More Oxygen to Chronic Cord, More Recovery

Posted by Sam Maddox in Research News on May 31, 2017 # Research

Spinal cord injury begins with sudden traumatic force but that’s only the beginning of the damage to the nervous system. A wave of secondary events soon follows, including release of cellular toxins, swelling, and loss of blood flow and vital oxygen to the damaged area.

A study just published in the journal Nature Medicine by a group in Canada reports that after SCI, blood flow is clamped shut along the entire length of the spinal cord.

This is news: Contrary to what most of us always assumed, capillaries remain closed chronically. Experimental animals with SCI had restricted blood flow at the injury site and below, long after injury.

This is the upside: Restoring oxygen to neuronal networks in the spinal cord induces repair and recovery.

According to a press release from the University of Alberta, where the study was done, this discovery will “fundamentally alter how we view spinal cord function and rehabilitation after spinal cord injuries.”

Improving the blood flow and increasing the oxygen in the spinal cord has not been a major focus of rehab, but it should be. The research team said that even by simply inhaling more oxygen one might improve motor function.

“We’ve shown for the first time that spinal cord injuries lead to a chronic state of poor blood flow and lack of oxygen to neuronal networks in the spinal cord,” says co-principal investigator Karim Fouad, professor of Rehabilitation Medicine and Canada Research Chair for spinal cord injury. “By elevating oxygen in the spinal cord we can improve function and re-establish activity in different parts of the body.”

This discovery happened by accident. The lead author Celia Li, a post-doc, and David Bennett, co-PI, were looking at injured rat spinal cords under a microscope and noticed the tiny capillaries contracted in response to application of the dietary amino acid tryptophan.

“Why would capillaries contract, when conventionally arteries are the main contractile vessels, and why should dietary amino acids circulating in the blood cause these contractions,” wondered Bennett. “That is just plain weird, that what you eat should influence blood flow in the spinal cord.”

Li, Bennett and Fouad found that SCI caused a particular enzyme (AADC, or aromatic l-amino acid decarboxylase) to be overproduced (upregulated, in science terms) in cells called pericytes. Unexpectedly, the the pericytes, which wrap the tiny capillaries in the circulatory system and act as a sort of valve, respond to AADC by releasing their own chemical signals (trace amines, synthesized from dietary amino acids), which activate the clamping down on the capillaries.

Here’s the scientific version, from the abstract:

We find that, months after the imposition of SCI, the spinal cord below the site of injury is in a chronic state of hypoxia owing to paradoxical excess activity of monoamine receptors (5-HT1) on pericytes, despite the absence of monoamines. This monoamine-receptor activity causes pericytes to locally constrict capillaries, which reduces blood flow to ischemic levels. Receptor activation in the absence of monoamines results from the production of trace amines (such as tryptamine) by pericytes that ectopically express the enzyme aromatic L-amino acid decarboxylase (AADC), which synthesizes trace amines directly from dietary amino acids (such as tryptophan). Inhibition of monoamine receptors or of AADC, or even an increase in inhaled oxygen, produces substantial relief from hypoxia and improves motoneuron and locomotor function after SCI.

How about blocking receptor activity related to AADC? Maybe that would unclamp the capillaries. “We blocked the AADC enzyme and found that it improved blood flow and oxygenation to the networks below the injury,” Bennett said. “This allowed the animals to produce more muscle activity.”

The scientists also exposed the animals to higher oxygen levels. “The rat could walk better,” Fouad says. “The change in oxygen restored function.” When oxygen levels returned to baseline the effect went away, indicating that the capillaries were still clamped down.

Fouad thinks the blood flow story ought to make an impact in neuroscience and rehabilitation but he’s not suggesting a therapy is right around the corner. “The biggest finding is really that we found that blood vessels, these capillaries, are controlled by cells that nobody really knew anything about. Just that knowledge opens so many windows, so many opportunities for treatments of various diseases and injuries of the brain and spinal cord.”

“There is still a long way to go when it comes to treatment and helping patients with spinal cord injuries,” said Fouad. “But this discovery has helped us understand the etiology of spinal cord injuries in a way we never did before. We can now design treatments that improve blood flow to produce long-term rehabilitation after SCI.

“Possibly even simple therapies such as exercise or just breathing will play a role in preventing long-term hypoxia and damage to the spinal cord. It’s a small but important step in the right direction, stemming from studying an obscure enzyme in the spinal cord -- and that’s the beauty of basic science.”

Next steps: to show this principle is the same in humans. Then the work will begin to perhaps find a clinically relevant way to inhibit the enzyme activity that shuts off blood flow.

Fouad: Consortium Schooled

Fouad began his interest in brain and spinal cord function studying how the nervous system controls motor output mechanisms in insects. Wanting his work to have more relevance to vertebrates, he began studying plasticity – the adaptive remodeling of nerve wiring after damage. He traveled to Zurich to present his work on neuroplasticity. Martin Schwab, the well-known spinal cord injury scientist, was in the audience.

“With a little luck,” said Fouad, “Martin heard my talk. He and I wondered whether the adaptive processes we saw in our animal models might apply in the spinal cord. Would we see similar adaptation?” Schwab offered Fouad a post-doc position, where he stayed on for four years. Schwab was then (and remains today) a principal investigator for the seven-lab Reeve International Consortium on Spinal Cord Research. Post-docs from each lab become Consortium Associates, and conduct much of the collaborative studies between the labs.

The collaborative Consortium model helped launch his career, Fouad said. “When I became independent (University of Alberta) one of my biggest experiments continued work that began with the Consortium,” said Fouad. “I was able to bring in people from the Mary Bunge lab (Miami Project), from Schwab’s group (Zurich) and others. We did a combination treatment in animals.”

That 2005 study is described by its title: “Combining Schwann cell bridges and olfactory-ensheathing glia grafts with chondroitinase promotes locomotor recovery after complete transection of the spinal cord.” This three-part strategy reduced effect of spinal cord scarring, provided a substrate to support nerve growth, and enabled regenerated nerve axons to exit the injury are and reenter the spinal cord. The combination provided “significant benefit” to treated animals.

Fouad sees SCI research evolving from a competitive environment toward a more collaborative way of working. “We as a field see SCI more comprehensively now. For a long time we were way too narrow in our thinking, looking at one molecule or one axon regeneration strategy to cure SCI. We came to our senses and realized that the word ‘cure’ is probably not appropriate. It’s going to be more like rebuilding. We have to look at the entire picture, and understand that everything seems to be linked.”