Regulatory effect of lithium on hippocampal blood-brain barrier integrity in a rat model of depressive-like behavior

Abstract

Objectives: Recent evidence has associated mood disorders with blood-brain barrier (BBB)/ neurovascular unit (NVU) dysfunction, and reduction in blood vessels coverage by the water channel aquaporin-4 (AQP4) immunoreactive astrocytes. Lithium is an established treatment for mood disorders, yet, its mechanism of action is partially understood. We investigated the effects of lithium on BBB integrity and NVU-related protein expression in chronic mild stress (CMS) rat model of depressive-like behavior.

Methods: Male Wistar rats were exposed for 5 weeks to unpredictable mild stressors with daily co-administration of lithium chloride to half of the stressed and unstressed groups. Sucrose preference and open field tests were conducted to validate the depressive-like phenotype, and dynamic contrast-enhanced MRI analysis was utilized to assess BBB integrity in brain regions relevant to the pathophysiology of depression. Hippocampal AQP4 and claudin-5 expression were studied using immunofluorescence, western blot, and enzyme-linked immunosorbent assays.

Results: Lithium administration to the stressed rats prevented the reductions in sucrose preference and distance traveled in the open field, and normalized the stress-induced hippocampal BBB hyperpermeability, whereas lithium administration to the unstressed rats increased hippocampal BBB permeability. Additionally, lithium treatment attenuated the decrease in hippocampal AQP4 to glial fibrillary acidic protein immunoreactivity ratio in the stressed rats and upregulated hippocampal claudin-5 and BDNF proteins expression.

Conclusions: Our findings suggest that lithium administration in a rat CMS model of depressive-like behavior is associated with attenuation of stressed-induced hippocampal BBB/NVU disruption. These protective effects may be relevant to the mode of action of lithium in depression.

Keywords: Lithium; aquaporin-4 (AQP4); blood-brain barrier (BBB); chronic mild stress (CMS); claudin-5; neurovascular unit (NVU).