Abstract
ObjectiveDexmedetomidine (DEX) exhibits neuroprotective effects as a multifunctional neuroprotective agent in numerous neurological disorders. However, in traumatic brain injury (TBI), the molecular mechanisms of these neuroprotective effects remain unclear. The present study investigated whether DEX, which has been reported to exert protective effects against TBI, could attenuate neuroinflammatory‐induced apoptosis and clarified the underlying mechanisms.MethodsA weight‐drop model was established, and DEX was intraperitoneally injected 30 min after inducing TBI in rats. The water content in the brain tissue was measured. Terminal deoxynucleotidyl transferase‐mediated dUTP nick‐end labeling (TUNEL) assays were performed on histopathological tissue sections to evaluate neuronal apoptosis. Enzyme‐linked immunosorbent assay and PCR were applied to detect the levels of the inflammatory factors, TNF‐α, IL‐1β, IL‐6, and NF‐κB.ResultsTBI–challenged rats exhibited significant neuronal apoptosis, which was characterized via the wet‐to‐dry weight ratio, neurobehavioral functions, TUNEL assay results and the levels of cleaved caspase‐3, Bax upregulation and Bcl‐2, which were attenuated by DEX. Western blot, immunohistochemistry, and PCR results revealed that DEX promoted Nrf2 expression and upregulated expression of the Nrf2 downstream factors, HO‐1 and NQO‐1. Furthermore, DEX treatment markedly prevented the downregulation of inflammatory response factors, TNF‐α, IL‐1β and NF‐κB, and IL‐6.InterpretationAdministering DEX attenuated inflammation‐induced brain injury in a TBI model, potentially via the Nrf2 signaling pathway.
Highlights
IntroductionThe pathophysiological mechanisms of traumatic brain injury (TBI) include primary brain tissue disruption and secondary brain injury, including excitotoxic damage, inflammation, increased vascular permeability, and oxidative stress.[1,2] Among these events, inflammation is considered an important contributor to the TBI pathophysiology and exacerbates neuronal damage during the process of secondary insult, which is characterized by peripheral inflammation, cell infiltration, and secretion of inflammatory mediators.[3,4] Sustained and excessive inflammation can exacerbate subsequent neurological impairment through secretion of proinflammatory mediators such as interleukin (IL)-1b, tumor necrosis factor (TNF)-a, and IL-6.1 Previous studies have confirmed that these acute-phase cytokines are regulated via the nuclear factor kappa B (NF-jB) signaling pathway after TBI and that NF-jB expression increases rapidly after brain injury.[5]Inflammation is linked with oxidative stress, or elevated intracellular levels of reactive oxygen species (ROS), which are considered the most potent inflammatory mediators.[6]Nuclear factor erythroid 2-related factor 2 (Nrf2) is an important transcription factor that regulates cellular antioxidant activity and has been shown to protect organs in several animal models.[7,8] Nrf2–mediated antioxidant gene expression can reduce the macrophage M1 phenotype a 2019 The Authors
Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association
neurological severity score (NSS) scores were higher in the traumatic brain injury (TBI) and TBI + vehicle groups than in the Sham and Sham + DEX groups 3 days after inducing TBI (P < 0.001)
Summary
The pathophysiological mechanisms of traumatic brain injury (TBI) include primary brain tissue disruption and secondary brain injury, including excitotoxic damage, inflammation, increased vascular permeability, and oxidative stress.[1,2] Among these events, inflammation is considered an important contributor to the TBI pathophysiology and exacerbates neuronal damage during the process of secondary insult, which is characterized by peripheral inflammation, cell infiltration, and secretion of inflammatory mediators.[3,4] Sustained and excessive inflammation can exacerbate subsequent neurological impairment through secretion of proinflammatory mediators such as interleukin (IL)-1b, tumor necrosis factor (TNF)-a, and IL-6.1 Previous studies have confirmed that these acute-phase cytokines are regulated via the nuclear factor kappa B (NF-jB) signaling pathway after TBI and that NF-jB expression increases rapidly after brain injury.[5]Inflammation is linked with oxidative stress, or elevated intracellular levels of reactive oxygen species (ROS), which are considered the most potent inflammatory mediators.[6]Nuclear factor erythroid 2-related factor 2 (Nrf2) is an important transcription factor that regulates cellular antioxidant activity and has been shown to protect organs in several animal models.[7,8] Nrf2–mediated antioxidant gene expression can reduce the macrophage M1 phenotype a 2019 The Authors. The pathophysiological mechanisms of traumatic brain injury (TBI) include primary brain tissue disruption and secondary brain injury, including excitotoxic damage, inflammation, increased vascular permeability, and oxidative stress.[1,2]. Among these events, inflammation is considered an important contributor to the TBI pathophysiology and exacerbates neuronal damage during the process of secondary insult, which is characterized by peripheral inflammation, cell infiltration, and secretion of inflammatory mediators.[3,4]. Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association.
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