Glutamate in brain injury: The role of NMDA receptors

NMDA receptors are a type of glutamate receptor in the brain. They have been found to play a role in the neurological damage that occurs after a stroke as well as irreversible neuron death after traumatic brain injury. However, these receptors are also important to normal brain activity, and attempts to inhibit NMDA receptors to control neurological damage after brain injury have had limited recent success.

What are NMDA receptors?

NMDA, or N-methyl-D-aspartate, is an amino acid derivative based on aspartic acid. It binds to a protein on the postsynaptic neuron known as an NMDA receptor. These receptors are one of two in the brain that bind the amino acid glutamate (see a slide show). Once the synapse is depolarized by the other glutamate receptor, glutamate binding to the NMDA receptor results in calcium (Ca2+) flux into the postsynaptic neuron. Calcium is a secondary messenger that activates signaling cascades within the neuron, including the generation of more glutamate receptors and retrograde activation of the synapse, resulting in synaptic enhancement and possibly leading to a phenomenon known as long-term potentiation.

Glutamate receptors in brain injury

As early as 1989 researchers found that the amino acids glutamate and aspartate are increased in the brain after traumatic brain injury and that blocking the NMDA receptors reduced the delayed tissue damage resulting from the injury. According to a 1992 review in the British Journal of Clinical Pharmacology, delayed tissue damage was thought to account for nearly half of the resulting damage of brain injury. However, later work in The Lancet Neurology that reviewed the failures of NMDA antagonists (i.e. blockers) in clinical trials of stroke and brain injury found that the signaling is more likely related to early damage and then later survival of the neuron. Thus, blocking the receptor exacerbated the early damage and prevented neuronal recovery.

Cerebral ischemia and NMDA receptor activation

Ischemia is a condition in which a tissue lacks oxygen. This can occur due to a lack of oxygen in the blood or restricted blood flow. In a stroke, cerebral blood vessels are cut off from receiving blood due to a clot or other blockage. In traumatic brain injury the brain tends to hemorrhage, resulting in blood loss and ischemia. DAPK1 is also known as death-associated protein kinase 1 as it is involved in apoptosis and cell death during ischemia. Interaction between this molecule and NMDA receptors would explain the role of the receptor in damage after brain injury.  

Research published in the journal Cell in 2010 found that DAPK1 interacts with the NMDA receptor during ischemia and is responsible for the transition between these different roles. DAPK1 binds to the intracellular portion of the NMDA receptor, causing its activation and neuronal damage via signaling cascades. Blocking DAPK1 reverts the NMDA receptor to its neuronal survival role and may be an approach for preventing brain damage after stroke and limit the damage from traumatic brain injury.

Preventing secondary injury

Though this work does not seem to have developed any helpful treatments to prevent secondary damage after traumatic brain injury, the research has increased understanding of the process that occurs. Ultimately, this knowledge will open doors to better prevention and treatment methods.