Targeting Prostaglandin Cell Signaling Pathway for the Potential Therapy of Neuroinflammation in Long COVID-associated Brain Fog
Ankeen Dajadian1, Wuyang (Franklin) Chen3, Manjoth Kaur4, Jun Ling2
1California University of Science and Medicine, 2MBS Program, California University of Science and Medicine, 3Western University College of Osteopathic Medicine, 4Midwestern University Arizona College of Osteopathic Medicine (AZCOM)
Objective:
This study investigates the effects of ramatroban as a dual antagonist of PGD2 and TxA2 receptors (DP2 and TP) on neuroinflammation, aiming to validate the potential application of ramatroban for treating long COVID associated brain fog.
Background:
Long COVID associated brain fog with cognitive impairment poses an unmet clinical need and healthcare burden. We investigate mechanisms of brain fog through prostaglandin (PG) cell signaling. PGs increase upon acute COVID-19, including prostaglandin D2 (PGD2), PGE2, and thromboxane A2 (TxA2); these PGs are thromboinflammatory and neuroinflammatory mediators and regulate synaptic activity and plasticity, constituting a major brain fog mechanism.
Design/Methods:
This study used PGD2 agonists for DP1 and DP2 receptors and TxA2 agonist for TP receptor to treat neuronal SH-SY5Y cells with the combination of ramatroban. Cell proliferation, differentiation, and apoptosis were analyzed by cell-based assays, flow cytometry, and Western blotting.
Results:
SY5Y cells were treated by DP1, DP2, TxA2 agonists alone to mimic acute SARS-CoV2 infection, then combined with ramatroban to examineits inhibitory effect on neuroinflammation. SY5Y cells were treated under normoxia (20% O2) and hypoxia (4% O2) conditions. 4% O2 partially induced SY5Y cell differentiation into neuronal phenotype. Combinational treatments with DP1 and DP2 agonists and ramatroban decreased cell death more effectively under 4% O2 than those under 20% O2, suggesting that neuron-physiological condition is important for ramatroban anti-inflammatory activity. This was not observed in combinational treatment with TP agonist and ramatroban, suggesting different responses of PG receptors to ramatroban. ERK2 was found most sensitive to inhibition by ramatroban, while ERK1 and AKT were less responsive, thereby identifying one mechanism of ramatroban on neuronal cell inflammation.
Conclusions:
This study is significant in identifying ramatroban's neuroprotective effect via suppressing DP1 and DP2 mediated inflammation, along with the specific effect via ERK2, making its application for brain fog treatment possible.
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