Repairing blood-CNS barriers: Future therapeutic approaches for neuropsychiatric disorders

Central nervous system (CNS) drug development faces significant difficulties that translate into high rates of failure and lack of innovation. The pathophysiology of neurological and psychiatric disorders often results in the breakdown of blood-CNS barriers, disturbing the CNS microenvironment and worsening disease progression. Therefore, restoring the integrity of blood-CNS barriers may have a beneficial influence in several CNS disorders and improve treatment outcomes. In this review, pathways that may be modulated to protect blood-CNS barriers from neuroinflammatory and oxidative insults are featured. First, the participation of the brain endothelium and glial cells in disruption processes is discussed. Then, the relevance of regulatory systems is analysed, specifically the hypothalamic-pituitary axis, the renin-angiotensin system, sleep and circadian rhythms, and glutamate neurotransmission. Lastly, compounds of endogenous and exogenous origin that are known to mediate the repair of blood-CNS barriers are presented. We believe that enhancing the protection of blood-CNS barriers is a promising therapeutic strategy to pursue in the future.