Dexmedetomidine inhibits astrocyte pyroptosis and subsequently protects the brain in in vitro and in vivo models of sepsis

Abstract

Sepsis is life-threatening and often leads to acute brain damage. Dexmedetomidine, an α2-adrenoceptor agonist, has been reported to possess neuroprotective effects against various brain injury but underlying mechanisms remain elusive. In this study, in vitro and in vivo models of sepsis were used to explore the effects of dexmedetomidine on the inflammasome activity and its associated glia pyroptosis and neuronal death. In vitro, inflammasome activation and pyroptosis were found in astrocytes following lipopolysaccharide (LPS) exposure. Dexmedetomidine significantly alleviated astrocyte pyroptosis and inhibited histone release induced by LPS. In vivo, LPS treatment in rats promoted caspase-1 immunoreactivity in astrocytes and caused an increase in the release of pro-inflammatory cytokines of IL-1β and IL-18, resulting in neuronal injury, which was attenuated by dexmedetomidine; this neuroprotective effect was abolished by α2-adrenoceptor antagonist atipamezole. Dexmedetomidine significantly reduced the high mortality rate caused by LPS challenge. Our data demonstrated that dexmedetomidine may protect glia cells via reducing pyroptosis and subsequently protect neurons, all of which may preserve brain function and ultimately improve the outcome in sepsis.

Potential therapeutic value of dexmedetomidine in COVID-19 patients admitted to ICU

“…Mice treated with dexmedetomidine exhibited reduced inflammation-induced cell death (pyroptosis) in astrocytes and in turn protected neurones in sepsis-induced brain injury. 8 The underlying protective mechanisms of dexmedetomidine include increasing parasympathetic tone, dampening of the inflammatory response, prevention of cell death, and inhibition of oxidative stress. 10 By increasing parasympathetic tone and decreasing sympathetic tone, dexmedetomidine appears to confer protective effects on immune function by effects on T cells and natural killer cells.…”

Dexmedetomidine attenuates LPS‐mediated BV2 microglia cells inflammation via inhibition of glycolysis

“…Dexmedetomidine, a highly selective α 2 ‐adrenergic receptor agonist, is widely used for the sedation of critically ill patients. Moreover, dexmedetomidine has been shown to attenuate LPS‐mediated pro‐inflammatory response and exhibit neuroprotective effects . In this study, we mainly focused on whether and how dexmedetomidine inhibits LPS‐mediated cellular glycolysis, thus attenuating inflammation in BV2 cells.…”

Neuroprotective Effects of Intraoperative Dexmedetomidine Infusion Combined With Goal-directed Hemodynamic Therapy for Patients Undergoing Cranial Surgery: A Double-blinded Randomized Controlled Trial

“…Dexmedetomidine has been reported to mitigate neuroin ammatory cascades, and inhibit catecholamine and glutamate release, thereby preventing regional cerebral ischemia [2,11], which commonly occurs during cranial surgery [1,10]. In addition, plausible mechanisms of neuroprotective effects of dexmedetomidine include the attenuation of neuronal necrosis, apoptosis, autophagy through the effects of an increase of focal adhesion kinase phosphorylation in hippocampus, inducing increases of brain derived neurotrophic factor expression [25] as well as inhibiting lipopolysaccharide-induced astrocyte pyroptosis [26]. The modi ed Barthel index was sensitive to in-hospital function changes [13,23], and 30-day mRS may re ect longer-term disability recovery after cranial surgery [21].…”