Abstract
Brain injury is a significant risk factor for chronic gliosis and neurodegenerative diseases. Currently, no treatment is available for neuroinflammation caused by the action of glial cells following brain injury. In this study, we investigated the quinpirole-mediated activation of dopamine D2 receptors (D2R) in a mouse model of traumatic brain injury (TBI). We also investigated the neuroprotective effects of quinpirole (a D2R agonist) against glial cell-induced neuroinflammation secondary to TBI in adult mice. After the brain injury, we injected quinpirole into the TBI mice at a dose of 1 mg/kg daily intraperitoneally for 7 days. Our results showed suppression of D2R expression and deregulation of downstream signaling molecules in ipsilateral cortex and striatum after TBI on day 7. Quinpirole administration regulated D2R expression and significantly reduced glial cell-induced neuroinflammation via the D2R/Akt/glycogen synthase kinase 3 beta (GSK3-β) signaling pathway after TBI. Quinpirole treatment concomitantly attenuated increase in glial cells, neuronal apoptosis, synaptic dysfunction, and regulated proteins associated with the blood–brain barrier, together with the recovery of lesion volume in the TBI mouse model. Additionally, our in vitro results confirmed that quinpirole reversed the microglial condition media complex-mediated deleterious effects and regulated D2R levels in HT22 cells. This study showed that quinpirole administration after TBI reduced secondary brain injury-induced glial cell activation and neuroinflammation via regulation of the D2R/Akt/GSK3-β signaling pathways. Our study suggests that quinpirole may be a safe therapeutic agent against TBI-induced neurodegeneration.
Highlights
Traumatic brain injury (TBI) is a global risk factor and the leading cause of neurological disability
We investigated the possible regulation of D2 receptors (D2R) in the cortical region of the brain, which is the primary target of brain injury, and explored the striatal region in a TBI mouse model
Our results suggest that quinpirole activates D2R, which plays a crucial role in several neuropathological events in ipsilateral cortex after brain injury
Summary
Traumatic brain injury (TBI) is a global risk factor and the leading cause of neurological disability. TBI leads to a primary injury, which is followed by a secondary brain injury. Primary brain injury refers to the direct mechanical force applied at the time of the initial impact on the brain. Secondary brain injury occurs as a consequence of the initial traumatic events. It refers to the involvement of the brain vasculature as well as the blood–brain barrier (BBB) disruption, which results in significant complications in the brain [4]. Neuroinflammation is the principal hallmark of brain injury, followed by astrocyte and microglia activation and release of pro-inflammatory cytokines and chemokines, which impair the endogenous self-repair
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