Neurotransmission Associated Neurotoxicity of Monosodium Glutamate

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Neurotransmission- Associated Neurotoxicity of
Monosodium Glutamate

• By Sarah Hardimon
• Chem. 471

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Introduction

• Monosodium Glutamate (also known as MSG) is the
  sodium salt of the amino acid glutamic acid, or
  glutamate.
• Glutamate is a normal amino acid neurotransmitter
  in the brain. (concentration around 8-12 µM)
• At abnormally high concentrations glutamate
  glutamate is classified as an excitatory
  neurotransmitter.

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Background

• MSG is used as a flavor enhancer that is to make
  foods more appetizing. It has no flavor of its
  own.
• First used in Japan. They use a sea vegetable
  (kombu) that had this flavor enhancing
  characteristic.
• (1908) Dr. Ikeda and Dr. Suzik isolated the
  taste-enhancing chemical- glutamate. They formed
  the Ajinomoto company-MSG marketing began.

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• MSG hit the U.S. market around 1940, without
  testing.
• (1969)Dr. John Olney (Dept. Psychiatry at
  Washington University St. Louis) found that MSG
  feed mice produced discrete brain lesions and
  destruction of hypothalamic nuclei.
• Since then many MSG neuro-studies have been
  preformed. Many have proposed linking glutamate
  excitotoxicity to neurological disorders such as
  seizures, migraines, Parkinsons disease,
  Alzheimer's, etc.

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• Two forms of glutamate- bound (linked to
  proteins) and free. Only the free form
  enhances flavor.
• After MSG is digested, glutamic acid is converted
  to glutamate. And when digested in the free
  form, as in MSG, the glutamate levels in the
  blood increase more significantly than when bound
  to proteins.

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Physical Data

• MSG fine white crystalline sold
• Soluble in alcohol and water

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Mechanism of Toxicity

• Glutamate is an neurotransmitter chemical that
  allows neurons (cells) to communicate between
  each other in the brain.
• The acute effect of glutamate is directly related
  to the immediate concentration of glutamate at
  the active site the neuron receptor- direct
  relationship of glutamate levels in the blood.
• At high conc., neurons fire abnormally. Cells
  undergo a process of delayed cell death known as
  excitotoxicity- cells are excited to death.

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Receptors Involved

• Two subtypes of glutamate receptors
• Ligand-gated (ionotropic)
• G-protein coupled (metabotropic)
• Ionotropic Receptors are further classified (or
  named) by their binding to specific agonist.
• N-methly-D-aspartate receptor (NMDA Rs) is the
  only know receptor that is regulated by both
  ligand (glutamate) and by voltage.
• NMDA Rs is the proposed site form glutamate
  toxicity.

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Neuron
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• Glutamate is stored in synaptic vesicles at nerve
  terminal and are released by an action potential
  from axon.
• Glutamate leaves the presynaptic cell
  (transmitting cell), crosses the narrow synaptic
  cleft (20 nm), and binds to the NMDA Rs on the
  postsynaptic cell (receiving cell).
• Binding to presynaptic cell opens Ca channel,
  which is normally blocked by Mg, causing
  excitation of postsynaptic cell.

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• Mg is removed by a depolarization in the membrane
  potential by an influx of Na ions from voltage
  gated ion channel as a result of glutamate
  binding to NMDA- a normal cell reaction.
• Glutamate excitation is normally terminated by
  reabsorption of glutamate across the presynaptic
  membrane.
• However, at high conc. Calcium channels get stuck
  open leading to neural swelling and cell death.

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• Only cells with NMDA Rs are affected
• Neuronopathy Toxicity damages dendrites and
  neural cell bodies of the neuron. Spares the
  axons. No chance for cell regeneration.

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• Glutamate acts on its receptor via a nitric oxide
  mechanism. Over stimulation can lead to
  accumulation of dangerous peroxynitrite free
  radicals.
• Ca influx results in the release of a chemical
  called arachidonic acid which cause the
  production of free radical, hydroxy radicals
• These radical are known to bind to proteins, DAN,
  lipid membranes.

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• Fortunately, antioxidants (Vitamins C, E, beta
  carotene) absorb these harmful radicals.
• However, chronic free radical exposure would
  result in an impaired functional reserve of
  antioxidant vitamins/minerals and enzymes.
• Also, neuron utilize a great deal of energy
  (ATP), via aerobic glycolysis, in order to pump
  glutamate back into presynaptic. Any loss of
  oxygen or glucose can increase the risk of
  exitotoxic injury- Asthma, starvation,
  hypoglycemia.

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Blood Brain Barrier Issue

• Inability of glutamate to pass through the blood
  brain barrier is one of the chief arguments for
  the proponents of MSG.
• However, several areas of the brain are not
  protected by the blood brain barrier.
• The hypothalamus is included in these sections of
  the brain, and where glutamate is the most
  important neurotransmitter, controls functions
  such as emotional control, caloric intake, immune
  system regulation, autonomic nervous systems,
  neuroedocrine regulation.

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• (1995) FDA classified MSG as a generally
  recognized as safe, or GRAS, substance.
• The FASEB conducted a study on the safety of MSG,
  and the FDA wrote a brief summary that wrote,
  expect possibly for asthma patients, MSG was
  found to be safe by the FASEB reviewers.
• However, there are many critics who feel that the
  FDA summary was a deception from the FASEB, which
  includes some of the FASEB reviewers.

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• FDA recognizes to people who may develop side
  effect
• Those intolerant to MSG when eaten in large doses
  and those with poorly controlled asthma.
• The FDA has proposed that any foods containing
  free glutamate must be declared on the label.
  However, there are many hidden names for both
  free and bound glutamate.
• To avoid a major public disaster the majority of
  baby-food manufactures voluntarily stopped adding
  MSG to there products.