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A dopamine D1-like receptor-specific agonist improves the survival of septic mice.

ABSTRACT: In this study, a murine sepsis model was developed using the cecum ligation and puncture (CLP) technique. The expression of the proinflammatory cytokines tumor necrosis factor alpha (TNF-α) and interleukin-1β (IL-1β) in the brain increased 6 h after CLP but decreased 24 h later when elevated endogenous dopamine levels in the brain were sustained. Methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride reduced dopamine levels in the striatum and increased mortality in septic mice. Dopamine D1-like receptors were significantly expressed in the brain, but not in the lungs. Intraperitoneally administered SKF-81297 (SKF), a blood-brain barrier-permeable D1-like receptor agonist, prevented CLP-induced death of septic mice with ameliorated acute lung injury and cognitive dysfunction and suppressed TNF-α and IL-1β expression. The D1-like receptor antagonist SCH-23390 abolished the anti-inflammatory effects of SKF. These data suggest that D1-like receptor-mediated signals in the brain prevent CLP-induced inflammation in both the brain and the periphery.

SUBMITTER: Tanaka K

PROVIDER: S-EPMC11016908 | biostudies-literature | 2024 Apr

REPOSITORIES: biostudies-literature

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A dopamine D1-like receptor-specific agonist improves the survival of septic mice.

Tanaka Koichi K Choudhury Mohammed E ME Kikuchi Satoshi S Takeda Ikuko I Umakoshi Kensuke K Miyaue Noriyuki N Mikami Kanta K Takenaga Ayane A Yagi Harumichi H Shinabe Rintaro R Matsumoto Hironori H Yano Hajime H Nagai Masahiro M Takeba Jun J Tanaka Junya J

iScience 20240327 4

In this study, a murine sepsis model was developed using the cecum ligation and puncture (CLP) technique. The expression of the proinflammatory cytokines tumor necrosis factor alpha (TNF-α) and interleukin-1β (IL-1β) in the brain increased 6 h after CLP but decreased 24 h later when elevated endogenous dopamine levels in the brain were sustained. Methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride reduced dopamine levels in the striatum and increased mortality in septic mice. Dopamine D1-li ...[more]

PMID: 38623339

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Project description:BackgroundMajor depressive disorder is a significant global cause of disability, particularly among adolescents. The dopamine system and nearby neuroinflammation, crucial for regulating mood and processing rewards, are central to the frontostriatal circuit, which is linked to depression. This study aimed to investigate the effect of post-weaning isolation (PWI) on depression in adolescent mice, with a focus on exploring the involvement of microglia and dopamine D1 receptor (D1R) in the frontostriatal circuit due to their known links with mood disorders.ResultsAdolescent mice underwent 8 weeks of PWI before evaluating their depression-like behaviors and the activation status of microglia in the frontostriatal regions. Selective D1-like dopamine receptor agonist SKF-81,297 was administered into the medial prefrontal cortex (mPFC) of PWI mice to assess its antidepressant and anti-microglial activation properties. The effects of SKF-81,297 on inflammatory signaling pathways were examined in BV2 microglial cells. After 8 weeks of PWI, female mice exhibited more severe depression-like behaviors than males, with greater microglial activation in the frontostriatal regions. Microglial activation in mPFC was the most prominent among the three frontostriatal regions examined, and it was positively correlated with the severity of depression-like behaviors. Female PWI mice exhibited increased expression of dopamine D2 receptors (D2R). SKF-81,297 treatment alleviated depression-like behaviors and local microglial activation induced by PWI; however, SKF-81,297 induced these alterations in naïve mice. In vitro, SKF-81,297 decreased pro-inflammatory cytokine release and phosphorylations of JNK and ERK induced by lipopolysaccharide, while in untreated BV2 cells, SKF-81,297 elicited inflammation.ConclusionsThis study highlights a sex-specific susceptibility to PWI-induced neuroinflammation and depression. While targeting the D1R shows potential in alleviating PWI-induced changes, further investigation is required to evaluate potential adverse effects under normal conditions.

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A dopamine D1-like receptor-specific agonist improves the survival of septic mice.

Publications

A dopamine D1-like receptor-specific agonist improves the survival of septic mice.

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