Dynamic Changes in Central and Peripheral Neuro-Injury vs. Neuroprotective Serum Markers in COVID-19 Are Modulated by Different Types of Anti-Viral Treatments but Do Not Affect the Incidence of Late and Early Strokes

Abstract

The balance between neurodegeneration, neuroinflammation, neuroprotection, and COVID-19-directed therapy may underly the heterogeneity of SARS-CoV-2′s neurological outcomes. A total of 105 patients hospitalized with a diagnosis of COVID-19 had serum collected over a 6 month period to assess neuroinflammatory (MIF, CCL23, MCP-1), neuro-injury (NFL, NCAM-1), neurodegenerative (KLK6, τ, phospho τ, amyloids, TDP43, YKL40), and neuroprotective (clusterin, fetuin, TREM-2) proteins. These were compared to markers of nonspecific inflammatory responses (IL-6, D-dimer, CRP) and of the overall viral burden (spike protein). Data regarding treatment (steroids, convalescent plasma, remdasavir), pre-existing conditions, and incidences of strokes were collected. Amyloid β42, TDP43, NF-L, and KLK6 serum levels declined 2–3 days post-admission, yet recovered to admission baseline levels by 7 days. YKL-40 and NCAM-1 levels remained elevated over time, with clusters of differential responses identified among TREM-2, TDP43, and YKL40. Fetuin was elevated after the onset of COVID-19 while TREM-2 initially declined before significantly increasing over time. MIF serum level was increased 3–7 days after admission. Ferritin correlated with TDP-43 and KLK6. No treatment with remdesivir coincided with elevations in Amyloid-β40. A lack of convalescent plasma resulted in increased NCAM-1 and total tau, and steroidal treatments did not significantly affect any markers. A total of 11 incidences of stroke were registered up to six months after initial admission for COVID-19. Elevated D-dimer, platelet counts, IL-6, and leukopenia were observed. Variable MIF serum levels differentiated patients with CVA from those who did not have a stroke during the acute phase of COVID-19. This study demonstrated concomitant and opposite changes in neurodegenerative and neuroprotective markers persisting well into recovery.

Hypothesized neuroprotective effect of minocycline against COVID-19-induced stroke and neurological dysfunction: possible role of matrix metalloprotease signaling pathway

“…Abbreviations: TNF-α, tumor necrosis factor-alpha; IL-1β, interleukin-1 beta; NF-κB, nuclear factor kappa B; PAR, protease activated receptor 1; t-PA, tissue plasminogen activator; LRP, lipoprotein receptor-related protein; MMP, matrix metalloproteinase; HIF, hypoxia-inducible factor; TIMP, tissue inhibitors of matrix metalloproteinase; BBB, blood brain barrier Laudanski et al 2021;Menéndez et al 2022). Furthermore, the proposed drugs should target the underlying mechanisms of COVID-19-induced stroke and post-stroke neurological events (Gholami et al 2021a, b;Laudanski et al 2021;Menéndez et al 2022). To this end, candidate agents should target the MMP signaling pathway and have both anti-stroke and neuroprotective effects.…”

“…Introduction of new drugs and advancement of potential therapies for patients with COVID-19 should be aimed at preventing COVID-19 post-infection complications such as stroke and neurodegeneration (Gholami et al 2021 ; Laudanski et al 2021 ; Menéndez et al 2022 ). One drug that might have neuroprotective effects and anti-stroke properties is minocycline (Laudanski et al 2021 ; Liu et al 2021 ).…”

“…Introduction of new drugs and advancement of potential therapies for patients with COVID-19 should be aimed at preventing COVID-19 post-infection complications such as stroke and neurodegeneration (Gholami et al 2021 ; Laudanski et al 2021 ; Menéndez et al 2022 ). One drug that might have neuroprotective effects and anti-stroke properties is minocycline (Laudanski et al 2021 ; Liu et al 2021 ). Previous studies indicate that minocycline has a protective effect on stroke-induced destructive signaling pathways; however, its effect on COVID-19-induced stroke and hypoxia/ischemia and its involvement in MMP is unknown and needs assessment (Liu et al 2021 ; Lu et al 2021 ).…”

“…New drugs and the advancement of potential therapies for patients with COVID-19 should be aimed at preventing COVID-19-induced downstream effects such as stroke and neurodegeneration (Gholami et al 2021 ; Laudanski et al 2021 ; Menéndez et al 2022 ). An important aspect of proposing drugs for the prevention and management of COVID-19-induced stroke and neurodegeneration should consider their neuroprotective role (Gholami et al 2021 ; Laudanski et al 2021 ; Menéndez et al 2022 ). Furthermore, the proposed drugs should target the underlying mechanisms of COVID-19-induced stroke and post-stroke neurological events (Gholami et al 2021a , b ; Laudanski et al 2021 ; Menéndez et al 2022 ).…”

“…An important aspect of proposing drugs for the prevention and management of COVID-19-induced stroke and neurodegeneration should consider their neuroprotective role (Gholami et al 2021 ; Laudanski et al 2021 ; Menéndez et al 2022 ). Furthermore, the proposed drugs should target the underlying mechanisms of COVID-19-induced stroke and post-stroke neurological events (Gholami et al 2021a , b ; Laudanski et al 2021 ; Menéndez et al 2022 ). To this end, candidate agents should target the MMP signaling pathway and have both anti-stroke and neuroprotective effects.…”