Researchers at Mayo Clinic have discovered that neuromyelitis optica antibodies (NMO-IgG) found in the multiple sclerosis (MS) variant neuromyelitis optica (Devic’s syndrome) lead to a build-up of glutamate. Glutamate, which is also found in monosodium glutamate (MSG) is considered an excitotoxin or chemical capable of injuring brain cells.
What is Glutamate?
Neurotransmitters are chemicals that allow nerves to communicate with brain and muscle cells. The neurotransmitter glutamate is essential for normal signal transmission between neurons including the motor neurons, which trigger muscle contraction. Advances in imaging techniques have also demonstrated that release of the major excitatory neurotransmitter glutamate initiates diverse signaling processes between neurons and the brain's immune system cells known as astrocytes. It's thought that this signaling could be crucial for the occurrence of brain imaging signals. Thus, defects in glutamate can interfere with brain imaging.
In excess, glutamate can directly damage brain cells. The premature death of motor neurons, in turn, produces the progressive paralysis characteristic of amyotrophic lateral sclerosis (ALS) and other neurological disorders.
Consequences of Excess Glutamate
Glutamate, in excess, is suspected of causing oxidative stress and leading to the destruction of neurons in Parkinson’s disease, amyotrophic lateral sclerosis and other autoimmune disorders.
Excess glutamate has also been suspected of destroying myelin and contributing to the disease process in multiple sclerosis.
The Mayo Clinic Study
In Devic’s syndrome, NMO antibodies bind to a protein that normally sops up excess glutamate. As a result, this protein is unavailable, and glutamate molecules lodge in the space between brain cells. In their report the Mayo authors suggest that glutamate-induced damage to nerve cells and their insulating myelin coats might be responsible for the neurological symptoms associated with Devic's disease.
Therapeutic Implications
If the Mayo group is able to confirm their results in vivo using nerve cell cultures, drugs to block the effects of glutamate could be developed as a therapy for neuromyelitis optica and related disorders. Therapeutic trials for glutamate blockers, created to treat other neurodegenerative diseases like Lou Gehrig's disease (or ALS), are already underway.
Low Dose Naltrexone and Glutamate
Glutamate excess and its reduction by low dose naltrexone (LDN) are the main facets of the hypothesis proposed by the Cornell pathologist Yash Agrawal in explaining the benefits of LDN described in MS (anecdotally and in clinical trials). In his research, Dr. John Hong a senior scientists at the National Institutes of Health, has shown how glutamate contributes to the disease process in Parkinson’s Disease. In his preliminary studies of low dose opiate antagonists such as naltrexone, Dr. Hong has also shown how these compounds reduce glutamate accumulations and stop disease progression in neurological disorders.
The Glutamate Link
In the Mayo Clinic Study published in October 2008, Dr. Vanna Lennon and her team have demonstrated that glutamate accumulates in the brain of patients with neuromyelitis optica. They propose that this is a result of NMO antiboides leading to glutamate excess. Dr. Lennon's study suggests that glutamate is responsible for the myelin destruction in this disorder.
Dr. Hong has previously shown the destructive role of glutamate in Parkinson’s disease. Dr. Yash Agrawal has explained how glutamate toxicity causes symptoms in both Lyme disease and multiple sclerosis. Dr. Agrawal explains that the ability of the beta-lactam antibiotic cefrixatone to reduce glutamate accumulations accounts for its effectiveness in Lyme disease. He proposes that both cefrixatone and low dose naltrexone, by having the potential to reduce glutamate accumulations, have therapeutic value in Lyme disease, MS, and other neurological disorders.
Thus, while the Mayo researchers propose finding ways to block glutamate, the benefits of low dose naltrexone and beta lactam antibiotics lie in their ability to reduce glutamate excess.
Resources:
Yash Agrawal, Low dose naltrexone therapy in multiple sclerosis, Medical Hypotheses, 2005;64: 721-724.
Yash P. Agrawal, Possible importance of antibiotics and naltrexone in neurodegenerative disease, Letter to the Editor, European Journal of Neurology, 2005; 12: 1.
Autoimmune Disease May Be Triggered By Neurotransmitter Defect, Medical News Today, Oct 7, 2008, accessed Oct 23, 2008.
Wei Zhang, Jau-Shyong Hong, Hyoung-Chun Kim, Wanqin Zhang, and Michelle Block, Morphinan Neuroprotection: New Insight into the Therapy of Neurodegeneration, Critical Reviews in Neurobiology, 2004; 16(4): 271-302.
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