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

Cellular and molecular neurobiology  ·  2026

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;

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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.

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