Background:
Inflammation and neurodegeneration are two characteristics of multiple sclerosis (MS). These responses cause damage to the nerve cells in the brain, preventing the cells from communicating with one another and leading to the varying symptoms seen in individuals with MS. One process that causes neurodegeneration is called oxidative stress. Used by many researchers as a biomarker of MS and disease progression, oxidative stress can damage mitochondria (the powerhouses of all cells within our body) and ultimately cause our nerve cells to degenerate. TEMPOL is a molecule that has antioxidant properties and has been shown to protect cells against oxidative stress in studies of other diseases such as hypertension, diabetes, spinal cord injury, etc.
In a new study published in Brain, Behaviour and Immunity, Dr. Jacqueline Quandt (University of British Columbia) – who was a recipient of an Operating Grant and Dr. Donald Paty Career Development Award from the MS Society - and her research team set out to explore whether TEMPOL can be reduce disease onset and severity in animals with MS-like disease called experimental autoimmune encephalomyelitis.
The Study:
Dr. Quandt’s team identified the need for oral therapeutics that would affect inflammation as well as neurodegeneration. To address this need, her team administered TEMPOL orally to mice for 2 weeks before undergoing a procedure to induce MS-like disease and compared them to control mice that were not given TEMPOL. The goal of this first experiment was to determine if TEMPOL reduced the onset of MS-like symptoms.
The goal of the second experiment was to find out if there were any changes in the progression of the disease. To accomplish this goal, the researchers gave a separate group of mice TEMPOL orally 7 days after the onset of MS-like disease.
In both experiments, the group used two different mouse models that mimicked MS-like symptoms. The outcome measures from these experiments were to measure disease severity and inflammation. Disease severity was measured using clinical signs of MS-like disease ranging from no disease (given a score of 0) to no mobility (given a score of 5). Inflammation, on the other hand, was evaluated as the number of newly invaded harmful immune cells into the spinal cord.
Results:
Mice that were given TEMPOL for two weeks before being induced to have MS-like disease showed delayed onset and reduced magnitude of symptoms. TEMPOL fed mice had lower disease severity, receiving an average score of 1 meaning that the only symptom seen was a limp tail. Comparatively, control mice not on the TEMPOL diet were given an average score ranging from 2-3, meaning they had mild to severe muscle weakness in their hind paws. Additionally, TEMPOL also reduced the level of inflammation that was seen in mice where close to 40% of mice did not have any harmful immune cells in the spinal cord. Dr. Quandt’s research group went on to show that instead of suppressing the immune system as is the mechanism of action of many disease modifying therapies (DMTs), TEMPOL changes the immune system’s activity, thereby protecting cells in the nervous system and reducing symptoms of MS-like disease.
In their second experiment, in which the research team was testing if TEMPOL changed the progression of MS-like disease, they found similar results: (1) reduced disease severity, and; (2) fewer harmful immune cells in the spinal cord.
Comment:
Overall, the study provides evidence that TEMPOL reduces the onset and severity of disease and inflammation in animals of MS-like disease. One key benefit of TEMPOL is that it can alter immune system responses without suppressing cells. Another important aspect of this study is that TEMPOL can be administered orally and meets the need to establish more DMTs that well tolerated, effective and with reduced risk profiles. In an interview for Centre for Brain Health, Dr. Quandt reiterated that these results, while in their early stages, are promising as TEMPOL modifies the way that harmful immune cells work without eliminating them entirely.
More studies are still needed to further explore the benefits of TEMPOL in animals with MS-like disease and answer questions such as: How does TEMPOL work and what molecules does it target? Is it safe? Does it have the potential to be translated into a drug? These basic biomedical studies are the essential first steps to determine if TEMPOL has the potential to be a safe and effective therapy for people living with MS.
Source:
Neil et al. (2017) Oral administration of the nitroxide radical TEMPOL exhibits immunomodulatory and therapeutic properties in multiple sclerosis models Brain Behav Immun. [Epub ahead of print].