Repurposing Dexmedetomidine: Early Pharmacological Hypothermia Enhances Neuroprotection and Improves Locomotor and...

Spinal cord injury (SCI) causes progressive secondary damage, yet translation of hypothermia, one of the few preclinical neuroprotectants, has been limited by slow, equipment-dependent cooling that rarely meets the therapeutic window. We tested whether repurposing dexmedetomidine (Dex), an FDA-approved α₂-agonist that blocks shivering and has intrinsic neuroprotection, could provide early pharmacological hypothermia to enhance recovery after SCI. Adult mice received moderate thoracic contusive SCI followed by intraperitoneal Dex (100 µg/kg) at 1 h postinjury. Core temperature, vital signs, and ECG were monitored for 24 h. Locomotor recovery, bladder function, tissue preservation, neuronal and axonal sparing, serotonergic circuitry, raphe activation, cytokine profiles, and ERK and RIPK1 signaling were assessed. Comparator groups included untreated injury, conventional surface cooling, hypothermia-prevention by heating, and ERK inhibition. At ambient room temperature (∼24°C), Dex induced rapid, stable moderate hypothermia (∼29-32°C for ∼16 h) without respiratory compromise or arrhythmia. This pharmacological hypothermia, combined with Dex's intrinsic actions, produced greater locomotor and bladder recovery than untreated injury or conventional cooling. Dex preserved perilesional tissue, neuronal survival, axonal integrity, and descending serotonergic input while restoring raphe activation. Mechanistically, Dex plus hypothermia synergistically suppressed acute proinflammatory cytokines, increased IL-10 at Days 7 and 14, activated early ERK-dependent survival signaling, and reduced acute RIPK1-associated injury; blocking hypothermia or ERK signaling attenuated these benefits. The neuroprotective effects of Dex were similar in both sexes. A single clinically relevant Dex dose provides dual-action therapy-pharmacological hypothermia plus intrinsic neuroprotection-offering an immediately translatable, equipment-free strategy for acute SCI and other neurotrauma.