Editor review of “Erythropoietin as a neuroprotective agent in traumatic brain injury” by Mammis et al

With brain trauma (radiologically), we see contusion, hemorrhage, edema, compression, suggestive ischemia, infarction and perhaps, herniation.

On the microscopic level, the changes that we all know consist of cell disruption, edema, hemorrhage, ischemia, and cell death.

At the cellular and molecular levels, the cell injury produces a cascade of effects after the disruption of the cell membrane. Those effects elicit an inflammatory process, a release of free oxygen radicals from the disabled metabolic processes. These free radicals can cause further cell membrane damage. Obviously, the neurotransmitters stored in the nerve endings are released into the extracellular spaces to produce further effects on adjacent cells. The intracellular enzymes that are released cause further damage to the surrounding cells and processes. These enzymes set in motion a series of molecular events in these damaged cells that place them on the path to cell death, or “apoptosis,” as it is called. This series of molecular events is called “programmed cell death” and is controlled by a sequence of metabolic events that can be genetically controlled. Genes govern factors that advance cell death or inhibit cell death during this “life and death struggle” of a cell.

Apoptosis is governed by molecular mechanisms involving enzymes called capsases. These enzymatic sequences can be activated internally or externally. Apoptosis can also occur without capsases through mitochondrial mechanisms.

The cell death can be determined microscopically by TUNEL staining in which the broken strands of the DNA are labeled with a compound that fluoresces under a special microscope and thus can reveal the number of cells that are dying.

Erythropoietin is known as a molecule that stimulates the production of red cells and is used to raise the hematocrit. It also has a neuroprotective role. It prevents apoptosis as it attaches to a receptor on the cell membrane initiating a series of molecular signaling events that shut off the apoptotic molecular cascade in the cell.

As Dusick mentions in his comments, many agents found to be successful in experimental animals have not been successful when tested clinically. He describes a number of reasons for these clinical failures, none the least of which is that all brain injuries are not the same. So, he suggests that a proper selection of patients be made so that the erythropoietin can be tested appropriately. We do not know what his selection process is. Eventually he believes that several agents may be used in a particular patient tailored to the damage each has.

This article is a short review of this subject and is worth reading with this background. There is a complex series of molecular events that occurs during cell injury. The reader should not be discouraged by all the names used to describe these events. Some of the names do not make much sense to the average reader. The best approach to these types of articles is to try to understand the general concept that is being discussed rather than giving up in frustration. This is information that you will want to know.