Increasing blood flow in the spinal cord by injecting a long-acting vasodilator can help prevent the progression of amyotrophic lateral sclerosis (ALS) in mice, a study shows.
The study, “Single injection of sustained-release prostacyclin analog ONO-1301-MS ameliorates hypoxic toxicity in the murine model of amyotrophic lateral sclerosis,” was published at the journal Scientific Reports.
Hypoxia (low oxygen level) has been found to contribute to the development and progression of several human diseases, including cancer and neurodegenerative disorders.
Studies have shown that in both ALS patients and mice with the disease, hypoxia signals are increased compared to healthy controls. Moreover, the blood-spinal cord barrier, which is composed of blood vessels and controls oxygen and nutrient supplies to the central nervous system, often is damaged in ALS.
These findings suggest that impaired oxygen supply to motor nerve cells of the spinal cord may have a role in ALS progression.
Researchers from Osaka University in Japan evaluated levels of the well-known biomarker of hypoxia, HIF-1alpha, in the spinal cord of ALS patients and genetically engineered mice carrying the mutated SOD1 gene, which is linked to familial ALS.
In accordance with previous data, the team found that in spinal cord samples taken from both patients and mice, the levels of HIF-1alpha were increased significantly compared to healthy controls. This finding further suggests that nerves cells in the spinal cord of ALS patients are in an environment with low oxygen levels.
Based on these results, researchers decided to explore the potential of an experimental vasodilator compound, ONO-1301-MS, to reverse this hypoxic effect.
ONO-1301 is a synthetic prostacyclin agonist that was designed to have a strong and longer-lasting blood vessel dilation effect compared to other similar available compounds. In previous studies, it decreased vascular tone and increased blood flow, improving the neurological function in rats with cerebral infarction (brain tissue dying due to lack of oxygen).
The team administrated a single subcutaneous (under-the-skin) injection of ONO-1301-MS, a sustained-release form of ONO-1301, in mice with mutated SOD1. These mice showed significantly improved motor function and increased body weight compared to placebo-treated mice.
Further analysis of mice’s spinal cord showed that those treated with ONO-1301-MS had significantly more live motor nerve cells. However, the treatment had no effect on inflammatory markers or mice survival rate, most likely due to ONO-1301-MS’ inability to fully alleviate the hypoxic stress induced by ALS.
A new analysis of HIF-1alpha levels confirmed that treatment with ONO-1301-MS reduced hypoxia in the spinal cord of mice with ALS.
Moreover, it could increase by approximately 2.5-fold the levels of brain-derived neurotrophic factor (BDNF), which is an important mediator of nerve cells’ survival, compared to placebo.
The team also found that the levels of mitochondria ATP (the energy source of cells) in the spinal cord of mice were partially restored upon treatment with ONO-1301-MS. This suggests that the treatment improved ATP production and blood supply in the spinal cord of mice with ALS.
Supported by these results, the team concluded that “increasing blood flow in hypoxic regions of the spinal cord might play an important role in protecting against neurodegeneration.”
Additional studies are warranted to clarify the potential role of hypoxia in ALS. Still, “a treatment modality that inhibits hypoxia holds great therapeutic promise for treating ALS patients,” they wrote.