Psychiatric Annals

PSYCHOPHARM PSNAPSHOTS 

Neuroprotection: Rescuing the Brain From Endogenous Assassins

Stephen M Stahl, MD, PhD

Abstract

Glutamic acid (glutamate) may not only be a normal excitatory neurotransmitter at low doses, but also an endogenous assassin at high doses. This is the third and final part of a series of visual lessons on glutamate. The first lesson covered glutamate receptors and the spectrum of excitation mediated by the NMDA (Nmethyl-d-aspartate) receptor subtypes. The second lesson showed the hypothetical consequences of increasing neuronal activation by glutamate; namely, that glutamate turns into an endogenous assassin capable of murdering neurons. The third lesson is shown below and deals with a novel therapeutic concept, namely neuroprotection. This is the idea of trying to block excessive glutamate. This hopefully would protect neurons at risk from damage or death due to excitotoxicity. The potential of rescuing the brain from the theoretical assassination of its neurons by glutamate is leading to the testing of many new therapeutic agents capable of blocking glutamate's actions.…

Glutamic acid (glutamate) may not only be a normal excitatory neurotransmitter at low doses, but also an endogenous assassin at high doses. This is the third and final part of a series of visual lessons on glutamate. The first lesson covered glutamate receptors and the spectrum of excitation mediated by the NMDA (Nmethyl-d-aspartate) receptor subtypes. The second lesson showed the hypothetical consequences of increasing neuronal activation by glutamate; namely, that glutamate turns into an endogenous assassin capable of murdering neurons. The third lesson is shown below and deals with a novel therapeutic concept, namely neuroprotection. This is the idea of trying to block excessive glutamate. This hopefully would protect neurons at risk from damage or death due to excitotoxicity. The potential of rescuing the brain from the theoretical assassination of its neurons by glutamate is leading to the testing of many new therapeutic agents capable of blocking glutamate's actions.

Figure 1. Too much glutamate at NMDA receptors lets too much calcium inside the cell. The consequences of this are activation of intracellular enzymes.

Figure 1. Too much glutamate at NMDA receptors lets too much calcium inside the cell. The consequences of this are activation of intracellular enzymes.

Figure 2. Enzymes activated by calcium generate free radicals, a dangerous chemical capable of damaging the cell.

Figure 2. Enzymes activated by calcium generate free radicals, a dangerous chemical capable of damaging the cell.

Figure 3. If the neuron's ability to eliminate free radicals is overwhelmed, these free radicals begin destroying the cell.

Figure 3. If the neuron's ability to eliminate free radicals is overwhelmed, these free radicals begin destroying the cell.

Figure 4. Once free radicals poison the cell's mitochondria, energy production stops, cell membranes are torn apart, and the neuron dies (ie, it degenerates).

Figure 4. Once free radicals poison the cell's mitochondria, energy production stops, cell membranes are torn apart, and the neuron dies (ie, it degenerates).

Figure 5. If too much glutamate starts this terrible cascade of excitotoxicity, perhaps an antagonist of glutamate at NMDA receptors would protect the neuron by not allowing too much calcium to enter the neuron in the first place.

Figure 5. If too much glutamate starts this terrible cascade of excitotoxicity, perhaps an antagonist of glutamate at NMDA receptors would protect the neuron by not allowing too much calcium to enter the neuron in the first place.

Figure 6. Another theoretical mechanism to interrupt the excitotoxic cascade would be to add free radical scavengers capable of neutralizing free radicals before they can damage the cell.

Figure 6. Another theoretical mechanism to interrupt the excitotoxic cascade would be to add free radical scavengers capable of neutralizing free radicals before they can damage the cell.

10.3928/0048-5713-19970501-03

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