How COVID-19 Hijacks Our Neural Pathways and the Medications That Might Help
When COVID-19 emerged, it was initially characterized as a severe respiratory illness. But as case numbers grew, neurologists noticed something disturbing: patients were reporting loss of smell and taste, headaches, confusion, and even strokes. These neurological manifestations weren't just rare occurrences—one study found they affected approximately 36% of patients 1 .
of COVID-19 patients experience neurological symptoms
higher stroke risk in severe COVID-19 cases
pathways for brain invasion identified
This revelation led scientists on a hunt to understand how a respiratory virus could cause such significant neurological damage. Their investigation uncovered a complex relationship between the virus and a crucial regulatory system in our bodies—the renin-angiotensin system (RAS)—with particular focus on a group of commonly prescribed blood pressure medications known as angiotensin receptor blockers (ARBs).
The "pressure pathway" - constricts blood vessels, increases blood pressure, promotes inflammation
The "protective pathway" - dilates blood vessels, reduces inflammation, provides antioxidant effects
The SARS-CoV-2 virus enters human cells by binding to angiotensin-converting enzyme 2 (ACE2), a crucial component of the protective pathway 6 . Think of ACE2 as a dedicated docking station that the virus cleverly exploits. When the virus binds to ACE2, the complex gets internalized by the cell, effectively reducing surface ACE2 availability 6 .
SARS-CoV-2 spike protein binds to ACE2 receptors on cell surfaces
Virus-ACE2 complex is internalized, reducing available ACE2
Reduced ACE2 disrupts the RAS balance, favoring the damaging classical pathway
Increased inflammation, blood vessel dysfunction, and potential organ damage
The virus may infect olfactory nerve terminals in the nasal cavity, explaining the frequent loss of smell reported by patients, potentially using this as a direct pathway to the brain 1 .
SARS-CoV-2 may infect the endothelial cells that form the blood-brain barrier, compromising this protective shield and gaining access to the brain tissue 2 .
Some evidence suggests the virus may travel from lung chemoreceptors directly to the brainstem through neural connections, potentially explaining why some patients experience respiratory failure that may have a central nervous system component 1 .
The virus may cross the blood-brain barrier through infected immune cells (the "Trojan horse" mechanism) or by directly infecting endothelial cells.
The neurological effects of COVID-19 range from mild to severe:
Studies indicate that cerebrovascular diseases are significantly more frequent in patients with severe COVID-19, with one report noting a threefold increase in prevalence among severe cases 1 . This suggests that the virus's impact on the cerebral vasculature represents a major contributor to COVID-19 severity.
A particularly illuminating 2025 study systematically investigated how SARS-CoV-2 affects the blood-brain barrier (BBB) using human brain microvascular endothelial cells (HBMECs) as a model system 2 .
Since normal brain endothelial cells express relatively low levels of ACE2, researchers first had to genetically modify HBMECs to express higher levels of human ACE2, creating HBMEC-ACE2 cells that could be effectively infected 2 . This approach mirrored what might happen in individuals with certain risk factors that could potentially increase ACE2 expression in the brain.
| Parameter Measured | Finding | Significance |
|---|---|---|
| Viral replication | Confirmed in ACE2-expressing cells | Demonstrates BBB cells can support viral growth |
| Barrier permeability | Significantly increased | Suggests mechanism for brain invasion |
| Leukocyte migration | Enhanced across infected barrier | May explain neuroinflammation |
| ACE2 function | Impaired in regulating KKS | Reveals novel mechanism of damage |
| DABK/B1R signaling | Amplified | Contributes to barrier disruption |
This research provided crucial evidence that SARS-CoV-2 can directly infect brain endothelial cells, compromise blood-brain barrier integrity, and disrupt critical regulatory systems—offering a plausible explanation for how the virus causes neurological damage and may contribute to long COVID symptoms 2 .
Understanding the complex relationship between COVID-19, ARBs, and the brain requires sophisticated research approaches:
Early in the pandemic, a theoretical concern emerged: since ARBs (like losartan, valsartan, and telmisartan) and ACE inhibitors are known to modulate the renin-angiotensin system, could they potentially increase ACE2 expression and thereby facilitate viral infection? This led to uncertainty about whether patients should continue these medications 6 .
Fortunately, subsequent research largely alleviated these concerns. Multiple studies found that not only were these medications not harmful, but they might actually provide protective benefits for COVID-19 patients 6 .
Angiotensin receptor blockers work by selectively blocking the AT1 receptors that the damaging angiotensin II molecule activates. In the context of COVID-19, this mechanism may provide several advantages:
By blocking AT1 receptors, ARBs prevent the pro-inflammatory effects of excessive angiotensin II, which is particularly important when ACE2 is downregulated by viral binding 1 .
ARBs have been shown to protect cerebral blood flow and blood-brain barrier function, potentially counteracting the barrier disruption caused by SARS-CoV-2 infection 1 .
The excessive immune response known as a "cytokine storm" contributes significantly to COVID-19 severity. ARBs may help moderate this response through their anti-inflammatory properties 1 .
Preclinical research indicates that ARBs can protect mitochondrial function, reduce oxidative stress, and support overall cellular health in the brain 1 .
| Mechanism | Effect | Relevance to COVID-19 |
|---|---|---|
| AT1 receptor blockade | Reduces angiotensin II-mediated inflammation | Counters inflammation from ACE2 downregulation |
| Blood-brain barrier protection | Maintains cerebral endothelial integrity | May limit viral entry to brain |
| Cerebral blood flow regulation | Improves perfusion | Counters ischemic stroke risk |
| Mitochondrial protection | Supports energy metabolism | Maintains neuronal health |
| Coagulation normalization | Reduces hypercoagulability | Lowers stroke risk |
A comprehensive meta-analysis that included 24,676 COVID-19 patients found that using ACE inhibitors or ARBs was not associated with a higher risk of severe illness or in-hospital death. On the contrary, the analysis suggested an overall protective effect of these medications 6 .
| Outcome Measure | ARB Group (n=6,903) | ACEi Group (n=710) | Significance |
|---|---|---|---|
| Crude in-hospital mortality | 5% | 8% | Odds ratio: 0.65 |
| Invasive mechanical ventilation | 5% | 8% | Odds ratio: 0.59 |
| Acute respiratory distress syndrome | Lower incidence | Higher incidence | Significant in crude analysis |
| Hospital stay duration | Shorter | Longer | Statistically significant |
| Acute ischemic heart events | Lower incidence | Higher incidence | Significant in propensity analysis |
A 2023 Japanese study comparing 6,903 patients on ARBs with 710 patients on ACE inhibitors found that the ARB group had lower crude in-hospital mortality (5% vs. 8%) and lower rates of invasive mechanical ventilation 7 .
While some differences diminished after statistical adjustment, the ARB group consistently showed a shorter hospital stay, suggesting potential benefits in recovery speed 7 .
The journey to understand the relationship between COVID-19, angiotensin receptor blockers, and the brain has revealed unexpected connections between a common class of medications and protection against neurological damage from viral infection.
While ARBs are not a magic bullet against COVID-19, the research suggests that these medications may provide valuable protective effects for the brain during infection, particularly for patients with pre-existing hypertension or other cardiovascular risk factors. The evidence indicates that patients on ARBs should continue their medication during COVID-19 infection, as discontinuing could potentially remove important protective mechanisms.
Perhaps most importantly, this research has opened new avenues for understanding how we might protect the brain not just from SARS-CoV-2, but potentially from other viruses that target the nervous system. The careful balance of our renin-angiotensin system appears to be far more important to brain health than previously recognized.
As we continue to navigate the aftermath of the pandemic, with many patients experiencing long COVID neurological symptoms, understanding these mechanisms becomes increasingly crucial. The silver lining may be that this difficult period has accelerated our understanding of the intricate connections between viral infections, brain health, and commonly used medications—knowledge that will undoubtedly serve us well in facing future health challenges.