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U of S researchers Drs. Gillian Muir (left) and Valerie Verge. Photo by Debra Marshall for SHRF.

Low oxygen therapy has high potential for spinal cord patients

Expose patient to low oxygen levels intermittently for short time periods. Combine with rehabilitative training. Repeat. They’re simple instructions for treating people and animals with spinal cord injuries, but the results have proven to be breathtaking.

It’s called acute intermittent hypoxia (AIH) therapy, and based on research studies conducted at the University of Saskatchewan (U of S), scientists are excited about its promise as a therapy for partial spinal cord injuries.

AIH therapy involves repeated exposure to low oxygen (hypoxic) levels for brief periods. This action triggers a chain of events in the nerve cells or neurons as they react to the mild stress.

“The AIH alerts the cells that they’re under stress,” explains Dr. Valerie Verge, a professor of anatomy and cell biology at the U of S College of Medicine. “The cell adapts by turning on specific genes and creating specific proteins that help the cell to survive the stress. They induce a strengthening of the existing neuronal connections which is referred to as plasticity.”

As director of the Cameco MS Neuroscience Research Center, Verge has a keen interest in neurological research. She shares her passion with Dr. Gillian Muir, a professor at the Western College of Veterinary Medicine (WCVM) and the co-principal investigator in a recent study published in PLOS ONE, a multi-disciplinary journal.

While Verge’s focus is on the cellular level, Muir is an expert in behavioural recovery after injury. She has collaborated on studies with Dr. Gordon Mitchell, a noted neuroscientist at the University of Florida, and she has been involved in multiple studies monitoring the functional recovery that occurs when AIH therapy is combined with rehabilitative training in patients with spinal cord injuries.

With funding from the Saskatchewan Health Research Foundation, the Canadian Institutes of Health Research and the United States Department of Defense, the scientists combined their expertise in an investigation of AIH therapy. Other members of their research team included Atiq Hassan and Dr. Breanna Arnold, both graduate students, and research associates Drs. Sally Caine and Behzad Toosi.

“The focus of this recent study was to look at what was changing in the cells of these animals in response to both the hypoxia exposure and the rehabilitative training,” Muir explains. “We looked for hypoxia-associated proteins, evidence that the cells were responding to the low oxygen, and we also looked for proteins associated with the plasticity — the proteins involved in strengthening connections between neurons.”

The researchers studied two groups of laboratory rats with partial spinal cord injuries. While both groups received seven days of rehabilitative motor therapy, only one group received daily AIH treatments along with the motor therapy. Each AIH treatment consisted of 10 five-minute cycles where the animals breathed hypoxic air (11 per cent oxygen) alternating with normal air (21 per cent oxygen).

Each week the research team compared the abilities of both groups as they performed specific motor tasks that had been mastered before the injury, and then they compared the cells in the spinal cords of both groups of animals.

Results confirmed that AIH leads to increases in the amount of specific proteins within cells linked to hypoxia and plasticity. Researchers also observed notable improvement in the functional abilities of the group that received both AIH and rehabilitative therapy.

“We think that this combination of treatment is important because the AIH makes the cells more accessible to plasticity — that is, more amenable to making stronger connections with other neurons,” says Muir. “The rehabilitation training activates the correct neural pathways and ensures that the appropriate neural circuitry becomes stronger.”

Those outcomes are significant for human medicine. Clinical and pre-clinical trials in the U.S. have already demonstrated that people with spinal injuries who received AIH therapy combined with rehabilitative training showed an improved ability to walk further and for longer periods of time.

A significant finding of the current study was evidence that the proteins connected with plasticity were increased in areas of the spinal cord other than just the injury site — an indication that hypoxia triggers a reaction from neurons in other parts of the body, including the brain.

Since AIH treatments expose the whole body to hypoxia, it’s possible that the nerve cells of the peripheral nervous system and the brain are also reacting to the low-level stress by creating the proteins associated with plasticity.

“In spinal cord injuries, we tend to focus on those areas that we know are directly responsible for controlling the muscles involved in the behaviour we are studying, such as walking. But it is likely that many parts of the nervous system need to change in order for a person or an animal to improve the way they move, how they can perform a particular task,” says Muir. 

This particular study has prompted even more questions and research regarding AIH therapy and its possibilities for enhancing nervous system function and even repairing damaged cells.

It’s been proven that AIH stimulates intact nerve cells to express hypoxia- and plasticity-related proteins, so a subsequent study is now investigating whether damaged cells in the peripheral nervous system are able to produce those proteins and then repair themselves.

“Any information we find by looking in the periphery may help us learn how to repair the spinal cord and brain,” says Verge. “Although there are differences between the brain and the spinal cord and the peripheral nervous system, many of the key pathways are quite similar in what they do.”

Muir is conducting a study that examines the value of AIH therapy as a long-term treatment used over three months rather than just one week. The study is also investigating whether AIH therapy is effective with chronic injuries where there’s a longer time gap between the injury and the beginning of therapy.

Although cautious about giving false hope, both Verge and Muir are optimistic that AIH therapy will have a positive impact on a wide range of injuries and conditions that affect the nervous system.

“We’re not necessarily trying to fix what’s been damaged in the spinal cord injury models,” says Muir. “What we’re doing with AIH is enhancing the plastic capability of the cells and neural pathways that are undamaged, no matter what the injury, and then trying to sculpt or strengthen those existing connections so that we get recovery of function. That’s the ultimate goal.”

Reference: Hassan A, Arnold BM, Caine S, Toosi BM, Verge VMK, Muir GD. “Acute intermittent hypoxia and rehabilitative training following cervical spinal injury alters neuronal hypoxia- and plasticity-associated protein expression.” May 18, 2018. PLOS ONE. 13(5): e0197486.

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