Abstract

BackgroundAlthough the neurotransmitter dopamine (DA) plays a crucial pathophysiologic role after traumatic brain injury (TBI), its function and specific underlying mechanisms of action remain unclear.MethodsAdult male mice underwent controlled cortical impact (CCI). We administered DA intraperitoneally to mice for 14 consecutive days, starting 8 h before CCI. On day 3 after brain injury, cortical lesion volume and brain water content were measured. On days 7–13, behavioral tests were performed.ResultsHerein we report that DA inhibits neural death after injury, which is mediated via the dopamine D1 receptor (DRD1). Our results also showed that DRD1 signaling promotes RIPK1 ubiquitination via the E3 ubiquitin ligase Chip and then degradation through autophagy. Importantly, in vivo data revealed that DRD1 signaling prevented neural death, suppressed neuroinflammation, and restored many TBI-related functional sequelae.ConclusionsThese data reveal a novel mechanism involving dopamine, and suggest that DRD1 activation positively regulates Chip-mediated ubiquitylation of RIPK1—leading to its autophagic degradation.

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