Alteration of the blood-brain barrier by COVID-19 and its implication in the permeation of drugs into the brain

Abstract

Diverse neurological symptoms have been reported in patients with SARS-CoV-2 disease (COVID-19), including stroke, ataxia, meningitis, encephalitis, and cognitive impairment. These alterations can cause serious sequelae or death and are associated with the entry of SARS-CoV-2 into the Central Nervous System (CNS). This mini-review discusses the main proposed mechanisms by which SARS-CoV-2 interacts with the blood-brain barrier (BBB) and its involvement in the passage of drugs into the CNS. We performed a search in PubMed with the terms “COVID-19” or “SARS-CoV-2” and “blood-brain barrier injury” or “brain injury” from the year 2019 to 2022. We found proposed evidence that SARS-CoV-2 infects neurovascular cells and increases BBB permeability by increasing the expression of matrix metalloproteinase-9 that degrades type IV collagen in the basement membrane and through activating RhoA, which induces restructuring of the cytoskeleton and alters the integrity of the barrier. The breakdown of the BBB triggers a severe inflammatory response, causing the cytokine storm (release of IL-1β, IL-6, TNF-α, etc.) characteristic of the severe phase of COVID-19, which includes the recruitment of macrophages and lymphocytes and the activation of astrocytes and microglia. We conclude that the increased permeability of the BBB would allow the passage of drugs that would not reach the brain in a normal physiological state, thus enhancing certain drugs’ beneficial or adverse effects. We hope this article will encourage research on the impact of drugs on patients with COVID-19 and recovered patients with sequelae, focusing mainly on possible dose adjustments and changes in pharmacokinetic parameters.

Neurofilament light chain on intensive care admission is an independent predictor of mortality in COVID-19: a prospective multicenter study

“…Sepsis may induce disruption of the blood–brain barrier (BBB) and may also cause cerebral hypoperfusion [ 5 ]. Similar mechanisms have been proposed in COVID-19 [ 6 , 7 ]. SARS-CoV-2 infection has been associated with neurological complications [ 8 ], and the severity of COVID-19 seems to be an important determinant [ 9 ].…”

Microgliosis, astrogliosis and loss of aquaporin-4 polarity in frontal cortex of COVID-19 patients

“…Several studies reported signs of neuroinflammation in tissue from COVID-19 patients (reviewed by (Almutairi et al, 2021; Brown et al, 2023; Gonçalves de Andrade et al, 2021; Hernández-Parra et al, 2023; Iadecola et al, 2020; Natale, Lukens, & Petri, 2022; Tremblay et al, 2020; Vanderheiden & Klein, 2022; A. C. Yang et al, 2021)). SARS-CoV-2 not only infects the respiratory tract but also other organs, including the brain and its cerebrovasculature (Y.…”

“…Among the cytokines are interleukin 2R, interleukin 6, interleukin 8, tumor necrosis factor (TNF, also known as TNF-alpha) and, interestingly, also the anti-inflammatory interleukin-10 (Devlin & Gombolay, 2023; Liu et al, 2020). Macrophages and lymphocytes penetrate the blood-brain barrier, activate microglial cells and astrocytes and finally determine neuroinflammation (Almutairi et al, 2021; Brown et al, 2023; Gonçalves de Andrade et al, 2021; Hernández-Parra et al, 2023; Iadecola et al, 2020; Tremblay et al, 2020; Vanderheiden & Klein, 2022). In our study, both microglial cells and astrocytes showed an activated phenotype in COVID-19 patients, confirming neuroinflammation.…”

Neutrophil extracellular traps and long COVID

“…However, in scenarios where the BBB is compromised, neutrophils infiltrate and NETs are often visualized in brain tissue where they contribute towards ongoing neuroinflammation ( 260 , 261 ). Recent studies proposed that COVID-19 facilitates BBB disruption by increasing the expression of matrix metalloproteinase-9 (MMP-9) which leads to basement membrane degradation ( 262 , 263 ). The levels of NETs in the brain have been directly related to the degree of neuroinflammation in model organisms of Alzheimer’s disease, meningitis, ischemic stroke, and traumatic brain injury ( 264 ).…”