Long-term cyclosporine A treatment promotes anxiety-like behavior: Possible relation with glutamate signaling in rat hippocampus

Abstract

Background: Chronic immunosuppressive treatment with cyclosporine A (CsA) leads to multiple side effects, including some that occur in the central nervous system (CNS). This study aims to investigate the impact of long-term CsA treatment on anxiety behavior and verify the alterations related to glutamate signaling in the rat hippocampus. Methods: Adult male Wistar rats were intraperitoneally injected with 15 mg/kg/day CsA for eight weeks, subjected to anxiety tests, and had their brains collected for biochemistry and Western blot analysis. Results: Herein, we reported that eight weeks of CsA treatment promoted an anxiety-like effect and increased N-methyl-D-aspartate receptor (NMDAR) GluN2 subunit levels, nitric oxide synthase, and cAMP-response element binding protein (CREB) activities. Limitations: Future work should consider the impact of long-term CsA treatment on NMDAR function, as well as on other neurotransmitter signaling pathways. Peripheral side effects should also be considered a factor that could lead to CsA-induced neuropsychiatric effects. Conclusions: In conclusion, this work reports modifications to CNS adaptive responses following chronic CsA treatment, which can influence anxiogenic behavior and other associated neurotoxic events. Understanding the mechanisms underlying CsA-induced neuropsychiatric side effects is an important step toward better symptom management in patients submitted to immunosuppression in the clinical setting.

Keywords

• Cyclosporine
• Anxiety
• Glutamate
• N-methyl-D-aspartate receptors
• CREB
• Nitric oxide synthase