A dopamine D1-like receptor-specific agonist improves the survival of septic mice while suppressing neuroinflammation

Abstract Background Sepsis is a leading cause of mortality in intensive-care units worldwide. It is accompanied by dysregulated systemic immune reactions, which lead to multiple organ failure. In addition to the peripheral organs, the brain is often affected by sepsis. Sepsis-induced brain dysfunction is termed sepsis-associated encephalopathy (SAE) and displays severity ranging from mild delirium to deep coma. SAE is known to increase the mortality of sepsis cases. Methods A murine sepsis model was prepared using the cecum ligation and puncture (CLP) technique. The expression of dopamine (DA) receptors (DRs) was examined by quantitative reverse transcription polymerase chain reaction (RT-PCR). Methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP) was used to decrease intracerebral DA levels. The blood-brain barrier (BBB)-permeable DA D1-like receptor selective agonist SKF-81297 (SKF), the BBB-impermeable D1R agonist fenoldopam, and DA were intraperitoneally administered shortly after CLP. CLP-induced changes in body temperature and mortality were then monitored every 12 h. Systemic and brain inflammation were investigated using flow cytometry, quantitative RT-PCR, and an enzyme-linked immunosorbent assay. SAE-like symptoms were evaluated using behavioral tests and electroencephalogram (EEG)/electromyogram (EMG) recordings. Results D1-like receptors were significantly expressed in the brain but not in the lung. MPTP aggravated mortality in septic mice. SKF, but not fenoldopam, prevented CLP-induced death of septic mice. SKF ameliorated acute lung injury-like pathology and inhibited leukocyte accumulation in the lung and in the brain. SKF suppressed the expression of TNFα and IL-1β in the periphery and brain. The Morris water maze and Y-maze tests revealed that CLP-induced cognitive dysfunction was ameliorated by SKF, and EEG/EMGs showed that SKF increased sleep duration after CLP. Conclusion These data suggest that endogenous DA prevents sepsis-induced neuroinflammation through D1-like receptors, and BBB-permeable D1-like receptor agonists can be novel drugs for treating sepsis. Neuroinflammation that causes SAE may be a critical cause of sepsis-induced death.