Advancing neuroprotective strategies post-anoxic brain injury: the role of ghrelin in cognitive and psychosocial recovery

Hypoxic-ischaemic encephalopathy (HIE) following cardiac arrest remains a substantial clinical challenge, carrying a high risk of poor neurological outcome. Moreover, survivors who regain consciousness often face long-term cognitive impairments and significant psychosocial difficulties, contributing to a considerable burden on patients, families, and healthcare systems.1 Despite advancements in critical care, the efficacy of several neuroprotective strategies has been limited in this context. Interventions such as targeted temperature management (TTM), maintaining high blood pressure targets, or inducing mild hypercapnia have been investigated extensively but have shown only modest benefits in improving neurological outcomes.2 These findings highlight an urgent need to explore and develop novel therapeutic approaches to enhance neuroprotection and long-term recovery in patients with HIE following cardiac arrest. Among those, ghrelin has emerged as a promising candidate for neuroprotection due to its multi-faceted roles in modulating neuroinflammation, promoting synaptic plasticity, and supporting neuronal survival. This hormone, primarily produced by enteroendocrine cells in the gastrointestinal tract, particularly in the stomach, plays a key role in appetite regulation through the activation of specific cells in the anterior pituitary gland and hypothalamus.3 The effects of ghrelin on the brain are mediated by the growth hormone secretagogue receptor (GHSR), a G-protein-coupled receptor abundantly expressed in the brain; GHSR stimulation is also involved in other essential regulatory processes, including energy homeostasis, the sleep–wake cycle, learning and memory, reward pathways, and stress responses.4 The active form of ghrelin, the acyl-ghrelin, is generated through the post-translational addition of caprylic acid by the enzyme ghrelin O-acyltransferase. In pre-clinical models, acyl-ghrelin has shown the capacity to reduce neuronal apoptosis and facilitate recovery in hippocampal networks following hypoxic insults.5,6 These properties position ghrelin as a compelling therapeutic agent for addressing the complex pathology of post-anoxic brain injury. However, clinical data in the effectiveness of ghrelin treatment in patients suffering from HIE are limited.