Dexmedetomidine modulates neuroinflammation and improves outcome via alpha2-adrenergic receptor signaling after rat spinal cord injury

Abstract

Background: Spinal cord injury induces inflammatory responses that include the release of cytokines and the recruitment and activation of macrophages and microglia. Neuroinflammation at the lesion site contributes to secondary tissue injury and permanent locomotor dysfunction. Dexmedetomidine (DEX), a highly selective a2-adrenergic receptor agonist, is anti-inflammatory and neuroprotective in both preclinical and clinical trials. We investigated the effect of DEX on the microglial response, and histological and neurological outcomes in a rat model of cervical spinal cord injury. Methods: Anaesthetised rats underwent unilateral (right) C5 spinal cord contusion (75 kdyne) using an impactor device. The locomotor function, injury size, and inflammatory responses were assessed. The effect of DEX was also studied in a microglial cell culture model. Results: DEX significantly improved the ipsilateral upper-limb motor dysfunction (grooming and paw placement; P<0.0001 and P¼0.0012), decreased the injury size (P<0.05), spared white matter (P<0.05), and reduced the number of activated macrophages (P<0.05) at the injury site 4 weeks post-SCI. In DEX-treated rats after injury, tissue RNA expression indicated a significant downregulation of pro-inflammatory markers (e.g. interleukin [IL]-1b, tumour necrosis factor-a, interleukin (IL)-6, and CD11b) and an upregulation of anti-inflammatory and pro-resolving M2 responses (e.g. IL-4, arginase-1, and CD206) (P<0.05). In lipopolysaccharide-stimulated cultured microglia, DEX produced a similar inflammation-modulatory effect as was seen in spinal cord injury. The benefits of DEX on these outcomes were mostly reversed by an a2-adrenergic receptor antagonist.Conclusions: DEX significantly improves neurological outcomes and decreases tissue damage after spinal cord injury, which is associated with modulation of neuroinflammation and is partially mediated via a2-adrenergic receptor signaling.

Dexmedetomidine reduces ventilator-induced lung injury via ERK1/2 pathway activation

“…dex has a high affinity for α2 adrenoceptor and it is widely used in critically ill patients (at 1-1.5 µg/kg/h) owing to its sedative effects without respiratory inhibition (25,26). Numerous studies have also reported the anti-inflammatory effects of Dex by reducing the expression of inflammatory factors in certain specific cases (27)(28)(29). Considering previous literature reports and clinical dose analysis (11,12), two doses of dex were examined in the present study.…”

Noradrenergic Signaling and Neuroinflammation Crosstalk Regulate Toxoplasma gondii-Induced Behavioral Changes

“…Indeed, guanabenz has a greater affinity for 2-ARs than NE (ref again). Inflammatory cytokine production by microglia, astrocytes and invading immune cells is suppressed by 2-AR agonists (Figure 3C) [63]. Furthermore, as well as modulating neurotransmission, guanabenz's immunomodulatory effects are highlighted by its systemic action on TLR signaling in mouse dendritic cells [64] and down-regulation of GM-CSF, IL-6, TNF, and IL-1 production in mouse macrophages [65].…”

“…"Beta blockers" are well known β-AR antagonists used systemically to reduce blood pressure that bind ARs in the heart and vasculature [72]. Agonists of the 2-AR, including guanabenz, exhibit a higher affinity for these receptors than NE and act to mimic the action of NE [62,63].…”

Dexmedetomidine Alleviates Microglia-Induced Spinal Inflammation and Hyperalgesia in Neonatal Rats by Systemic Lipopolysaccharide Exposure

“…Dexmedetomidine, a mainly selective adrenergic α2 receptor agonist, has been widely used in pediatric clinical practice for sedation ( Mahmoud et al, 2020 ). It has been reported that dexmedetomidine (DEX) displays an anti-neuroinflammatory and neuroprotective property, possibly through the inhibition of microglial activation and microglial polarization toward the M1 phenotype ( Yeh et al, 2018 ; Gao et al, 2019 ). Moreover, DEX can induce M2 microglial polarization and increase levels of microglia-associated anti-inflammatory cytokines ( Sun et al, 2018 ; Gao et al, 2019 ; Qiu et al, 2020 ), which may also implicate its anti-inflammatory effect.…”

“…It has been reported that dexmedetomidine (DEX) displays an anti-neuroinflammatory and neuroprotective property, possibly through the inhibition of microglial activation and microglial polarization toward the M1 phenotype ( Yeh et al, 2018 ; Gao et al, 2019 ). Moreover, DEX can induce M2 microglial polarization and increase levels of microglia-associated anti-inflammatory cytokines ( Sun et al, 2018 ; Gao et al, 2019 ; Qiu et al, 2020 ), which may also implicate its anti-inflammatory effect. Nevertheless, it remains unclear whether DEX can attenuate inflammation and hyperalgesia triggered by systemic LPS injection during the neonatal period.…”