Understanding Post-COVID-19: Mechanisms, Neurological Complications, Current Treatments, and Emerging Therapies

Abstract

COVID-19, a highly infectious disease, caused a worldwide pandemic in early 2020. According to the World Health Organization (WHO), COVID-19 has resulted in approximately 774 million cases and around 7 million deaths. The effects of COVID-19 are well known; however, there is a lack of information on the pathophysiological mechanisms underlying the symptoms that comprise Post-Acute COVID-19 Syndrome (PACS) or Long COVID-19. Neurological sequelae are common, with cognitive dysfunction being one of the foremost symptoms. Research indicates that elevated inflammatory levels and increased oxidative stress may play a role in the etiology and severity of PACS. Treatment options are extremely limited, and there is no consensus among the medical and scientific communities on how to manage the disease. Nevertheless, many scientists advocate for using antioxidants for symptomatic therapy and cognitive behavior therapy for supportive care. Additionally, current research aims to ameliorate several aspects of the inflammatory cascade. This review highlights the intracellular and extracellular pathways crucial to the neurological manifestations of PACS, providing valuable information for healthcare professionals and scientists. Given the complex nature of PACS, understanding these pathways is essential for developing new treatment options. Assessing PACS is challenging, and reviewing current therapeutic options while proposing a triad of potential therapeutic elements will add value to clinical assays and guidelines. Current therapeutic strategies, such as antioxidants/vitamin supplements, neurogenic stem cell therapy, and mitochondrial therapy, could be combined to enhance their effectiveness. Future research should focus on validating these approaches and exploring new avenues for the effective treatment of PACS.

Keywords: PACS; cognitive dysfunction; long COVID-19; mitochondrial therapy; post-acute COVID-19 syndrome.

Graphical abstract

Figure 1

Neurological affectations in PACS patients. Patients suffering from PACS can develop symptoms such as cognitive disorders, fatigue, headaches, hyposmia/hypogeusia, and myalgia/ muscle weakness. Cognitive dysfunction can be further divided in forms such as executive function, processing speed, category fluency, attention, sleep disorders, memory encoding, and recall. This is due to neuroinflammatory cytokines and chemokines that lead to activation of microglia and changes to subcortical white matter, loss of oligodendrocytes, loss of oligodendrocyte precursor cells and myelin. Autoantibodies also play a role and have been found to be involved in the etiology of PACS in the CSF of patients. Patients can also present with headaches as the virus is interconnected with receptors such as angiotensin-converting enzyme 2 (ACE2) receptors in neurons and gene-related peptide (CGRP). Moreover, SARS-CoV-2 also plays a role in T-cell mediated inflammation in olfactory epithelium which is potentially an etiology for hyposmia. Furthermore, metabolic issues have been implied in the pathophysiology of PACS patients in the form of mitochondrial dysfunction. Moreover, mitochondrial changes such as abnormal cristae, loss of cytochrome c oxidase activity, and subsarcolemmal accumulation could also be involved in myopathy in PACS patients. Created in BioRender. Rivadeneira, (M) (2024) https://BioRender.com/z91b271.

Figure 2

Current treatment options for PACS patients. Treatment for PACS patients can be categorized into symptomatic, supportive, and rehabilitative approaches. Symptomatic treatments include the use of Vitamin C alone or combined with L-Arginine to reduce fatigue by lowering ROS levels, as well as antihistamines to decrease mast cell activation. Apheresis has shown promise in some studies, while physical rehabilitation, particularly light aerobic exercise, has been effective in alleviating fatigue and dyspnea. Supportive treatment primarily targets the neurological and psychiatric symptoms of PACS, with Cognitive Behavioral Therapy (CBT) being the leading approach. Other pharmacological interventions, such as blocking anthranilic acid to reduce cognitive dysfunction and ROS levels, are under investigation. Lithium is also being used to mitigate brain fog, anxiety, and cognitive dysfunction by increasing mitochondrial number, size, and cytochrome c content. Additionally, other substances under study include Dextroamphetamine-amphetamine, Naltrexone, Montelukast, Deupirfenidone, Nicotinamide riboside, Leronlimab, melatonin, adaptogens, hyperbaric oxygen therapy, and probiotic therapy. Rehabilitative treatment includes self-monitoring strategies, such as serial pulse oximetry readings, along with self-care practices. Created in BioRender. Zambrano, (K) (2024) https://BioRender.com/m70j058.

Figure 3

New potential treatments for neurological manifestations in PACS patients. We suggest a triad of antioxidant/vitamin supplements, neurogenic stem cell therapy and mitochondrial therapy. Due to high levels of ROS and inflammation seen in brain damage we suggest that supplementation such as Tempol (a synthetic antioxidant compound that mimics the activity of superoxide dismutase, an enzyme that naturally protects cells from oxidative stress by neutralizing superoxide radicals). can have promising results in neuroinflammation by reducing hydroxyl radicals, as well as decrease inflammatory cytokines such as IL-1, IL-2, IFN-γ, and TNF-α, along with a decrease in the activation of NF-κB in the optic nerve. Vitamin A can also help in cell cycle regulation and improve cognitive impairments in executive function and memory. Vitamin C can aid in neurite outgrowth, cell maturation and has been reported to improve attention, language, and memory ability. Vitamin D has been linked to improve hippocampal neurogenesis, while vitamin E has aided in preservation of attention, perceptual/motor speed, memory, and language. Additionally polyphenols and polyphenol rich food such as blueberries, strawberries and grape seeds increase and promote neurogenesis while simultaneously reducing ROS. Meanwhile, stem cell therapy has been suggested to be potential treatment in inflammatory states, this treatment has been known to reduce IL-6 and inhibit dendritic cells and B cells, T cells, and NK cells, decreasing M1 and enhancing M2 activation. Moreover, stem cell therapies has been known to decrease proinflammatory cytokine expression levels as is the case with IL‐6, IL‐1α, and IFN‐γ. Mitochondrial therapy has also been used in several pathologies where they have shown the ability to improve ischemia-reperfusion injuries, mitochondria are able to incorporate into neurons, astrocytes and microglia. Mitochondrial therapy has had favorable results in Alzheimer mice models, diabetes associated cognitive impairment, and Parkinson mice animal models. Created in BioRender. Zambrano, (K) (2024) https://BioRender.com/h44d942.