Excitotoxicity and Neuroprotection

Stephen M. Stahl, M.D., Ph.D.


Issue: Excitatory neurotransmission is a normal physiologic process mediated by the neurotransmitter glutamate. Too much glutamate release can be destructive and literally excite a neuron to death in a process called excitotoxicity. Blocking this process may be neuroprotective and prevent brain disorders mediated by excitotoxicity.


Can a neuron be excited to death? Some interesting new findings about glutamate suggest that this excitatory neurotransmitter not only talks to neurons, but can also scream at them, strangle their dendrites, and even assassinate them.1-7

One of the key glutamate receptors is called NMDA, named after its selective ligand N-methyl-d-aspartate.1,2 Once glutamate binds to its NMDA receptor, this opens an ion channel in the neuronal membrane so the nerve can drink calcium. Sipping calcium is exciting to a neuron and a normal reaction when glutamate is speaking pleasantly.

Too much glutamate can behazardous to your health

When glutamate screams at a neuron, it reacts by drinking more calcium. Imbibing too much calcium can anger intracellular enzymes, which then generate nasty chemicals called free radicals.1,3-6 A small commune of free radicals can crash the chemical party in the postsynaptic dendrite and strangle it.

Why would the neuron allow this to happen? It is possible that the brain needs this excitotoxic mechanism so that glutamate can act as a gardener in the brain, pruning worn out branches from dendrite trees so that healthy new sprouts might prosper. However, this also equips glutamate with a powerful weapon that can be misused to cause various pathologic states.1,3-6

When glutamate decides to act as an abusive bully, neurons may seize, panic, become manic, or become psychotic. Furthermore, such symptoms of calcium intoxication may be followed by an unfortunate glutamate hangover in the form of destroyed dendrites that can never be excited again.

Glutamate as endogenous assassin

At the far end of the excitotoxic spectrum, glutamate's molecular mischief can run rampant and actually murder entire neurons by overwhelming calcium poisoning and free-radical mayhem.1,3 Certain illnesses such as Alzheimer's disease, Parkinson's disease, Lou Gehrig's disease (amyotrophic lateral sclerosis), and even schizophrenia may hire glutamate as a methodical assassin, eliminating a whole subpopulation of pre-designated neurons.7 This is a systematic process consistent with the pace of such neurodegenerative disorders. In the case of stroke, glutamate may form an army of hit-men, and then massacre an entire region of distressed ischemic neurons in the midst of a catastrophic molecular mess.3

In summary, glutamate's actions can range across a vast spectrum. It can be a friendly neuronal conversationalist or a screaming hypothetical mediator of symptoms of mental illness. After an abusive tirade, glutamate may even strangle the dendrite it excited. As excitotoxicity escalates, glutamate can become a serial murderer of neurons, wiping them out in a devastating cumulative process over months and years. At an extreme, glutamate is a mass murderer, wreaking the destruction of localized neurons during the chaos of stroke.

Can the brain be rescued or protected?

At least two approaches to collaring glutamate are showing promise.1,3-6 The first is to protect the neuron from drinking too much calcium by blocking NMDA receptors with antagonists. Thus, neurons are allowed to quench their thirst in normal excitatory neurotransmission, but not guzzle so much calcium that they become excitotoxically inebriated. Numerous NMDA antagonists are able to mitigate neuronal death, including ischemic stroke. Clinical testing of such compounds will be rapidly accelerating in the near future. Such approaches are deemed neuroprotective since they arrest glutamate before it can assassinate any more neurons.

Another approach to developing treatments for illnesses that may be mediated by excitotoxicity is to rescue the cellular machinery once glutamate's cascade of doom has been activated. Thus, free-radical scavengers are being developed that neutralize pesky free radicals. Certain chemicals can do this including vitamin E and experimental agents called lazaroids (so-named because they purport to raise neurons from the dead, like the biblical Lazarus). These and other agents are being developed, especially for slow neurodegenerative conditions such as tardive dyskinesia and Alzheimer's disease. As free radicals may be a final common pathway for cellular demise, ranging from atherosclerosis to dementia, the race to discover clinically effective scavengers of these destructive free-radical devils is proceeding fast apace.1,3-7

References

1. Stahl SM. Essential Psychopharmacology. New York, NY: Cambridge University Press; 1996

2. Alexander SPH, Peters JA. Receptor and Ion Channel Nomenclature. Trends Pharmacol Sci 1997(suppl)

3. Koroshetz WJ, Moskowitz MA. Emerging treatments for stroke in humans. Trends Pharmacol Sci 1997;17:227-233

4. Olney JW, Farber NB. Glutamate receptor dysfunction and schizophrenia. Arch Gen Psychiatry 1995;52:998-1007

5. Olney JW. Excitatory amino acids and neuropsychiatric disorders. Biol Psychiatry 1989;26:505-525

6. Olney JW, Labruyere J, Wang G, et al. NMDA antagonist neurotoxicity: mechanism and protection. Science 1991;254:1515-1518

7. Stahl SM. Apoptosis. J Clin Psychiatry 1997;58:183-184


Brainstorms aims to provide updates of novel concepts emerging from the neurosciences that have relevance to practitioners.

From the Clinical Neuroscience Research Center in San Diego and the Department of Psychiatry at the University of California San Diego.