how life affects the brain, Lehrer, J., February 23, 2006, http://www.seedmagazine.com/news/2006/02/the_reinvention_of_the_self.php?page=7
Schaffer, Lu, Lai, Kaspar, and Gage, A Protein Called Sonic the Hedgehog: Brain Protein to Fight Against Brain Diseases, Including Alzheimer's, The Daily Californian
Toda, H. & Takahashi, J., Department of Neurosurgery, Clinical Neuroscience, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto (2001), and Iwakami, Kimura, Hoki, Mozumi-Kitamura, Ono and Hashimoto; Japan Research Laboratories, Toyama Chemical Company Ltd., Toyama, Japan; (2001), Gafting neural stem cells improved the impaired spatial recognition in ischemic rats
Windrem, M. Ph.D., et al., University of Rochester Medical Center, http://www.eurekalert.org/pub_releases/2004-02/uorm-nca021304.php

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The above photo, courtesy of David Schaffer, shows neural stem cells (stained blue). The green stain is an indication of mature neurons.


The diagram below shows the comparison of hippocampal neural activity between a primate brain and the brain of a laboratory rat.  

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Thanks Barbara,

A very interesting study. You can email me at imperialpref@yahoo.com  

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