LPS-induced blood-brain barrier disruption: assessing lithium’s molecular and therapeutic effects

Bipolar disorder (BD) is a chronic and severely debilitating psychiatric illness that affects approximately 2% of the world population. While lithium compounds remain the hallmark mood-stabilizing agent for the treatment of BD, their exact mechanism of action is unknown. There is growing evidence suggesting that the inflammation of the blood-brain barrier (BBB), combined with the passage of pro-inflammatory cytokines into the central nervous system, is a contributing factor to the pathophysiology of a number of neuropsychiatric diseases, including BD. However, in the case of BD, the role of inflammation remains understudied. We tested lithium’s ability to prevent inflammatory disruption in the BBB, implicating the role of inflammation in the pathophysiology of BD. In our study, we assessed if chronic pre-treatment with lithium was able to prevent BBB disruption in the Sprague Dawley rat. Lipopolysaccharide (LPS) was administered to induce an inflammatory response and subsequently disrupt the BBB 24 hours before sacrifice. Intravenous administration of sodium fluorescein (NF) was used to quantify the degree of BBB disruption. The results were compared to a group of sham-injected rats. Western blot analysis will also be completed on the tight junction proteins occludin and claudin-V to assess changes in BBB integrity. Through the NF assays, we were able to demonstrate that lithium partially prevents BBB disruption in several brain regions – including the prefrontal cortex, cortex, and striatum – and whole brain samples, as compared to LPS-only negative controls. The results suggest that lithium may have a therapeutic action in an animal model of BBB disruption. Our novel approach to studying BD through inflammation of the BBB will open new avenues for understanding BD’s pathophysiology and will advance our understanding of lithium’s therapeutic mood-stability properties.

Written by Aaron Edward, Jay Patel, Ritesh Daya, Benicio Frey, Ram Mishra

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