Rheumatoid arthritis (RA) is an autoimmune condition that results in significant joint inflammation and leaves patients in excruciating pain. But did you know that neuropsychiatric side effects like depression and cognitive decline are frequently present along with the disease? According to prior research, up to 70% of RA patients may experience these cognitive disorders. The neuroinflammation that results from systemic inflammation is thought to be the cause of these neurological symptoms. The precise mechanisms underlying this cognitive impairment in RA are still unknown.
In the past, a group under the direction of Director C. Justin Lee at the Institute for Basic Science (IBS) in Daejeon, South Korea, examined the hippocampus of dementia patients to learn more about the general mechanism underlying memory impairment. The team found that reactive astrocytes release more MAO-B-dependent gamma-aminobutyric acid (GABA), which causes neurological problems.
In cells of several organs, such as the brain and the immune system, MAOs, which include MAO-A and MAO-B, are enzymes that catalyze the oxidation of monoamines and are bound to the outer mitochondrial membrane. Prior studies suggested that MAO inhibitors could help rheumatoid arthritis patients with pain and stiffness more than 30 years ago. But these results haven’t been followed up on, and there hasn’t been much more research on the role of MAO in RA even today.
Director Lee’s team recently discovered that fibroblast-like synoviocyte cells (FLSs), which were isolated from joint tissues of rheumatoid arthritis patients, exhibit aberrant MAO-B expression as a result of the inflammatory compound interleukin-1 (IL-1), which is responsible for RA. It was found that these cells express MAO-B and GABA in an abnormal manner.
According to the research team’s findings, the expression of MAO-B and MAO-B products, like GABA and H2O2, can aggravate joint inflammation by increasing the expression of proinflammatory factors. Also, the tissue from people with rheumatoid arthritis had much higher levels of MAO-B and GABA than the tissue from people with osteoarthritis (OA), which usually has lower levels of inflammation.
It’s noteworthy that the researcher found that the rheumatoid arthritis animal model displayed worsening cognitive impairment. Normal, healthy mice had no trouble remembering a new object or location in routine behavioral experiments. On the other hand, it was shown that RA model mice couldn’t recognize new objects and things, which is a sign of a disorder called cognitive impairment.
Similar to the joint tissues, the hippocampus also showed aberrantly increased astrocytic MAO-B-dependent GABA secretion, which is thought to be the primary contributor to this cognitive dysfunction. It is well known that GABA, which is mediated by hippocampal astrocytic MAO-B, inhibits neurons, impairing memory and cognition. Since inflammation affects astrocytes, it was thought that as the rheumatoid arthritis disease got worse, astrocytes would also be affected, which would lead to a loss of brain power.
According to the first author, Dr. WON Woojin, “The cause and course of cognitive impairment have not been well understood up to this point because research on rheumatoid arthritis has only addressed the mechanism of inflammation. We were able to identify the cause of cognitive impairment using a novel method involving astrocytes and MAO-B. ”
The IBS scientists then made the decision to give the rheumatoid arthritis animal model an MAO-B inhibitor called “KSD2010.” Phase 1 clinical trials for the newly created selective and reversible MAO-B inhibitor KDS2010 are currently underway. When given to mice, it was found that the joint inflammation subsided and cognitive function improved simultaneously.
When considered as a whole, this research showed that in rheumatoid arthritis patients, aberrant MAO-B expression serves as the common underlying mechanism for both joint inflammation and cognitive impairment. This makes it possible to treat both of these symptoms with a single medication.
It was first proposed that reactive astrocytes brought on by chronic inflammation cause cognitive impairment in rheumatoid arthritis . “Director C. Justin LEE, who oversaw this project, explains that KDS2010, a newly created and enhanced MAO-B inhibitor, is anticipated to be a successful rheumatoid arthritis treatment of the future.”
