B R A I N S T O R M S Clinical Neuroscience Update

Excitotoxicity and Neuroprotection

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

© CopyrightIssue: Excitatory 1997 neurotransmission Physicians is a normalPostgraduate physiologic process Press, Inc. mediated by the neurotransmitter glutamate. Too much glutamate release can be destructive and literally excite a to death in a process called . Blocking this process may be neuroprotective and prevent brain disorders mediated by excitotoxicity.

an a neuron be excited toOne personal copy may be printed death? Some interesting new C findings about glutamate Take-Home Points suggest that this excitatory neurotrans- ◆ Excitotoxicity may be how the brain discards useless mitter not only talks to , but can also scream at them, strangle their den- connections or prunes poorly functioning neurons drites, and even assassinate them.1Ð7 ◆ Angry neurons release glutamate if provoked by poisons, One of the key glutamate receptors suffocation, or genetic programs is called NMDA, named after its selec- 1,2 tive ligand N-methyl-D-aspartate. ◆ Glutamate may be the “hit-man” who assassinated neurons in Once glutamate binds to its NMDA re- , Alzheimer’s disease, and other neurodegenerative ceptor, this opens an ion channel in the disorders, possibly including schizophrenia neuronal membrane so the nerve can drink . Sipping calcium is excit- ◆ Antagonists to key glutamate receptors may arrest the assassin ing to a neuron and a normal reaction and prevent neuronal murder when glutamate is speaking pleasantly.

Too much glutamate can be hazardous to your health erate nasty chemicals called free radi- become manic, or become psychotic. 1,3Ð6 When glutamate screams at a neu- cals. A small commune of free radi- Furthermore, such symptoms of cal- ron, it reacts by drinking more calcium. cals can crash the chemical party in the cium intoxication may be followed by Imbibing too much calcium can anger postsynaptic dendrite and strangle it. an unfortunate glutamate hangover in intracellular enzymes, which then gen- Why would the neuron allow this to the form of destroyed dendrites that can happen? It is possible that the brain never be excited again. needs this excitotoxic mechanism so BRAINSTORMS is a monthly section of The that glutamate can act as a gardener in Glutamate as endogenous assassin Journal of Clinical Psychiatry aimed at providing updates of novel concepts emerging from the the brain, pruning worn out branches At the far end of the excitotoxic neurosciences that have relevance to the from dendrite trees so that healthy new spectrum, glutamate’s molecular mis- practicing psychiatrist. sprouts might prosper. However, this chief can run rampant and actually mur- From the Clinical Neuroscience Research Center in San Diego and the Department of also equips glutamate with a powerful der entire neurons by overwhelming Psychiatry at the University of California San weapon that can be misused to cause calcium poisoning and free-radical Diego. various pathologic states.1,3Ð6 mayhem.1,3 Certain illnesses such as Reprint requests to: Stephen M. Stahl, M.D., Ph.D., Editor, BRAINSTORMS, 8899 University When glutamate decides to act as an Alzheimer’s disease, Parkinson’s dis- Center Lane, Suite 130, San Diego, CA 92122. abusive bully, neurons may seize, panic, ease, Lou Gehrig’s disease (amyotro-

246247 J Clin Psychiatry 58:5, May 1997 B R A I N S T O R M S Clinical Neuroscience Update

Normal excitatory neurotransmission Glutamate antagonist blocks excitotoxic neurotransmission

glutamate glutamate antagonist

Neuroprotection

Excess calcium activates enzyme glutamate antagonist phic lateral sclerosis), blocks excitotoxic are being developed © Copyright 1997 Physicians Postgraduateneurotransmission Press, Inc. and even schizophre- Excitotoxicity that neutralize pesky nia may hire glutamate Neuroprotection free radicals. Certain as a methodical assassin, chemicals can do this eliminating a whole sub- including and Enzyme produces free radical population of pre-desig- Excitotoxicity experimental agents nated neurons.7 This is a called lazaroids (so- E systematic process con- Excess calcium named because they pur- activatesthe end enzyme sistent with the pace of is near port to raise neurons Neuroprotection E such neurodegenerative from the dead, like the disorders. In the case of Excitotoxicity biblical Lazarus). These stroke, glutamate may and other agents are be- Free-radicalOne personal scavenger copy mayFree beRadical printed form an army of hit-men, ing developed, especially Finally, free radicals destroy the cell and then massacre an en- for slow neurodegenera- tire region of distressed tive conditions such as ischemic neurons in the tardive dyskinesia and midst of a catastrophic Alzheimer’s disease. As molecular mess.3 free radicals may be a In summary, gluta- final common pathway mate’s actions can range Neuroprotection E for cellular demise, rang- Free-radicalFree radical scavenger across a vast spectrum. It scavenger ing from atherosclerosis can be a friendly neuro- to dementia, the race to nal conversationalist or a discover clinically effec- screaming hypothetical Adapted with permission from reference 1. tive scavengers of these mediator of symptoms of destructive free-radical mental illness. After an devils is proceeding fast abusive tirade, glutamate apace.1,3Ð7 ◆ may even strangle the dendrite it their thirst in normal excitatory neuro- excited. As excitotoxicity escalates, transmission, but not guzzle so much glutamate can become a serial mur- calcium that they become excito- REFERENCES derer of neurons, wiping them out in a toxically inebriated. Numerous NMDA 1. Stahl SM. Essential Psychopharmacology. New devastating cumulative process over antagonists are able to mitigate neuro- York, NY: Cambridge University Press; 1996 months and years. At an extreme, glu- nal death, including ischemic stroke. 2. Alexander SPH, Peters JA. Receptor and Ion tamate is a mass murderer, wreaking Clinical testing of such compounds Channel Nomenclature. Trends Pharmacol Sci 1997(suppl) the destruction of localized neurons will be rapidly accelerating in the near 3. Koroshetz WJ, Moskowitz MA. Emerging treat- during the chaos of stroke. future. Such approaches are deemed ments for stroke in humans. Trends Pharmacol neuroprotective since they arrest gluta- Sci 1997;17:227Ð233 4. Olney JW, Farber NB. dys- Can the brain be rescued mate before it can assassinate any more function and schizophrenia. Arch Gen Psychia- or protected? neurons. try 1995;52:998Ð1007 At least two approaches to collaring Another approach to developing 5. Olney JW. Excitatory amino acids and neuro- 1,3Ð6 psychiatric disorders. Biol Psychiatry 1989;26: glutamate are showing promise. treatments for illnesses that may be 505Ð525 The first is to protect the neuron from mediated by excitotoxicity is to rescue 6. Olney JW, Labruyere J, Wang G, et al. NMDA drinking too much calcium by block- the cellular machinery once gluta- antagonist neurotoxicity: mechanism and pro- tection. Science 1991;254:1515Ð1518 ing NMDA receptors with antagonists. mate’s cascade of doom has been acti- 7. Stahl SM. . J Clin Psychiatry 1997;58: Thus, neurons are allowed to quench vated. Thus, free-radical scavengers 183Ð184

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