Brain Leukocytes as the Potential Therapeutic Target for Post-COVID-19 Brain Fog

Abstract

After recovering from the acute phase of coronavirus disease 2019 (COVID-19), many patients struggle with additional symptoms of long COVID during the chronic phase. Among them, the neuropsychiatric manifestations characterized by a short-term memory loss and inability to concentrate are called “brain fog”. Recent studies have revealed the involvement of “chronic neuro-inflammation” in the pathogenesis of brain fog following COVID-19 infection. In the COVID-related brain fog, similarly to neurodegenerative disorders caused by neuro-inflammation, brain leukocytes, such as microglia and lymphocytes, are hyperactivated, suggesting the overexpression of delayed rectifier K⁺-channels (Kv1.3) within the cells. In our previous patch-clamp studies, drugs, such as antihistamines, statins, nonsteroidal anti-inflammatory drugs, antibiotics and anti-hypertensive drugs, suppressed the Kv1.3-channel activity and reduced the production of pro-inflammatory cytokines. Additionally, newer generation antihistamines, antibiotics and corticosteroids strongly stabilize mast cells that directly activate microglia in the brain. Taking such pharmacological properties of these commonly used drugs into account, they may be useful in the treatment of COVID-related brain fog, in which the enhanced innate and adaptive immune responses are responsible for the pathogenesis.

Regardless of the severity of Coronavirus disease 2019 (COVID-19), a high proportion of patients struggle with “post-COVID-19 syndrome” or “long COVID”, a condition characterized by long-term health problems that persist after recovering from COVID-19 [1]. Long COVID potentially affects nearly every organ system, causing respiratory, cardiovascular, neurological symptoms and systemic manifestations including generalized fatigue, muscular weakness and sleep disorders [1]. Table 1 summarizes the symptoms, known mechanisms and rationalized treatment targets of acute and chronic phases of COVID-19 infection [1–4]. In long COVID, in addition to common neurological symptoms, such as headache, dizziness and numbness, some patients experience neuropsychiatric manifestations characterized by a short-term memory loss, inability to concentrate, depression and anxiety [5, 6]. These symptoms are called “brain fog”, indicating a cognitive impairment caused by neural circuit dysfunctions [5, 6]. Concerning the pathogenesis of the COVID-related brain fog, recent studies suggested the involvement of autoimmunity, viral neuro-invasion, oxidative stress, hypoxic neuronal injury or microvascular coagulopathies [7]. However, despite such findings, supportive management, such as cognitive behavioral therapy and the use of anti-depressants or herbal medications, is currently the mainstay of treatment for brain fog [6, 8, 9].

Table 1.

Summary of symptoms, mechanisms and treatment targets of acute and chronic phases of COVID-19

	Acute phase (first 4 weeks from infection)	Chronic phase (after 4 weeks)
Symptoms	• Nasopharyngeal (sore throat, runny nose) • Respiratory (cough, dyspnea) • Systemic (fever, headache, fatigue)	• Respiratory (persistent cough, dyspnea, hypoxia) • Cardiovascular (palpitation, chest pain) • Neurological (headache, dizziness, numbness) • Neuropsychiatric (short-term memory loss, inability to concentrate, depression, anxiety) • Systemic (fatigue, muscular weakness, insomnia)
Known mechanisms	• Viral attack • Inflammatory response • Cytokine storm	• Immune response • Chronic inflammation • Pulmonary fibrosis • Coagulopathy
Treatment targets	• Anti-viral medications • Immunomodulatory agents (cytokine inhibitors, immune globulin)	• Supportive management • Rehabilitation • Vaccination • Anti-coagulation

Recently, several studies have additionally revealed the involvement of “chronic neuro-inflammation” in the pathogenesis of COVID-related brain fog [5, 6, 10]. In patients with neuropsychiatric symptoms following COVID-19 infection, in addition to the elevation of serum C-reactive protein (CRP) levels [11], pro-inflammatory cytokines, such as interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) and interferon-α (IFN-α), were actually increased in both the peripheral blood and cerebrospinal fluid [12, 13]. Additionally, in the brain of these patients, microglia, the brain-resident macrophages that are stimulated by these cytokines [5, 6], were highly activated with the formation of microglial nodules [14, 15]. These nodules are the product of microglial phagocytosis of degenerating neurons that were attacked and killed by cytotoxic T-lymphocytes [16]. In patients with COVID-related brain fog, in addition to microglia, lymphocytes were also activated and actually increased in the brain [14, 15]. Therefore, the enhanced immune responses by these leukocytes were likely to be responsible for the pathogenesis of neuro-inflammation in COVID-related brain fog.

Brain leukocytes, such as microglia and T-lymphocytes, mainly express delayed rectifier K⁺-channels (Kv1.3) on their cell membranes [17, 18]. The channels play a pivotal role in the activation and the proliferation of the leukocytes themselves, which thus trigger the innate and adaptive immune responses [17, 18]. Previously, in our rat models with advanced-stage chronic kidney disease (CKD), we demonstrated that both macrophages and T-lymphocytes had distinctly proliferated, and pro-inflammatory cytokines, such as IL-2 and TNF-α, were significantly increased within the inflamed kidneys [17, 19]. In these macrophages and T-lymphocytes, the expression of Kv1.3-channels was up-regulated and the pharmacological inhibition of the channels significantly slowed the progression of renal fibrosis. From these results, the Kv1.3-channels were considered primarily to over-activate the immune responses, which subsequently facilitated the progression of CKD [17, 19]. Recently, besides CKD and other chronic diseases, such as chronic obstructive pulmonary disease and inflammatory bowel disease [17, 20], neurodegenerative disorders, such as Alzheimer’s disease, Parkinson’ s disease, multiple sclerosis and schizophrenia, are now also regarded as chronic inflammatory diseases [21, 22]. In these neuro-inflammatory diseases, macrophages and lymphocytes were actually over-activated or had proliferated within the brain, and the expression of Kv1.3-channels was up-regulated within the cells [21, 22].

In the management of COVID-related brain fog, first of all, it is important to rule out other causes of brain fog, such as strokes and seizures, which may warrant additional evaluation and medications. Additionally, in the treatment of COVID-related brain fog, a multi-disciplinary and individual approach should be required for each patient [8]. This includes the evaluation of (1) cognition, (2) neuroinflammation markers, (3) psychological factors and (4) sleep disorders. Recent clinical studies have revealed the therapeutic efficacies of antihistamines and anti-cholesterol drugs (statins) [6, 23, 24]. Despite the lack of pharmacological evidence, these agents actually ameliorated the neuropsychiatric symptoms together with a reduction in peripheral inflammatory markers [6, 24]. On the other hand, an in vitro study additionally demonstrated the efficacy of nonsteroidal anti-inflammatory drugs (NSAIDs) for neuro-inflammation, since these drugs directly reduced the activity of microglia [25]. In our patch-clamp studies using murine thymocytes, antihistamines (cetirizine, fexofenadine, azelastine, terfenadine), statins (pravastatin, lovastatin, simvastatin) and NSAIDs (indomethacin, diclofenac, salicylate) suppressed the activity of lymphocyte Kv1.3-channels and thus reduced the pro-inflammatory cytokine production [26–28]. These findings would further clarify the additional pharmacological mechanisms by which antihistamines, statins and NSAIDs are effective for COVID-related brain fog, where the enhanced immune responses are responsible for the pathogenesis (Fig. 1). In our following patch-clamp studies, we additionally demonstrated the inhibitory properties of antibiotics (clarithromycin, chloroquine) and anti-hypertensive drugs (nifedipine, benidipine, diltiazem, verapamil) on lymphocytes Kv1.3-channels [17, 29–31]. Taking such pharmacological properties of these commonly used drugs into account, they would also be beneficial in the treatment of COVID-related brain fog, since the channel blockade could suppress the activity of brain macrophages (microglia) and lymphocytes (Fig. 1).

Fig. 1.

Roles of mast cells and Kv1.3-channels in the activation pathway of brain leukocytes (microglia or lymphocytes) and as the targets of commonly used drugs for COVID-related brain fog. Kv1.3-channels promote calcium influx and trigger the proliferation and activation of brain macrophages (microglia) or lymphocytes. The increased cytosolic calcium concentration stimulates the phosphatase calcineurin, which de-phosphorylates the nuclear factor of activated T cells (NFAT), causing its accumulation in the nucleus and binding to the promoter region of cytokine-encoding genes. Antihistamines, statins, nonsteroidal anti-inflammatory drugs (NSAIDs), antibiotics and anti-hypertensives, which inhibit Kv1.3-channels, or antihistamines, antibiotics and corticosteroids, which stabilize mast cells, directly or indirectly suppress the activity of brain leukocytes and the subsequent immunological response

Additionally, recent studies also revealed the contribution of mast cells to the pathogenesis of neuro-inflammation in COVID-related brain fog [32]. According to these studies, brain mast cells that produce pro-inflammatory cytokines directly increased the activity of microglia (Fig. 1). These findings strongly indicated the additional pharmacological efficacy of suppressing mast cells in the treatment of COVID-related brain fog. In our separate patch-clamp studies, by monitoring the changes in the whole-cell membrane capacitance in rat peritoneal mast cells, we provided in vitro evidence that newer generation antihistamines (olopatadine, ketotifen, cetirizine, levocetirizine), antibiotics (clarithromycin) and corticosteroids (hydrocortisone, dexamethasone) strongly inhibit the process of exocytosis [33–37]. In morphological analyses as well, these drugs actually suppressed the degranulation from mast cells, suggesting their pharmacological efficacy as potent mast cell stabilizers. By stabilizing brain mast cells and thus repressing the activity of microglia, they could also be used in the treatment of COVID-related brain fog (Fig. 1). However, in when antibiotics and corticosteroids, we have to be very careful since the overuse of antibiotics has caused a worldwide problem with antibiotic resistance [38], while the use of corticosteroids has been associated with a worse clinical outcome of COVID-19 [39].

Multisystem Inflammatory Syndrome in Adults (MIS-A) is a condition recently recognized by the US Center for Disease Control (CDC) [40]. It is characterized by diffuse multiorgan symptoms, including malaise, myalgia, chest tightness, brain fog and other neuropsychiatric symptoms, which persisted for months after COVID-19 infection. Since these symptoms are very similar to those associated with Mast Cell Activation Syndrome (MCAS), its possibility should also be evaluated in any patients who present symptoms of COVID-related brain fog [41]. MCAS could be treated with a liposomal formulation of flavone luteolin together with rupatadine, an antihistamine [41]. They inhibit the release of pro-inflammatory mediators from mast cells, such as platelet activating factor (PAF) and other chemokines, that are responsible for the pathogenesis of cytokine storms in COVID-19.

Conclusion

Drugs, such as antihistamines, statins, NSAIDs, antibiotics and anti-hypertensive drugs, suppressed the Kv1.3-channel activity and pro-inflammatory cytokine production from leukocytes. Additionally, newer generation antihistamines, antibiotics and corticosteroids strongly stabilized mast cells, which directly activate microglia in the brain. Given the pharmacological properties of these commonly used drugs, they may be useful in the treatment of COVID-related brain fog since the enhanced innate and adaptive immune responses are responsible for the pathogenesis. Nevertheless, we must be very careful in implementing these medications in humans.

Author contributions

I.K. wrote the main manuscript text and prepared the figure and table. The author reviewed the manuscript.

Funding

Funding was provided by Salt Science Research Foundation (Grant No.: 2218).

Data availability

Enquiries about data availability should be directed to the authors.

Declarations

Competing interests

The authors declare no competing interests.