Rapamycin and Suramin Effects on TNF-⍺-Mediated Mast Cell and Brain Microvascular Endothelial Cell Dysfunction

Area of Science:

• Neuroscience
• Immunology
• Cell Biology

Background:

• Chronic blood-brain barrier (BBB) disruption is linked to neurodegenerative diseases.
• Impaired brain microvascular endothelial cells (BMECs) and immune cell interactions contribute to BBB dysfunction.
• The Akt/mTOR/GSK pathway is crucial for angiogenesis and immune cell activation, offering potential therapeutic targets.

Purpose of the Study:

• To investigate BMEC and mast cell (MC) dysfunction under inflammatory conditions (TNF-α).
• To analyze the role of the Akt/mTOR/GSK pathway in BMEC-MC crosstalk.
• To compare the effects of suramin and rapamycin on inflammatory responses and BBB integrity.

Main Methods:

• Primary human BMECs and HMC-1.2 mast cell line were used.
• Cells were stimulated with TNF-α and treated with suramin or rapamycin.
• Measurements included oxidative stress (PGE2), cytokine/chemokine production, and pathway intermediate phosphorylation (p-p70S6K, p-RPS6, p-GSK3α/β).

Main Results:

• TNF-α stimulation increased oxidative stress, pro-inflammatory cytokines, and pathway activation in both BMECs and MCs.
• Coculture exacerbated intracellular cytokine levels in MCs, with rapamycin showing modest effects on extracellular mediators.
• Suramin reduced extracellular inflammatory markers and increased PDGF-BB (BBB-stabilizing), but also increased intracellular BMEC cytokines and did not resolve MC activation.

Conclusions:

• TNF-α induces significant BMEC and MC dysfunction and inflammatory crosstalk.
• Suramin demonstrates partial BBB-protective effects but fails to fully resolve MC-mediated inflammation.
• Targeting the Akt/mTOR/GSK pathway presents complex therapeutic potential for neuroinflammatory BBB disruption.