Our brains depend on a steady oxygen supply, and problems can arise when cells cannot properly use the oxygen reaching them.
Scientists investigating what happens when that balance breaks down have tested an unexpected approach in mice with Parkinson’s-like symptoms: reducing oxygen delivery to their tissues.
Mice given an experimental drug combination became quicker at descending a pole and could hold onto a cage lid for longer. Treatment began after their movement problems had already appeared.
The researchers call their approach “hypoxia in a pill” because it recreates some effects of breathing low-oxygen air.
Parkinson’s damages brain cells that produce dopamine, a chemical that helps regulate movement. The disease also involves the buildup of a protein called alpha-synuclein.
Damage associated with this protein can disrupt the tiny energy-producing structures inside cells, called mitochondria. These structures use oxygen to help generate energy.
“Our current working hypothesis is that when there is mitochondrial dysfunction, oxygen is not being consumed properly, and this leads to an oxygen mismatch, i.e., oxygen delivery is greater than oxygen utilization,” Harvard Medical School physician-scientist Vamsi K. Mootha told ScienceAlert.
By reducing oxygen delivery, the team aims to limit that mismatch and the damage that comes with it.
In a 2025 study, the researchers showed that mice with Parkinson’s-like symptoms benefited from continuously breathing air with 11 percent oxygen. Ordinary air contains about 21 percent. In the new study, they tested whether drugs could achieve similar effects.
Hong Wang and colleagues used two compounds that complement each other. The first, GBT601, makes the blood release less of its oxygen into tissues. Because the body can compensate by producing more oxygen-carrying red blood cells, the second compound, PT2399, limits that response.
For the experiment, the scientists injected alpha-synuclein fibrils into the mice’s brains to trigger protein buildup and movement difficulties. Six weeks later, once movement problems had developed, they began giving the drugs orally each day.
Over the following six weeks, treated animals improved in the pole and cage-hang tests, while mice given only the injection of liquid without the protein solution kept getting worse. The combination also reduced excess brain oxygen and lowered a marker of fat damage in brain tissue, but did not improve an anxiety-like behavior measure.
Mootha said improvements with either inhaled low oxygen or the drug approach can begin as early as one to two weeks after treatment starts.
Better movement does not show that nerve cells have been restored. Mootha explained that in the 2025 experiment, mice already had movement problems when delayed treatment began, but no nerve cell loss had been detected yet. The mice regained movement abilities and avoided subsequent nerve cell loss even though the buildup of alpha-synuclein remained unchanged.
The new study did not report dopamine neuron counts in the main paper, so it does not establish whether the combination protects those cells.
The team also tried the combination in two other disease models. In mice modeling Leigh syndrome, a rare disorder affecting cellular energy production, the combination extended median lifespan from 62 to 158 days. In a model of Friedreich’s ataxia, which affects movement and coordination, it stopped further deterioration without reversing existing difficulties.
After six weeks of treatment in control mice, the researchers found no increase in a heart measurement linked to pulmonary hypertension, a risk of prolonged low oxygen.
“Hypoxia can be dangerous, so an important challenge is being able to achieve hypoxia therapy that is safe and effective,” Mootha cautioned.
“All of our work to date is pre-clinical, in mouse models, and much more work is required before moving this concept into humans.”
The research has been published in PNAS.
This article was fact-checked by Rachel Garner and edited by Fiona MacDonald. While we pride ourselves on our process, we are only human. If you spot a mistake, please let us know.
