Surprising Culprit Worsens Stroke, TBI Damage

Posted on October 1, 2022

Scientists report that in the aftermath of a stroke or TBI, a group of amino acids that typically support brain function contributes significantly to the brain destruction that can follow both these injuries. The surprising evidence is that four common nonexcitatory amino acids that usually make proteins essential to brain function instead cause irreversible, damaging swelling of the astrocytes that support neurons. 

A stroke ensuing from a ruptured or blocked blood vessel in the brain or traumatic brain injury (TBI) disrupts the uniquely, super-tightly woven endothelial cells that line blood vessels in the brain that ensure nothing escapes from the blood that might hurt our brains. Following these significant brain events, the protective blood-brain barrier can become leaky, and its components can escape.

Plasma (the fluid part of the blood) escapes into the nearby stressed brain area. Usually, small molecules like oxygen are the ones that can pass through the blood-brain barrier, and larger molecules like amino acids are selectively permeable to ensure the right amount of right factor gets delivered directly to cells that need them. Transporters inside membranes of the endothelial cells enable select items, including amino acids and glucose, to be delivered.

The most common amino acid glutamate, which stimulates neurons to action, is delivered by transporters t. Glutamate, a chemical messenger or neurotransmitter that binds to the NMDA receptor, plays an essential role in functions like breathing learning, and memory. It works by activating channels that let calcium, sodium, and potassium in. But, too much receptor activation means excess calcium and sodium, followed by excess fluid, which is fatal to nerve cells.

The scientific team looked into the less-studied nonexcitatory amino acids. They used sophisticated technology, including two-photon laser microscopy, to look into living tissue in real-time. In this case, brain slices and high-resolution electron microscopy images directly examine the tissue for evidence of injury to astrocytes and neurons. Four nonexcitatory amino acids include L-alanine, glycine, L-glutamine, and L-serine, plentiful in plasma.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  

The astrocytes and neurons become flooded with these amino acids once the blood-brain barrier becomes leaky. The brain cells are overfilled with them, which increases sodium inside the cells. The sodium attracts water, and the expanded brain cells take up more space, which is unsafe in the closed confines of the skull.

Astrocytes protect themselves by opening channels that allow excess water and molecules to escape. Glutamate also escapes overstimulating the NMDA receptors, which, in turn, overstimulates the injured neurons that dramatically enlarge, burst, and die.

Electron microscopy revealed that everything was messed up at synapses where transmission happens. It was surprising to see the amount of damage induced by the nonexcitatory amino acids. When the nonexcitatory amino acids were removed, neurons' ability to communicate was restored after 30 minutes of adequate oxygen. When the NMDA receptors were inhibited during hypoxia, the nonexcitatory amino acids did not have the same harmful impact.

But their obvious role in the destruction that resulted intervenes in the vicious circle, a new target in the destruction that happens after a stroke or TBI. The transporters that move amino acids may be a good target, with some local pharmacologic intervention to reduce or prevent their activity in the immediate aftershock of a stroke or TBI.

This new approach will be used in conjunction with existing methods, including surgical measures to decrease pressure inside the skull once it gets too high. Upto 90% of patients with brain injuries experience collateral harm to brain tissue adjacent to the site of the damage, called the penumbra, hours and sometimes even days later, worsening injury and potential recovery prospects.

Glutamate, the most abundant excitatory neurotransmitter, usually is recycled continuously by the body. Astrocytes convert it into glutamine, an amino acid, which is taken up by neurons that convert it back to glutamate. Too much glutamate is linked with neurodegenerative diseases like Alzheimer's and Parkinson's.