ドーパミンD1様受容体アゴニストは免疫抑制効果により外傷性脳損傷を改善する

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.