Awakening Recovery: Enhancing Orexinergic Tone After Acute CNS Damage

Acute injuries to the central nervous system (CNS) converge on a shared pathophysiology of energetic failure, vascular disruption, and neuroimmune activation. These events destabilize the same metabolic and arousal networks governed by the orexin (hypocretin) system, a hypothalamic hub that synchronizes energy balance, wakefulness, and motivation. Experimental evidence across ischemic, hemorrhagic, traumatic, and systemic models shows that orexin signaling falls sharply during metabolic crisis and gradually reactivates with recovery of vigilance and homeostasis. Controlled enhancement of this system through peptide, pharmacological, or physiological means can limit secondary injury, stabilize autonomic function, and foster motor and cognitive rehabilitation. This review integrates preclinical and clinical evidence linking orexin modulation to neuroprotection and functional restoration, and discusses opportunities and challenges for translating mechanistic insight into therapy. It also outlines practical strategies to enhance orexinergic tone, highlighting the recent development of selective small-molecule orexin agonists and non-invasive delivery routes that make translational exploration increasingly feasible. Orexin emerges as a unifying neuromodulatory target that bridges acute metabolic rescue with long-term behavioral recovery.