Investigation of blood-brain barrier disruption in an animal model of mania induced by D-amphetamine

Abstract

• Inflammation and oxidative stress are linked to mood symptoms and cognitive dysfunction in BD. • BBB disruption has been proposed as a key mechanism of BD pathophysiology. • This study evaluated BBB disruption in a rat model of mania induced by AMPH. • AMPH and lithium did not affect BBB integrity given by brain levels of claudin-5. • TNFα and TBARS levels in specific brain regions did not differ between groups. High levels of inflammation and oxidative stress are observed in bipolar disorder (BD) being further associated with mood symptoms and cognitive dysfunction. Due to the crosstalk between the periphery and central nervous system, the blood-brain barrier (BBB) disruption has been considered a key mechanism of the BD pathophysiology. This study aimed to evaluate claudin-5 expression in the brain of a model of mania induced by D -amphetamine (AMPH). Wistar rats were injected with AMPH (2 mg/kg i.p.) and treated with lithium (47.5 mg/kg i.p.). Locomotor behavior was assessed, followed by euthanasia, blood collection, and brain removal. Tumor necrosis factor (TNF) α and thiobarbituric acid reactive substances (TBARS) were quantified in the serum and brain tissue, and claudin-5 was quantified in the brain. AMPH-injected animals exhibited increased locomotor activity. In the serum, TBARS levels were augmented in lithium-treated groups, while TNFα was not detected. In the brain, TBARS and TNFα did not differ between groups but were positively andstrongly correlated in the striatum of AMPH-injected rats. Contrary to our hypothesis, AMPH and lithium injections did not affect claudin-5 levels in the brain. The main limitations include the lack of a dynamic marker of BBB integrity and limited number of biomarkers analyzed. This is one of the first attempts to investigate the effects of AMPH on BBB integrity, and no disruption was observed. Still, we provide rationale for future research to elucidate the importance of BBB disruption in BD, recently proposed as a marker of illness progression.