About one-third of COVID-19 patients experience neurological symptoms, which can include loss of taste and smell, headache, memory loss, delirium, and brain inflammation. These symptoms are likely due to the effects of the causative virus, SARS-CoV-2, on the central nervous system (CNS), including the virus’s ability to alter the function of the blood-brain barrier, which acts as a gatekeeper, keeping harmful substances from reaching the brain.
The impact of SARS-CoV-2 on blood-brain barrier function is similar to that of cocaine and other psychostimulant drugs, a commonality that has raised questions about whether the virus, in the presence of psychostimulants, inflicts even greater CNS damage and whether the two share a similar molecular mechanism. Now, equipped with a new grant from the National Institute on Drug Abuse (NIDA) of the National Institutes of Health, researchers at the Lewis Katz School of Medicine at Temple University have an unprecedented opportunity to explore these questions. The NIDA grant is expected to provide up to $2.5 million over five years. The researchers will focus in particular on mechanisms underlying the effect of SARS-CoV-2 on the blood-brain barrier and potential interactions between the virus and cocaine.
“People with substance use disorders are highly susceptible to infection with SARS-CoV-2 and frequently have more neurological symptoms,” said Ellen Unterwald, PhD, Chair and Professor of the Department of Neural Sciences and Director and Professor of the Center for Substance Abuse Research at the Lewis Katz School of Medicine and co-principal investigator on the new NIDA grant.
Other investigators on the grant include Gabriela C. Brailoiu, MD, Professor of Pharmaceutical Sciences at Thomas Jefferson University and co-leader of the new study; Eugen Brailoiu, MD, Adjunct Associate Professor at the Center for Substance Abuse Research at the Katz School of Medicine; and Wenzhe Ho, MD, MPH, Professor of Pathology and Laboratory Medicine at the Lewis Katz School of Medicine.
“We suspect that even just occasional use of cocaine may alter the blood-brain barrier in ways that exacerbate the effects of SARS-CoV-2 infection,” Dr. Unterwald explained.
That idea is based in part on the team’s research in rats, in which a miniature microscope inserted into the brain allowed for direct, real-time observation of cellular changes. Those studies showed that, independently, within minutes of entering the body, cocaine and SARS-CoV-2 significantly increase the permeability of the blood-brain barrier. The findings of that work suggest that the presence of the virus and cocaine together, in the body at the same time, could potentially magnify damage to the blood-brain barrier and CNS function.
With the new funding, Drs. Unterwald, Brailoiu, and Brailoiu can now investigate mechanisms of SARS-CoV-2 signaling in the CNS microvasculature of the blood-brain barrier in order to better understand exactly how the virus alters the barrier’s permeability. They are especially interested in the virus’s spike protein, which is essential for the virus to gain entry into the CNS. The spike protein may also have a common intracellular point of interaction with cocaine, namely the Sigma-1 receptor, which is expressed by cells comprising the blood-brain barrier vasculature. The Sigma-1 receptor regulates vital intracellular processes, including calcium signaling and reactive oxygen species homeostasis.
The results of the work will fill a critical gap in what is known about mechanisms by which SARS-CoV-2 disrupts blood-brain barrier function and how the virus interacts with cocaine at this level. “Our findings are likely to have implications for the identification of new therapeutic approaches for COVID-19 in individuals who use cocaine,” Dr. Unterwald added.
Research described herein is supported by the National Institute on Drug Abuse of the National Institutes of Health, under Award Number R01DA054921. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.