Biochemical and neurological changes post-COVID-19: A focus on oxidative metabolism – A case–control study

INTRODUCTION

In recent years, the global medical community has deepened its understanding of the long-term sequelae associated with COVID-19. While the initial focus was largely on respiratory symptoms, clinicians including those practicing in Kazakhstan have reported that a notable proportion of patients exhibit persistent neurological complications long after recovery from the acute phase of COVID-19. These include cognitive impairments, emotional instability, headaches, and sensory abnormalities.^[1-7]

While several studies have addressed post-COVID-19 neurological manifestations, the underlying biochemical mechanisms remain insufficiently explored. Increasing evidence suggests that oxidative stress and systemic inflammation may contribute to nervous system dysfunction. For instance, literature data indicate elevated interleukin-6 levels in 30% of long COVID-19 cases, with C-reactive protein and tumor necrosis factor-alpha elevated in 15% each. Decreased hemoglobin concentrations were observed in 10% of patients. Abnormalities in cytokine/chemokine profiles and other biochemical parameters accounted for 23.9% and 39.1% of detected deviations, respectively. In addition, biomarkers such as neurofilament light chain and glial fibrillary acidic protein, crucial for axonal and astrocytic integrity, have been found in peripheral blood, suggesting ongoing neurodegeneration or damage.^[8]

Clinical observations in our center have similarly identified patients with otherwise unremarkable recoveries who nonetheless exhibited persistent neurological dysfunction. These observations prompted us to explore potential redox imbalances and their associations with post-COVID-19 neurological complaints.

MATERIALS AND METHODS

This study was conducted in accordance with the ethical principles of the Helsinki Declaration and received approval from the Ethics Committee of Karaganda Medical University (Protocol No. 18, dated April 12, 2021). Participants were randomly selected among individuals with confirmed COVID-19 infection and clinical recovery within the preceding 3–6 months. Informed consent was obtained from all participants, and personal data were anonymized [Figure 1].

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Figure 1:

Graphic design of the study.

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Neurological status was assessed using standardized clinical instruments, including the Beck Depression Inventory, Hospital Anxiety and Depression Scale I and II, and the composite autonomic symptom score 31. Participants were categorized into two groups based on the presence or absence of post-COVID-19 neurological symptoms. An additional control group consisted of 30 healthy individuals without a history of COVID-19.

Biochemical analyses included the measurement of reactive carbonyl derivatives (RCDP) using the Levine method,^[9] advanced oxidation protein products (AOPP) through the Witko-Sarsat technique,^[10] malondialdehyde (MDA), and nitric oxide levels (quantified using high-performance liquid chromatography, Agilent). Enzymatic activity of adenosine deaminase (ADA) and myeloperoxidase (MPO) was assessed using standard assay kits (VL-MEDIA Ltd.).

RESULTS

Significantly elevated levels of RCDP and MDA were observed in both patient groups compared to controls, indicating increased oxidative stress. Interestingly, AOPP concentrations were lower in participants with neurological symptoms. Elevated nitrite ion levels were detected across all post-COVID-19 groups, while ADA and MPO activities exhibited variability. Cluster analysis revealed distinct biochemical patterns associated with symptom severity, particularly among those with neurological complications, highlighting notable oxidative imbalance and neutrophil activation [Figure 2].

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Figure 2:

Main clusters by indicators of blood neutrophils of the studied groups.

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DISCUSSION

Our findings suggest that certain biochemical disturbances persist well beyond the acute phase of COVID-19. Specifically, increased RCDP and nitrite ion levels in symptomatic individuals imply sustained oxidative and inflammatory processes. Concurrently, decreased AOPP and ADA activity may reflect impaired antioxidant defenses. While these findings require validation in larger cohorts, they support the hypothesis that neuroinflammation and redox imbalance play key roles in post-COVID-19 neurological syndromes.

CONCLUSION

This study underscores the biochemical distinctions between post-COVID-19 patients with and without neurological symptoms, particularly in relation to oxidative stress and immune activation. These insights may aid in the development of early diagnostic tools and targeted interventions aimed at mitigating long-term neurological outcomes of COVID-19.