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Abstract <p>Traumatic brain injury (TBI) causes progressive nervous tissue degeneration long after the initial injury due to secondary neuroinflammatory reactions. G protein-coupled dopamine D1-like receptors, which elevate intracellular cAMP levels, have been shown to mediate the suppressive effects on lipopolysaccharide (LPS)-induced proinflammatory activation of microglia and macrophages. The present study investigated whether or not the D1-like receptor-specific agonist SKF-81297 (SKF) administered intraperitoneally once daily for 3days starting 1&#xa0;h after TBI could ameliorate TBI in a rat model of stab wounds in the forebrain. SKF reduced the volume of TBI-induced brain tissue loss, increased mobile activity, and ameliorated cognitive dysfunction two months after TBI. A single dose of SKF suppressed the expression of IL-1β and TNFα in brain tissue by reducing oxidative injury at 24&#xa0;h post-TBI. SKF decreased the energy metabolism of microglia, macrophages, and neutrophils in TBI brain. SKF prevented LPS-induced translocation of NFκB into the nuclei of primary cultured microglia. The agonist clenbuterol (CLB) for adrenergic β2 receptor, another Gs-linked GPCR, exerted comparable ameliorative effects in TBI model rats by suppressing neuroinflammation. In summary, SKF may exert anti-inflammatory effects by suppressing the NFkB pathway through increasing cAMP similarly to CLB and also by decreasing energy metabolism of inflammatory cells, leading to amelioration of TBI-induced brain degeneration.</p> Graphical Abstract <p></p>

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A Dopamine D1-Like Receptor Agonist Ameliorates Traumatic Brain Injury Through its Immunosuppressive Effects

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月28日

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  • Mohammed E. Choudhury,
  • Ayane Takenaga,
  • Haruto Yamamoto,
  • Hiroto Yamauchi,
  • Emiri Koga,
  • Naoki Abe,
  • Noriyuki Miyaue,
  • Shirabe Matsumoto,
  • Keisuke Sekiya,
  • Akari Kusakawa,
  • Naohito Tokunaga,
  • Koichi Tanaka,
  • Takeharu Kunieda,
  • Masahiro Nagai,
  • Junya Tanaka,
  • Tasuku Nishihara

摘要

Abstract

Traumatic brain injury (TBI) causes progressive nervous tissue degeneration long after the initial injury due to secondary neuroinflammatory reactions. G protein-coupled dopamine D1-like receptors, which elevate intracellular cAMP levels, have been shown to mediate the suppressive effects on lipopolysaccharide (LPS)-induced proinflammatory activation of microglia and macrophages. The present study investigated whether or not the D1-like receptor-specific agonist SKF-81297 (SKF) administered intraperitoneally once daily for 3days starting 1 h after TBI could ameliorate TBI in a rat model of stab wounds in the forebrain. SKF reduced the volume of TBI-induced brain tissue loss, increased mobile activity, and ameliorated cognitive dysfunction two months after TBI. A single dose of SKF suppressed the expression of IL-1β and TNFα in brain tissue by reducing oxidative injury at 24 h post-TBI. SKF decreased the energy metabolism of microglia, macrophages, and neutrophils in TBI brain. SKF prevented LPS-induced translocation of NFκB into the nuclei of primary cultured microglia. The agonist clenbuterol (CLB) for adrenergic β2 receptor, another Gs-linked GPCR, exerted comparable ameliorative effects in TBI model rats by suppressing neuroinflammation. In summary, SKF may exert anti-inflammatory effects by suppressing the NFkB pathway through increasing cAMP similarly to CLB and also by decreasing energy metabolism of inflammatory cells, leading to amelioration of TBI-induced brain degeneration.

Graphical Abstract