Spinal cord injury (SCI) causes progressive secondary damage, yet translation of hypothermia, one of 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 post-injury. 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 peri-lesional tissue, neuronal survival, axonal integrity, and descending serotonergic input while restoring raphe activation. Mechanistically, Dex plus hypothermia synergistically suppressed acute pro-inflammatory cytokines, increased IL-10 at day 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. Significance Statement This study identifies dexmedetomidine (Dex), an FDA-approved α₂-agonist, as a rapid and pharmacologically driven method to induce sustained hypothermia following spinal cord injury (SCI). Compared with conventional physical cooling, which is slow, equipment-dependent, and often difficult to implement, Dex induced reliable early hypothermia and produced greater recovery of locomotor and bladder function in murine models. Dex also preserved spinal tissue and descending pathways, providing a mechanistic basis for its functional benefits. Given Dex’s established clinical use and safety profile in monitored medical settings, these findings highlight Dex-induced hypothermia as a promising and highly translatable therapeutic strategy for acute SCI.
Khabbaz et al. (Fri,) studied this question.