Nitric Oxide May be the Key to Protecting the Blood-Brain Barrier

A new study published by a team of microbiologists from the Karolinska Institutet in Stockholm, Sweden has concluded that nitric oxide produced by inducible nitric oxide synthase (iNOS) in the brain may serve a vital role in protecting the “integrity of the blood-brain barrier (BBB)” following infection with African trypanosomiasis.

In the human brain, nitric oxide acts as a neurotransmitter and a vital part of the signaling pathways that operate between cerebral blood vessels, neurons, and glial cells. iNOS is expressed in macrophages and glial cells in response to pro-inflammatory cytokines (ie, IFN-γ or TNF) as a result of ischemia or trauma, and has been shown to play a role in increased permeability of the BBB and lesions in the nervous tissue. According to the authors, the Swedish study findings are notable because, historically, “a high concentration of nitric oxide has either been shown to protect against intracellular infections” (by killing microbes) or to “mediate damage to the host during infectious or inflammatory diseases.”

Conversely, study co-author Martin E Rottenberg, PhD, Professor, Microbiology Department, Tumor and Cell Biology, Karolinska Institute, told Contagion, “We show that nitric oxide is protective, surprisingly by inhibiting infection-induced neuroinflammation.”

The authors of the study, which was published online on February 25 by the journal PLOS Pathogens, infected six- to eight-week old mice models with African trypanosomiasis, a parasitic disease that, in humans, is characterized by fever, headache, and joint pain. This stimulated the production of nitrites and nitrosylated proteins in the plasma and brains of the subject mice.

“We focused on how the trypanosomes manage to get through the so-called BBB,” Dr. Rottenberg explained. “Invasion through the BBB in this model of infection is mediated by the host immune responses that are stimulated by the parasite. Such immune responses also stimulate the release of nitric oxide that maintains the restricted permeability of the BBB. The mechanism we propose is that nitric oxide hampers the production of molecules that mediate tissue invasion.”

Indeed, the researchers found that infected mice without iNOS (to produce nitric oxide) had elevated levels of parasites and host immune cells in the brain due to an increased permeability of the blood vessels in the BBB. Conversely, in normal mice, infection stimulated an increase in iNOS levels in macrophages, which led to the production of nitric oxide. According to Dr. Rottenberg, TNF mediates the increased permeability to proteins, leukocytes, and parasites in the brain of mice lacking iNOS and nitric oxide inhibited both TNF production by macrophages and its inflammatory function.

“We believe that this principle has the potential as a supplementary treatment in this and/or other neuroinflammatory diseases by compounds that generate high nitric oxide levels, if ways of proper delivery can be designed,” Dr. Rottenberg noted. “[However], this is not a clinical paper and we have not tested the effect of drugs that release nitric oxide, the regulation of nitric oxide release or the delivery of nitric oxide during other conditions of brain inflammation or invasion by microbes. Thus, we cannot predict the effects of these findings in clinical practice. On the other hand, in our view these findings justify testing of such substances in other clinically relevant experimental animal models of neuroinflammatory diseases. Intensified testing of ways to enhance nitric oxide bioavailability in the cerebral vessels to improve clinical outcome in diseases with an element of neuroinflammation is foreseen as a result of our study.”

Brian P. Dunleavy is a medical writer and editor based in New York. His work has appeared in numerous healthcare-related publications. He is the former editor of Infectious Disease Special Edition.