TAYLOR BOROWETZ

Francisco Cayabyab believes he and his associates made bounding steps toward better stroke treatments.

Researcher and assistant professor Francisco Cayabyab and his team may have recently discovered a way to minimize the permanent brain damage caused by stroke or traumatic brain injury.

Cayabyab has been in the area of neuroscience for over a decade, and has created a large body of academic work, with the most recent study garnering well-deserved attention.

The publication Cayabyab and his team have worked on relates to how strokes — the blockage of blood vessels in the brain — result in delayed brain damage hours and even days after the initial event.

They were posed with a question that has been puzzling neuroscientists for decades. To answer it, they turned to an animal with a brain very similar in structure to a human: the rat.

In their experiments, the team induced a mild stroke by removing some of the small blood vessels located on the top-right-hand side of the brain. This method prevents nutrients and oxygen from reaching the cells that the blood vessel feeds.

Most stroke research states that all of the cells within the immediate site of damage are dead, but there is an area just around this ischemic core that have cells that could be rescued, Cayabyab said. His research found that even a mild stroke on the surface of a rat’s brain can have an immediate impact on the whole brain.

“We think that it’s a landmark study because it represents a paradigm shift on how we normally view stroke damage occurs,” he said.

The learning and memory forming centres of the brain, called the hippocampus, are located in the medial temporal lobe. These areas are very sensitive to traumatic brain injuries. Cayabyab found that a stroke on one hemisphere of the brain can have an effect on the other as well.

Parts of the hippocampus are more vulnerable because they contain fewer calcium binding proteins that lead to a flood of calcium ions into the cell. When they reach damaging levels, the cell undergoes programmed cell death. The ease of damaging these sensitive areas worsens the permanent deterioration generated by the trauma.

Cayabyab and his team performed a massive set of studies to show that heightened levels of adenosine in the brain are responsible for damage to the hippocampus days or even weeks after a stroke. Adenosine signals sleep and waking cycles as well as patterns of alertness. Its levels fluctuate on a day-to-day basis as they accumulate during the day, causing fatigue, and are absorbed during sleep.

For over 40 years it has been believed that when an individual has a stroke or a traumatic brain injury, the major molecule released from neurons and supporting cells is glutamate, which is thought to produce the neurotoxicity that causes neural damage. There are certain glutamate receptors that are damaged when subject to diseases or strokes. Subsequently, calcium permeability can be affected, which can in turn affect adenosine levels. Cayabyab said that adenosine signaling is likely the cause of the delayed neural cell death that occurs following a stroke.

Cayabyab points to valuable clinical data showing that patients who have had a tiny transient ischemic stroke in the brain see a massive surge in blood plasma concentrations of adenosine two-to-three days later.

He explained that when an individual has a stroke, the neurons are overexcited into releasing not only glutamate but also a substance called adenosine triphosphate (ATP), which provides cellular energy.

ATP doesn’t stay outside the cells long, but is rapidly broken down by enzymes that turn them into adenosine. This process of converting the excess ATP is part of the reason adenosine levels stay elevated after a stroke.

There are also transporters on the surface of the brain cells that start to malfunction, so that their intake cannot keep up with the increased adenosine levels, Cayabyab said. 

“Accumulation of adenosine becomes a huge problem.”

Cayabyab and his team did not only identify the components of this problem: they have also developed a possible solution.

“We have a peptide called YD, which is basically a peptide that we designed based on what we discovered in our recent paper. There are certain molecular switches, if you will, that are turned on by prolonged adenosine receptor stimulation,” he said. “And one of these molecular switches, it turns out, can be inhibited by having this peptide administered or inserted into the cells.” 

The term YD is a shorthand for the chemical buildup of the peptide, the full nature of which could not be disclosed due to a pending patent application. 

In their preliminary studies, which are still ongoing, they injected the rats with the YD peptide before they induced the stroke. Cayabyab and his team found that there is extensive neuroprotection taking place in the hippocampus which  decreases neurodegeneration.

To find out if they were successful, the team looked at long-term potentiation, a test used to see if learning occurs on in-vitro brain slices, and found it was greatly depressed when animals were subjected to the in vivo stroke model. When injected with the peptide before a stroke was induced, however, the animals retained normal long-term potentiation. 

This result of normal long-term potentiation shows huge promise to the possibility of minimizing brain damage.

In these prior experiments the peptide was administered first as a preventative. The next step is to start injecting the peptide at two and three hours after the stroke has been induced, in order to mimic what would happen clinically.

Cayabyab’s recommendation is to rush individuals to the hospital immediately following a stroke so that a blood thinning agent can be administered. This process is called reperfusion, and allows blood flow to resume in the areas of the brain that were deprived of oxygen and nutrients following a stroke. 

Although reperfusion is not actually a cure, it is a way to reduce damage. The possibility of reperfusion ischemic injury also exists, where the return of circulation can cause inflammation and oxidative damage such as cognitive deficit, paralysis and partial paralysis.

“If we can reduce the damage of the brain cells that control, for example, learning or brain cells that control movement, then I think we can do a lot more for stroke patients than we currently do now,” Cayabyab said.

He said that they are currently in the process of filing a patent for YD because it’s such a major discovery. They are hoping to pair up with a pharmaceutical company that has the funds to help find small molecules that mimic the effect of this peptide, its neuroprotective effect and the reversal of memory loss. If this is achieved, the results could be tremendous.

“We looked at alternative ways to produce neuroprotection, and I think we have stumbled upon something that is quite novel,” Cayabyab said. “Nobody has really made the connection until now.”

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Photo: Katherine Fedoroff/Photo Editor