#CMSC2018 — Inhibiting Oxidative Stress Enzyme Promotes Resealing of Blood-Brain Barrier in MS Mouse Model

Inhibiting an oxidative stress enzyme called myeloperoxidase protects the blood-brain barrier in a mouse model of multiple sclerosis (MS), limiting the migration of immune cells and halting their attack on nerve cells, researchers have found.

Disruption of the blood-brain barrier is a hallmark of various disorders, including MS, and when damaged, it can no longer prevent immune cells and large molecules from entering the central nervous system, which may trigger inflammation and damage to neurons. There is no approved MS therapy that specifically targets this protective shield.

Results of the research were recently shared in a presentation, titled “Myeloperoxidase as a Therapeutic Target in Multiple Sclerosis,” delivered by Bonnie N. Dittel, PhD, from the Blood Research Institute in Wisconsin, at the 2018 Consortium of Multiple Sclerosis Centers Annual Meeting in Nashville, Tennessee.

Myeloid cells are a type of immune cell that release reactive oxygen species, which can promote nerve cell damage and degeneration of the myelin sheath when released uncontrollably, a condition known as oxidative stress.

Myeloperoxidase is one of the most potent oxidative-promoting enzymes that myeloid cells release in response to an injury or threat leading to inflammation. Previous studies detected the presence of myeloperoxidase in and around MS lesions. Previous data also showed that myeloperoxidase promotes blood-brain barrier dysfunction.

Researchers hypothesized that inhibiting the enzyme could have positive effects, and for that, they developed a myeloperoxidase inhibitor called KYC (N-acetyl lysyltyrosylcysteine amide).

Previous results showed that a mouse model for human MS, the experimental autoimmune encephalomyelitis (EAE) model, treated with KYC had a decrease in disease scores compared with control mice, who were treated with an innocuous solution.

Moreover, treatment with KYC not only reduced the levels of myeloperoxidase in the central nervous system but also the number of infiltrating immune cells, such as macrophages and neutrophils.

In her presentation, Dittel shared new results showing how treatment with KYC impacts the blood-brain barrier.

She showed that KYC is a potent and specific inhibitor of myeloperoxidase, and that it can lead to a reduction in myeloid cells within the central nervous system in mice, ultimately contributing to recovery from EAE.

Notably, the administration of KYC in EAE mice resulted in a resealing of the blood-brain barrier.

Based on the results, Dittel concluded that “KYC inhibition of MPO [myeloperoxidase] should be a safe therapeutic for the treatment of MS.”