Repurposing Treatment of Wernicke–Korsakoff Syndrome for Th-17 Cell Immune Storm Syndrome and Neurological Symptoms in COVID-19: Thiamine Efficacy and Safety, In-Vitro Evidence and Pharmacokinetic Profile

Abstract

Coronavirus disease identified in 2019 (COVID-19) can be complicated by the Th17 cell-mediated IL-17 proinflammatory response. We tested if thiamine can effectively lower the Th17 response in a clinical study [Proinflammatory state in alcohol use disorder patients termed as disease controls (DC)] and corroborated the results using an in vitro study. We developed an effective dose range and model for key pharmacokinetic measures with the potential of targeting the cytokine storm and neurological symptoms of COVID-19. Three-week 200 mg dose of thiamine was administered to sixteen DC patients. Eight healthy volunteers (HV) were also included in this investigation. A subsequent in vitro study was performed to validate the effectiveness of thiamine [100 mg/day equivalent (0.01 μg/ml)] treatment in lowering the Th17 proinflammatory response in a mouse macrophage cell line (RAW264.7) treated with ethanol. Based on recent publications, we compared the results of the IL-17 response from our clinical and in vitro study to those found in other proinflammatory disease conditions (metabolic conditions, septic shock, viral infections and COVID-19) and effective and safe dose ranges of thiamine. We developed a pharmacokinetic profile for thiamine dose range as a novel intervention strategy in COVID-19. DC group showed significantly elevated proinflammatory cytokines compared to HV. Thiamine-treated DC patients showed significant lowering in IL-17 and increase in the IL-22 levels. In humans, a range of 79–474 mg daily of thiamine was estimated to be effective and safe as an intervention for the COVID-19 cytokine storm. A literature review showed that several neurological symptoms of COVID-19 (∼45.5% of the severe cases) occur in other viral infections and neuroinflammatory states that may also respond to thiamine treatment. Thiamine, a very safe drug even at very high doses, could be repurposed for treating the Th17 mediated IL-17 immune storm, and the subsequent neurological symptoms observed in COVID-19. Further studies using thiamine as an intervention/prevention strategy in COVID-19 patients could identify its precise anti-inflammatory role.

CD147 antibody specifically and effectively inhibits infection and cytokine storm of SARS-CoV-2 and its variants delta, alpha, beta, and gamma

“…When compared with the hACE2 mouse model, SARS-CoV-2-infected hCD147 mice presented stronger inflammatory responses, including activation of the NF-κB pathway, Th17 cell responses, and activation of proinflammatory cytokine and chemokine signaling pathways, which were all reported to be involved in exudative alveolar pneumonia. 27 , 46 , 47 The difference in the phenotype of hACE2 and hCD147 transgenic mice may attribute to their different expression profile. CD147 is expressed on various types of proinflammatory cells including Th17 cells, neutrophils, NK cells, 48 , 49 where ACE2 is rarely expressed.…”

The Role of Cytokines and Chemokines in Severe Acute Respiratory Syndrome Coronavirus 2 Infections

“…In addition, because both IL-17 and IL-22 originate in Th17 cells, the dysregulation of the above cytokines could contribute to several proinflammatory diseases ( 206 ). Therefore, applying Th17-inhibiting therapies such as thiamine to reduce the Th17 mediated pro-inflammatory response ( 101 ) may be an effective treatment for decreasing cytokine storms ( 207 ). In one study, 16 patients a proinflammatory state from alcohol use disorder were treated with thiamine, and it significantly reduced IL-17 levels and ameliorated the Th17 responses ( 207 ).…”

Neuroprotective Effects of Thiamine and Precursors with Higher Bioavailability: Focus on Benfotiamine and Dibenzoylthiamine

“…A very recent study showed a lowering of the Th-17 cell-mediated IL-17 response by thiamine (200 mg per day for three weeks) in patients with elevated proinflammatory cytokines and suggested the use of this vitamin to target the COVID-19 cytokine storm observed in some patients [ 88 ]. We expect that DBT, because of its much higher anti-inflammatory properties compared to thiamine [ 29 ], would be even more efficient.…”

“…However, all these effects require rather high concentrations (50–250 µM) of BFT and they may thus not be relevant in vivo. Notwithstanding, thiamine administration in high doses clearly has anti-inflammatory properties in vivo [ 88 ].…”