|Posted on Saturday, July 21, 2001 - 5:41 pm: || |
Mike sent this to me from work. I know how bad my vision gets when I ingest too much glutamate. In fact, my optomotrist sent me home to wait another week before he would test my eye pressure the last time I was checked. He knows how high it has gotten before when I have been "poisoned", and that day, I was still coming down from an "episode".
"Tuesday July 10 07:22 PM EDT
New Drug Focuses On Treating Glaucoma
Doctors believe that there may more to glaucoma, a blinding disease, than high pressure in the eye.
Previous treatments focused on lowering blood pressure in the eye, but researchers have a new drug that could bring glaucoma patients new hope.
Phyllis Bargonetti has glaucoma and is at risk of losing her sight. It's a situation that, she said, she doesn't like to think about.
"I sort of block it out. I'm very optimistic that my vision will be preserved," Bargonetti said.
Researchers may have a lead in treating glaucoma. Instead of the traditional treatment of lowering pressure, a drug called Memantine works on the cells.
"If you can strengthen the nerve cell or find a way to rescue it or strengthen it against the causes of the damage, then you can prolong vision that much longer," New York Eye and Ear Infirmary ophthalmologist Dr. Robert Ritch said.
The new theory is to use Memantine to keep potentially harmful substances released by dying cells from affecting healthy cells.
"Blocking the glutamate channel is like putting thousands of little fingers in little hole! s in the dike which is the cell wall," Ritch said.
Ritch said that if Memantine works, it would help patients who have the intraocular pressure controlled but have experienced vision loss.
For Bargonetti, glaucoma is a life challenge.
"My life proceeds. I try not to let it get in my way," she said.
Memantine is currently approved for the treatment of Alzheimer's disease (news - web sites) because of its ability to protect nerve cells from being damaged."
|Posted on Saturday, July 21, 2001 - 5:46 pm: || |
The above news release is from a Yahoo news gathering service: KSAT ClickOnSA.com July 10, 2001
|Posted on Sunday, July 22, 2001 - 7:02 am: || |
More on excitotoxins and glaucoma:
|Posted on Sunday, July 22, 2001 - 9:53 am: || |
Very interesting, Deb and Roy. Retina damage was one of the things that caused researchers to conclude that taurine needed to be added to cat food and baby formula. It's all connected.
|Posted on Sunday, July 22, 2001 - 1:44 pm: || |
Carol, Deb & Roy,
My family has a history of Glaucoma and my eye doctor has been monitoring my pressure levels since they tend to be high.
I thought I had posted a site that mentioned the glutamate link before, but I cant find it -- however, I did save the article at the site and have pasted it below -- sorry about the length.
PS. When I read the article a few months ago to my mother who is blind from glaucoma, I was surprised at how upset she became. She had suffered heart palpitations for years from MSG, but when the realization that the same stuff may have been involved in causing her blindness, she really took it hard.
New Cause of Glaucoma Found
Discovery may lead to novel treatments for the blinding disease
By William J. Cromie
For a very long time, eye specialists thought that glaucoma, a disease responsible for blinding an estimated 10 million people worldwide, was caused by too much pressure in the eye.
For a long time, Evan Dreyer believed there was more to it than that. He was not alone. Several of his colleagues at the Medical School and its affiliated hospitals agreed with him.
One day in 1989, Dreyer, who heads the glaucoma service at Massachusetts Eye and Ear Infirmary, was having lunch with one of those colleagues, Stuart Lipton, an associate professor of neurology at Children's Hospital. The conversation got around to research done in 1957, which showed that monosodium glutamate (MSG) injected into the skin and eyes of rats damaged their retinas. That's the screen at the back of the eye where what you see is imaged and then sent to the brain.
"The damage looks much the same as destructive changes in human retinas caused by glaucoma," Dreyer observed. Lipton concurred.
That conversation triggered a long investigation wherein they studied everything published about glutamate damage in the eyes and brain. Glutamate is produced naturally in these organs, and when a molecule of sodium is added to it, it becomes MSG, a seasoning often used in Chinese food.
The researchers then spent six years gathering and testing samples from the eyes of 47 people who underwent cataract surgery, 26 of whom had glaucoma. Careful analysis of tissue between the lens and retina revealed that the eyes of the 26 glaucoma patients showed excess amounts of glutamate.
This month, Dreyer and his colleagues announced proof of the connection that everyone else had missed for 39 years.
"We've shown for the first time that something besides pressure is responsible for the vision loss caused by glaucoma," Dreyer said. "And the finding promises to lead to new drug treatments for glaucoma, hopefully in the near future."
He quickly adds that the MSG, which gives some lovers of Chinese cuisine howling headaches, will not blind you. "Absolutely no evidence exists that MSG taken by mouth has anything to do with eye or brain damage in adults," Dreyer assures us.
Treatments in Sight
One of the most serious eye disorders in people older than 60 years, glaucoma is responsible for 15 percent of adult blindness in the United States. An estimated 4 million to 10 million people in this country suffer from the disease.
"The estimate is so broad because many cases go undiagnosed," explains Dreyer, who is also an assistant professor of ophthalmology at the Medical School. "It's a silent disease that often goes undetected until it reaches an advanced stage. That's a good reason to have regular checkups."
If eyedrops, pills, and other medications don't relieve the pressure caused by buildup of fluids, physicians resort to surgery. "But even with excellent pressure control, many people still go blind," Dreyer says. "That's why we felt so strongly that something else is involved."
With the help of David Zurakowski of Children's Hospital, Dreyer and Lipton did a statistical study that pinpointed glutamate and eliminated other factors such as age, sex, race, and other medical conditions.
If this chemical was a poison from outside the body, researchers would have a relatively easy task finding out where it comes from and how to get rid of it. But glutamate, produced by nerve cells in the eyes and brains, is necessary for both sight and life.
"Without it, you not only go blind, you die," Dreyer says emphatically. "It's overproduction that makes it toxic. Our data suggest that the worse the glaucoma, the higher the glutamate. A doubling of normal amounts eventually kills the retina."
This situation leaves scientists with two problems, discovering the cause of glutamate's overabundance and finding a drug that will stop its excesses but not block its vital functions. "The latter is a 'Holy Grail' being pursued in dozens of university and drug-company laboratories," Dreyer notes.
This frenzy is fed by the fact that drugs to control glutamate may also help people who suffer from Alzheimer's disease, stroke, AIDS dementia, and amyotrophic lateral sclerosis (ALS).
The Food and Drug Administration (FDA) recently approved riluzole, a glutamate regulator, for ALS, a muscle-wasting malady also known as Lou Gehrig's disease. But Dreyer believes riluzole has too many side effects to use for glaucoma treatment. He and his colleagues are taking a hard look at memantine, a glutamate blocker not yet approved by the FDA. Another possibility is dextromethorphan, a weakened form of which is a main ingredient in cough syrups.
"These and other drugs are being tested on patients with a variety of diseases," Dreyer notes.
Glutamate also seems to be involved in the death of brain cells in Alzheimer's victims. And high levels of it can result from a blocked brain artery, which often triggers stroke.
"All the evidence convinces me that glutamate is a part of the final pathway that leads to the death of nerve cells in the brain and eyes," Dreyer maintains. "Pursuing this idea to reach a successful treatment for glaucoma might take anywhere from three to 30 years, depending on how long we need to find the right drug and drug delivery system. I hope to see that happen before I retire."
Dreyer is 39.
New Ideas, New Century
by Laura J. Rongé, Contributing Editor
Leading glaucoma thinkers David L. Epstein, MD, Steven M. Podos, MD, and Milton Bruce Shields, MD, join us for a "virtual roundtable," offering ideas on today's tough questions. From what's new in neuroprotection to altering trabecular outflow to what's ahead in glaucoma genetics, they offer a look at 21st-century glaucoma care.
What are some approaches to neuroprotection? What is the potential for nitric oxide synthase inhibitors as IOP-independent neuroprotective agents in glaucoma?
Dr. Shields: One potential pressure-independent neuroprotective agent may be memantine, a glutamate receptor blocker. Glutamate is a physiologic neurotransmitter that becomes excitotoxic with excessive release, as occurs with the primary insult to retinal ganglion cells. The amino acid stimulates the NMDA receptor, which leads to increased calcium influx and cell death. By blocking this action of glutamate, memantine may protect axons from collateral damage in the glaucomatous process. A four-year trial is under way to test this hypothesis.
Concerning nitric oxide synthase, it has been reported that excess nitric oxide may be damaging to retinal ganglion cell axons, and nitric oxide synthase-2 has been demonstrated in glaucomatous eyes. Aminoguanidine, an NOS-2 inhibitor, may protect retinal ganglion cells in glaucomatous models, so this is another potential IOP-independent neuroprotective agent, and undoubtedly many more will be identified and evaluated in the coming years.
Dr. Podos: If neuroprotection is the preservation and rescue of damaged retinal ganglion cells and their neighbors in the presence of these noxious insults, one can obviously lower intraocular pressure, enhance blood supply, provide neurotrophins or block the excitotoxic cascade. Robert Schumer and I, in Archives of Ophthalmology in 1994, outlined some specific approaches, reviewing the advances of our neuroscience colleagues. In 1996 in Archives of Ophthalmology, Evan Dreyer and colleagues, including our Mount Sinai team, reported on the increase of glutamate in the vitreous of glaucomatous eyes. Thus, we have concentrated on blocking the excitotoxic cascade as a glaucoma neuroprotective therapy. Possibilities include blocking glutamate receptors such as the NMDA receptor at its various sites, calcium channel blockade, inhibiting nitric oxide synthase, scavenging free radicals, or blocking apoptosis such as using caspase inhibitors. These modalities are being tested in a variety of animal models, none of which are ideal, and a human trial of a glutamate blocker, memantine, is now being initiated at multiple institutions including Mount Sinai.
The interesting concept that nitric oxide synthase-2 is up regulated in the optic nerve heads of glaucomatous rat and human eyes lends credence to this approach. Arthur Neufeld and co-workers have recently reported in the Proceedings of the National Academy of Sciences that an NOS inhibitor fed to glaucomatous rats for six months is a pharmacologic protectant of the retinal ganglion cells. Prior studies have shown that an NMDA receptor inhibitor is also therapeutic in this same rat model of chronic elevation of intraocular pressure.
We are clearly entering a new era of potential glaucoma therapies. However, proving their efficacy in humans will be a long and arduous task.
What are some new approaches to altering trabecular outflow?
Dr. Podos: Despite the excitement of neuroprotection, we and our patients need new drugs that lower intraocular pressure by working on the traditional outflow pathways. Prospects in this regard are favorable.
In 1876 Laqueur first reported the reduction of intraocular pressure after using the cholinergic agent physostigmine. In years following, pilocarpine was the mainstay of glaucoma therapy. Since the demise of pilocarpine use, ophthalmology has not had an agent that works primarily on trabecular outflow. Yet in high-pressure glaucoma, the problem lies in the trabecular meshwork. Alpha-2 adrenergic agonists work by reducing inflow, and current prostanoids work by enhancing uveoscleral outflow. We need an agent that reduces resistance in the meshwork without the side effects of the miotics. The pioneering work in 1977 of Paul Kaufman re-investigating such agents as the cytochalasins that disrupt the cytoskeleton and increase outflow facility must be mentioned. The literature is replete with other attempts including those of David Epstein and co-workers on ethacrynic acid and Kaufman et al. on other actin-disrupting drugs such as H7 and latrunculin. Much promising research is ongoing in this area.
My research team has taken a different approach to searching for drugs that improve trabecular outflow. We have reported on two classes of compounds that clearly reduce intraocular pressure by increasing tonographic outflow facility in glaucomatous monkey eyes. One class is the alpha-1A adrenergic antagonists and the other is the isoprostanes. We are especially excited by the latter, a class of prostanoids structurally and metabolically very different from latanoprost. In fact, 8-iso PGE2, our lead compound, has an intraocular pressure effect additive to latanoprost.
Dr. Epstein: My personal bias is that it should be easier to understand and develop novel therapies for a simple connective tissue like the trabecular meshwork outflow pathway than it will be for a complex neurobiological structure such as the optic nerve. However, I may be wrong! Unfortunately both areas of focus suffer from too few investigators for such important problem areas of visual morbidity and loss.
I believe that the cytoskeleton (the internal protein structure of cells that is constantly being rearranged to alter cell shape and attachment to other cells, thereby changing the geometry of the outflow pathway) is an important focus for novel outflow glaucoma therapy. We have increasing evidence that the trabecular meshwork is, in fact, a very dynamic structure due to this cytoskeletal modulation, with the geometry of the outflow pathway channels on a macrolevel changing constantly under the influence of micro-events involving the cytoskeleton, cell contacts, shape, etc., of the cells in this tissue. In fact, our hypothesis is that abnormalities in the adaptation of these changes in response to various stresses, for example, to changes in intraocular pressure, may be part of an important glaucoma mechanism. There is a growing interest in this conceptual approach, and investigators such as Kaufman, Alvarado, Geiger, Borras, Rao, and Russell have contributed important information in this area.
These investigators are developing many potential drugs with beneficial cytoskeletal influences and excellent systemic safety profiles. It seems to be coming down to pharmacodynamic issues of delivering appropriate drug levels to the trabecular meshwork tissue.
Terete Borras has successfully performed gene therapy to the trabecular outflow pathway and inserted genes that are turned on in this tissue. Restoring normal outflow function by this gene therapy approach is the ultimate in focused pharmacology to the tissue. The technique entails simply placing the adenovirus carrier in the aqueous humor by injection. The accessibility and immune privilege of the anterior chamber makes this an ideal approach and a very exciting development for the future treatment of trabecular glaucoma.
What's new in genetics? What is the latest on the myocilin (TIGR) gene?
Dr. Epstein: Finally we have a most important clue to glaucoma mechanisms by the linkage of the myocilin (TIGR) gene to certain forms of glaucoma, especially juvenile open-angle glaucoma (JOAG), through outstanding work from the University of Iowa, department of ophthalmology, by Ed Stone, MD, PhD, and Wallace L.M. Alward, MD, and others. JOAG has many phenotypic differences from the more common adult primary open-angle glaucoma (POAG). Specifically, JOAG, to me, is a true trabecular meshwork glaucoma with characteristically high intraocular pressure. The work of the Iowa group, R. Rand Allingham, MD, at Duke University Eye Center in Durham, North Carolina, and Janey Lee Wiggs, MD, PhD, at Tufts University Medical School in Boston, has indicated that this myocilin mutation explains only a small number of cases of primary open-angle glaucoma. Nevertheless, for the first time, we have a true cellular "handle" on what might cause glaucomatous processes in the outflow pathway.
Most impressive is the work of Stamer and McKay, indicating that the myocilin (TIGR) protein is important for vesicle movement and function in the cell. In my several decades as a glaucomatologist, I have never until now heard any "vesicular theoryc of glaucoma. How humbling to me! Further, the cytoskeletal field may be converging here as the McKay and Stamer data seem to imply that myocilin (TIGR) effects on vesicles are part of an important function relating to cell-to-cell adhesion factors and junctions that are also under cytoskeletal control. (So I may have been half right!)
Another very interesting twist, although the field is in constant flux and new data are being generated as we speak, is the findings of Borras, Gonzales, and Caballero, which indicate that through their gene transfer techniques, increasing myocilin (TIGR) protein expression in outflow pathway cells may actually improve outflow! The work of Russell and Tamm also supports this.
Although the myocilin (TIGR) protein was first identified by Polansky and Nyugen in trabecular meshwork cells as a result of steroid treatment in very important experiments, the work of Alvarado has subsequently indicated that this is likely not the mechanism for steroid-induced glaucoma (which instead seems to involve changes in the junctions between cells, which again fits into this broader cytoskeletal theme).
Therefore increased myocilin (TIGR) expression may be an important, adaptive beneficial mechanism (for example, an attempt involving vesicles to change junctional function). The work of Tamm, Russell and Lutjen-Drecoll would also support this. Therefore a mutation, which conceptually would represent "haploinsufficiency," would cause glaucoma by some loss in this important adaptive mechanism (loss of function), and this would also fit with the known late (noncongenital) onset of the disease. The final word is not in, and there are still alternative explanations; however, there is wonderful excitement about specifically studying a new protein that is involved in the glaucomatous process.
Also exciting is the work of Gonzales and Borras, using differential gene display techniques and showing, under the stress of increased intraocular pressure, that several genes are "turned on" in the trabecular meshwork. We are developing many clues to adaptive mechanisms on a cellular level that can increase outflow, and many novel pharmacological (pharmacogenetic) possibilities to, we hope, soon "cure" at least trabecular glaucoma.
What damages the optic nerve in glaucoma?
Dr. Shields: What damages the optic nerve? Ophthalmologists have been debating that question for at least 150 years. The mechanisms leading to glaucomatous optic neuropathy are multifactorial, with a relative elevation of intraocular pressure being one causative risk factor. Actually, pressure is probably one of the primary destructive events. The initial insult to the retinal ganglion cell or axon sets in motion a very complex cascade of events, resulting in the death of that cell, as well as secondary responses that may either destroy or protect adjacent cells. Ischemia may be another primary event, and there are probably others yet to be disclosed. We are also learning more about the ever-growing number of secondary responses that may lead to collateral death of ganglion cells. These secondary responses are the focus of consideration for potential pressure-independent neuroprotective agents.
Dr. Podos: What damages the optic nerve in glaucoma? I wish I knew. Although elevated intraocular pressure is the single most comitant finding, it is neither necessary nor sufficient for the production of glaucomatous optic neuropathy. Clearly there are other possible noxious insults that may or may not relate to intraocular pressure. These include vascularization at the optic nerve head, axoplasmic flow at the lamina cribrosa and excitotoxicity at the retinal ganglion cells. Evidence exists for reduced blood supply, blockage of reverse axoplasmic flow of neurotrophins and elevation of excitotoxins like glutamate that lead through a cascade to apoptotic death.
|Posted on Sunday, July 22, 2001 - 6:46 pm: || |
It upsets me whenever I read some scientist say that we should not worry about the MSG in food....that it's only the glutamate in our cells already that is causing the condition when cells die and glutamate is released. Are they so completely unaware of the vast amount of glutamate people ingest today, that could very well be the reason there is this excess glutamate in our organs, tissues, brains, and bones in the first place????? The answer is most likely "yes", they are unaware, because they think it's mainly found in Chinese food...hence the challenge we have convincing these "experts" and teaching them about the hidden sources. It doesn't take a rocket scientist to know that exogenous and endogenous glutamate are one and the same.
|Posted on Monday, July 23, 2001 - 2:15 pm: || |
Deb, I agree with you, but it's all too common in the medical profession to ignore the role pounds of ingested food and drink have on the body while extolling the miraculous virtues of a miniscule 5 mg of medication. The patients are not the only blind ones in this story.
|Posted on Monday, July 23, 2001 - 2:29 pm: || |
I am reminded of the five wise men and the elephant story, where five wise blind men all are trying to understand an elephant, but it is so big that each one can only feel one part, and so the big picture eludes them all. The food scientists, busy making unfood in their Betty Crocker make believe ovens, don't tell the neuroscientists what they are putting in the food supply, the doctor doesn't understand enough neuroscience, and the neuroscientists don't see the whole patient. Meanwhile, the food ingredient makers are busy playing God, trying to improve on nature by making a racing gasoline version of sustainance for our model T bodies that haven't changed much in thousands of years. Meanwhile, the patient is in the dark, trusting everyone. It's a great big mess. If they're ever going to put two and two together, we'll have to do it for them.