The Intersection of circadian rhythms and the blood-brain barrier with drug efficacy and delivery in neurological disorders

Circadian rhythms typically maintain a 24-hour cycle which determines the regulation of many genes and proteins including, but not limited to, those which control the permeability of the blood brain barrier (BBB). The BBB acts as a boundary between circulating blood and the brain, protecting the brain from toxicants, maintaining homeostasis, and regulating perfusion. Importantly, the BBB regulates the efficacy of drug delivery into the central nervous system (CNS). Emerging evidence demonstrates a bi-directional relationship between circadian rhythm dysfunction, neurological disorders, and/or BBB disruption. This means that impaired BBB functions and circadian rhythm dysregulation can be both the driver of neurological disease and the result. As such, both represent an opportunity for therapeutic intervention which can prevent disease development, manage symptoms, or mediate disease progression. This review seeks to describe the changes in both the BBB and circadian rhythms in a series of neurological (stroke, epilepsy, traumatic brain injury), neurodegenerative (Alzheimer's disease, Parkinson's disease), and psychiatric disorders (major depressive disorder, schizophrenia). We also describe therapeutic approaches for protecting against both BBB and circadian rhythm dysfunction, methods of surpassing the BBB, and bolstering drug efficacy with chronotherapeutic strategies.