Drugging cold-response networks for neuroprotection.

Area of Science:

• Neuroscience
• RNA Biology
• Pharmacology

Background:

• Therapeutic hypothermia offers neuroprotection but faces clinical challenges.
• Pharmacological approaches are needed to replicate hypothermia's benefits at normothermia.
• Recent advances highlight RNA mechanisms in cellular cold responses.

Purpose of the Study:

• To present a framework for developing normothermic hypothermia mimetics.
• To focus on RNA-based mechanisms for cold-mimicking drug discovery.
• To outline a roadmap for translating these findings into clinical applications.

Main Methods:

• Reviewing membrane thermosensors and intracellular temperature decoders.
• Focusing on RNA layer mechanisms, including alternative splicing and RNA G-quadruplexes (rG4).
• Proposing splice-switching antisense oligonucleotides and rG4-oriented chemotypes as key modalities.

Main Results:

• RNA mechanisms like temperature-gated splicing and rG4 thermometers are key.
• An RNA-binding motif protein 3 (RBM3)-centric roadmap is proposed.
• Development of normothermic hypothermia mimetics is feasible.

Conclusions:

• RNA layer mechanisms offer a viable strategy for normothermic neuroprotection.
• Targeting RNA offers a promising path for developing novel therapeutics.
• Defining pharmacodynamic anchors and safety gates is crucial for clinical translation.