Dexmedetomidine attenuates traumatic brain injury: action pathway and mechanisms

• Published in: Neural regeneration research Vol. 13; no. 5; pp. 819 - 826
• Main Authors: Wang, Dong, Xu, Xin, Wu, Yin-Gang, Lyu, Li, Zhou, Zi-Wei, Zhang, Jian-Ning
• Format: Journal Article
• Language: English
• Published: India Wolters Kluwer India Pvt. Ltd 01.05.2018; Medknow Publications and Media Pvt. Ltd; Medknow Publications & Media Pvt. Ltd; Tianjin Neurological Institute, Key Laboratory of Post-Neuroinjury Neuro-repair and Regeneration in Central Nervous System, Ministry of Education and Tianjin City, Tianjin, China%Department of Cardiovascular, Tianjin Children's Hospital, Tianjin, China; Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, China; Medknow Publications & Media Pvt Ltd; Wolters Kluwer Medknow Publications
• Subjects: Apoptosis; Brain injuries; Contusions; Custom design; Cytokines; Dexmedetomidine; Dosage and administration; Drug therapy; Enzymes; Fluorescent antibody technique; Gene expression; Inflammation; Laboratory animals; nerve regeneration; traumatic brain injury; neuroinflammation; nuclear factor kappa B; NLRP3 inflammasome; brain edema; blood-brain barrier; tight junction proteins; apoptosis; neuroprotection; dexmedetomidine; neural regeneration; Neutrophils; Pathogens; Proteins; Risk factors; Traumatic brain injury; Tumor necrosis factor-TNF; Beijing China; United States > US; China; Japan; blood-brain barrier; brain edema; dexmedetomidine; neural regeneration; neuroinflammation; neuroprotection; nuclear factor kappa B; tight junction proteins; traumatic brain injury; apoptosis; nerve regeneration; NLRP3 inflammasome
• ISSN: 1673-5374; 1876-7958
• DOI: 10.4103/1673-5374.232529

Traumatic brain injury induces potent inflammatory responses that can exacerbate secondary blood-brain barrier (BBB) disruption, neuronal injury, and neurological dysfunction. Dexmedetomidine is a novel α2-adrenergic receptor agonist that exert protective effects in various central nervous system diseases. The present study was designed to investigate the neuroprotective action of dexmedetomidine in a mouse traumatic brain injury model, and to explore the possible mechanisms. Adult male C57BL/6J mice were subjected to controlled cortical impact. After injury, animals received 3 days of consecutive dexmedetomidine therapy (25 µg/kg per day). The modified neurological severity score was used to assess neurological deficits. The rotarod test was used to evaluate accurate motor coordination and balance. Immunofluorescence was used to determine expression of ionized calcium binding adapter molecule-1, myeloperoxidase, and zonula occluden-1 at the injury site. An enzyme linked immunosorbent assay was used to measure the concentration of interleukin-1β (IL-1β), tumor necrosis factor α, and IL-6. The dry-wet weight method was used to measure brain water content. The Evans blue dye extravasation assay was used to measure BBB disruption. Western blot assay was used to measure protein expression of nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3), caspase-1 p20, IL-1β, nuclear factor kappa B (NF-κB) p65, occluding, and zonula occluden-1. Flow cytometry was used to measure cellular apoptosis. Results showed that dexmedetomidine treatment attenuated early neurological dysfunction and brain edema. Further, dexmedetomidine attenuated post-traumatic inflammation, up-regulated tight junction protein expression, and reduced secondary BBB damage and apoptosis. These protective effects were accompanied by down-regulation of the NF-κB and NLRP3 inflammasome pathways. These findings suggest that dexmedetomidine exhibits neuroprotective effects against acute (3 days) post-traumatic inflammatory responses, potentially via suppression of NF-κB and NLRP3 inflammasome activation.