Role of CRF and the hypothalamic-pituitary-adrenal axis in stroke: revisiting temporal considerations and targeting a new generation of therapeutics.

Ischaemic neurovascular stroke represents a leading cause of death in the developed world. Preclinical and human epidemiological evidence implicates the corticotropin-releasing factor (CRF) family of neuropeptides as mediators of acute neurovascular injury pathology. Preclinical investigations of the role of CRF, CRF receptors and CRF-dependent activation of the hypothalamic-pituitary-adrenal (HPA) axis have pointed toward a tissue-specific and temporal relationship between activation of these pathways and physiological outcomes. Based on the literature, the major phases of ischaemic stroke aetiology may be separated into an acute phase in which CRF and anti-inflammatory stress signalling are beneficial and a chronic phase in which these contribute to neural degeneration, toxicity and apoptotic signalling. Significant gaps in knowledge remain regarding the pathway, temporality and systemic impact of CRF signalling and stress biology in neurovascular injury progression. Heterogeneity among experimental designs poses a challenge to defining the apparent reciprocal relationship between neurological injury and stress metabolism. Despite these challenges, it is our opinion that the elucidated temporality may be best matched with an antibody against CRF with a half-life of days to weeks as opposed to minutes to hours as with small-molecule CRF receptor antagonists. This state-of-the-art review will take a multipronged approach to explore the expected potential benefit of a CRF antibody by modulating CRF and corticotropin-releasing factor receptor 1 signalling, glucocorticoids and autonomic nervous system activity. Additionally, this review compares the modulation of CRF and HPA axis activity in neuropsychiatric diseases and their counterpart outcomes post-stroke and assess lessons learned from antibody therapies in neurodegenerative diseases.