Stimulation of dopamine D2 receptor via quinpirole protects against brain damage after brain injury in mice

Abstract

Backgroung Brain injury is a major risk factor for the development of chronic neurodegenerative diseases. The disease still lacks a potential candidate to treat brain injury associated neurodegeneration. In the present study we aims to investigate the expression of Dopamin D2 receptor in the cortical region as well as in striatum of the injured mouse brain and further explored the neuroprotective effects of selective D2R agonist quinpirole against brain injury-associated neuropathological events after brain injury.Methods In order to test our hypothesis, a normal mice were subjected into TBI mouse model by producing penetrating injury using scalpel blade. A dose of 1mg/kg of quinpirole was daily injected to the TBI mice via intraperitonally for 7 days after producing injury. Further, the immunoblots and immunohistochemistry analysis were performed for both in vivo and in vitro.Results Our biochemical and immunohistological results demonstrated that brain injury suppresses the expression levels of D2R and deregulate the downstream signaling molecules in the cortex and striatum afte TBI at day 7. Treatment with a selective D2R agonist quinpirole regulates GSK3-β/IL-1β/Akt signaling and reduced neuroinflamation after brain injury. Concomitantly, Quinpirole treatment regulated Blood brain-barrier breakdown, reduced neuronal apoptosis and regulated synaptic dysfunction after brain injury. This is the first evidence, which showed that quinpirole treatment reduced secondary brain injury-induced neuropathological evidence in the cortex via D2R/Akt/GSK3-β signaling pathway. Moreover, our in vitro results demonstrated that quinpirole reversed MCM-mediated deleterious effects and significantly regulated D2R/GSK3-β/Akt level in HT22 cells.Conclusion Our results suggest that regulation of Dopamine D2 receptor via quinpirole would be a promising therapeutic strategy against brain injury-induced neurodegeneration.