By David N. Leff
Q: Why should very young children be shielded from Chinese restaurant syndrome?
A: ¿Because,¿ explained neurophysiologist Meiken Nedergaard, ¿small kids don¿t have great blood-brain barriers. That¿s why they shouldn¿t ingest monosodium glutamate [MSG], because glutamate can enter their brain and actually kill nerve cells.
¿The amino acid, glutamate,¿ she continued, ¿is an essential and ubiquitous neurotransmitter. It¿s involved in almost everything the brain does, and has many, many functions. But when released in the brain by glioblastoma cells, it is toxic to the surrounding neurons. Normally, glutamate elsewhere in the body can¿t enter the brain, because of the blood-brain barrier. But anything like meningitis or head trauma can break down that barrier. Once inside, excessive glutamate overactivates the neurons, which all have glutamate receptors, and kills them. It¿s the brain¿s primary excitatory transmitter. Glioma tumors secrete their own glutamate, so obviously don¿t need to penetrate the blood-brain barrier.
¿Glutamate neurotoxicity,¿ Nedergaard added, ¿has been implicated in stroke, brain trauma, multiple sclerosis, dementia and neurodegenerative diseases, such as Alzheimer¿s [AD] and Parkinson¿s [PD], but never before with glioblastomas. This final common pathway to neuronal death by apoptosis is glutamate. Normal glial cells in normal brain,¿ she added, ¿have as one of their major functions controlling glutamate and maintaining it at low levels. But it appears that process is reversed when the glial cells transform themselves into malignant cells and release glutamate instead.¿
Nedergaard is a professor of neurology at New York Medical College in Valhalla, N.Y. She is senior author of the cover-story article in the September 2001 issue of Nature Medicine. Its title: ¿Glutamate release promotes growth of malignant gliomas.¿
¿The report shows for the first time,¿ she told BioWorld Today, ¿that a tumor actively secretes a toxic compound, namely glutamate, that kills surrounding normal cells. Most tumors can destroy their surroundings just by the physical pressure of local expansion. But gliomas secrete glutamate into their margins, thereby killing those cells, too. That¿s a new aspect we report.
¿The other aspect,¿ Nedergaard went on, ¿is that drugs that antagonize the effect of glutamate are available, and in clinical use for treating other diseases. They are not being used to treat gliomas, but they do exist. A glutamate antagonist called memantine is the most efficient. It¿s actually being used in Germany as adjunctive treatment of AD and PD. Memantine is an antagonist that mimics the effects of glutamate,¿ she went on. ¿It¿s a very small compound that binds to the neurotransmitter¿s receptors on neurons.¿
Rights to memantine are held for various indications and locations by Merz and Co., of Germany; Forest Laboratories Inc., of New York; Lundbeck A/S, of Copenhagen, Denmark; and Neurobiological Technologies Inc., of Richmond, Calif.
Taking On Formidable Glioma Challenge
¿About 20,000 Americans are diagnosed with a brain tumor yearly,¿ Nedergaard observed. ¿Incidence peaks around 45 years of age. Mortality is almost 100 percent, and mean survival only 12 months, which shows how aggressively these tumors grow.¿
Her paper in Nature Medicine reported that ¿glutamine-secreting glioma cells, implanted in the brain striata of adult rats, triggered neuronal degeneration in vivo. Moreover, those tumor cells displayed a clear growth advantage when compared with their non-glutamate-secreting counterpart animals.
¿Glutamate-secreting gliomas,¿ the article continued, ¿promote an inflammatory response within surrounding tissue, possibly induced by the neuronal death or by glutamate itself. These observations support the idea that glutamate secretion by neoplastic glia promotes tumor expansion by enhancing the inflammatory response within tumor surroundings.¿
Using bioluminescence to reveal the presence of glutamate, the co-authors found that tumor cells releasing high levels of the neurotransmitter grew 15 times more rapidly than non-glutamate-releasing neurons. Also, tumor growth and cell death accelerated in the inflamed areas around the glutamate-secreting glioblastomas. In rats carrying malignant gliomas, memantine reduced the spatial expansion of their tumors.
These results have prompted Nedergaard and her team to try the glutamine antagonist, memantine, in human glioma patients. ¿It¿s very interesting,¿ she pointed out, ¿because there have been few side effects associated with taking memantine. It¿s not a drug that is cytotoxic, that kills cells. Rather, I think its mode of action is entirely different. It affects a receptor, so it can be used to supplement ongoing chemotherapy,¿ she added. ¿Preliminary data suggest that memantine and cytotoxic chemotherapeutic compounds have some synergistic effects.
¿We haven¿t tried that new drug in patients,¿ she observed, ¿but we want to now. Not in animal models again, but I think we have to go and try it in humans. And since memantine is already approved in Germany ¿ though not in the USA ¿ it would be ideal to try it here in this country. We are in the process of applying to the FDA for an [investigational new drug application] permitting Phase I adjunctive clinical trials. These would test perhaps 50 patients in several centers.¿
Future Points Out Roads Less Traveled
Accompanying her paper is a ¿News & Views¿ commentary titled: ¿Excitotoxic destruction facilitates brain tumor growth.¿ It culminates with this cautionary message: ¿Several pharmaceutical companies developed glutamate receptor antagonists during the 1990s, although many of these compounds failed in large clinical trials for stroke, and were dropped from further product development. Nevertheless, these on-the-shelf¿ agents are at hand and might provide an ideal starting point for preclinical and possibly clinical tests of the role of glutamate in brain tumor development if momentum gathers around the present findings.¿
But Nedergaard has another string to her bow: ¿There¿s an intriguing possibility that gliomas express a different type of glutamate receptor than normal brain cells do. If this proves to be true,¿ she concluded, ¿there might be interest in developing drugs that directly target the malignant tumor cells, and not the normal glutamate brain function.¿