Drugging cold-response networks for neuroprotection.

Abstract

Therapeutic hypothermia is robustly neuroprotective in models but slow to initiate and hard to sustain clinically. This gap motivates pharmacological strategies that capture 'cold' protection at normothermia. Recent advances across the cold-response landscape have made RNA layer mechanisms operational. These include temperature-gated alternative splicing coupled to nonsense-mediated decay and temperature-sensitive RNA secondary structure elements such as RNA G-quadruplexes (rG4) thermometers, which are now quantifiable and tractable. In this review, we present a development-oriented framework that spans membrane thermosensors, intracellular temperature decoders, and downstream cold effectors. We focus on RNA layer mechanisms while treating upstream non-RNA elements as contextual adjuncts. We outline an RNA-binding motif protein 3 (RBM3)-first translational roadmap mainly built on two orthogonal modalities: splice-switching antisense oligonucleotides and rG4-oriented chemotypes. Lastly, we define pharmacodynamic anchors, realistic clinical windows, and safety gates for early-phase testing of normothermic hypothermia mimetics.