Dexmedetomidine Acts via the JAK2/STAT3 Pathway to Attenuate Isoflurane-Induced Neurocognitive Deficits in Senile Mice

Abstract

BackgroundPrevious studies showed that isoflurane-induced cognitive deficits could be alleviated by dexmedetomidine in young animal subjects. In the current study, we examine whether dexmedetomidine could also alleviate isoflurane-induced cognitive deficits in senile animals.MethodsSenile male C57BL/6 mice (20 months) received dexmedetomidine (50 μg/kg, i.p.) or vehicle 30 minutes prior to isoflurane exposure (1.3% for 4 h). Cognitive function was assessed 19 days later using a 5-day testing regimen with Morris water maze. Some subjects also received pretreatment with α2 adrenoreceptor antagonist atipamezole (250 μg/kg, i.p.), JAK2 inhibitor AG490 (15 mg/kg i.p.) or STAT3 inhibitor WP1066 (40 mg/kg i.p.) 30 minutes prior to dexmedetomidine.ResultsIsoflurane exposure increased and reduced the time spent in the quadrant containing the target platform in training sessions. The number of crossings over the original target quadrant was also decreased. Dexmedotomidine attenuated such effects. Effects of dexmedotomidine were reduced by pretreatment with atipamezole, AG490 and WP1066. Increased phosphorylation of JAK2 and STAT3 in the hippocampus induced by isoflurane was augmented by dexmedetomidine. Effects of dexmedetomidine on JAK2/STAT3 phosphorylation were attenuated by atipamezole, AG490 and WP1066. Isoflurane promoted neuronal apoptosis and increased the expression of cleaved caspase-3 and BAD, and reduced Bcl-2 expression. Attenuation of such effects by dexmedotomidine was partially blocked by atipamezole, AG490 and WP1066.ConclusionDexmedetomidine could protect against isoflurane-induced spatial learning and memory impairment in senile mice by stimulating the JAK2/STAT3 signaling pathway. Such findings encourage the use of dexmedetomidine in geriatric patients receiving isoflurane anesthesia.

Dexmedetomidine-mediated neuroprotection against sevoflurane-induced neurotoxicity extends to several brain regions in neonatal rats

“…Interestingly, in the DEX 50 mg kg À1 group we found a significant increase in apoptosis in the CA1 region of the hippocampus. A high sensitivity of the CA1 region of the hippocampus to DEX has also been observed in neonatal mice treated with DEX 50 mg kg À1 alone, 67 suggesting that this region is particularly sensitive to high doses of DEX in the developing brain. However, Pancaro and colleagues 65 found that DEX alone (30 or 45 mg kg À1 ) induced significant apoptosis in sensorial cortical regions including the S1 region but not in the hippocampus.…”

Dexmedetomidine ameliorates lipopolysaccharide‐induced acute kidney injury in rats by inhibiting inflammation and oxidative stress via the GSK‐3β/Nrf2 signaling pathway

“…↓: enhanced; ⊥: attenuated; AKI: acute kidney injury; DEX: dexmedetomidine; GSK-3β: glycogen synthase kinase-3β; HO-1: heme oxygenase-1; IL-6: interleukin 6; IL-18: interleukin 18; IL-1β: interleukin-1β; LPS: lipopolysaccharide; NQO1: NAD(P)H quinone oxidoreductase-1; Nrf2: nuclear factor erythroid 2-related factor 2; ROS: reactive oxygen species; SB216763: GSK-3β inhibitor; TNF-α: tumor necrosis factor α [Color figure can be viewed at wileyonlinelibrary.com] DEX is thought to exert its organoprotective effects mainly by binding to α2-AR . The concentrations of DEX (25 μg/kg) and Atip (250 μg/kg) used in the present study were based on previous work (Cui et al, 2015b;Si et al, 2016) and on a binding affinity ratio of 10:1 for the agonist-antagonist (Virtanen, Savola, & Saano, 1989). The IRs (I 1 R, I 2 R, I 3 R) are another class of DEX-binding receptors that have mainly been investigated for their involvement in anesthesia and analgesia (H. Zhang, Yan, et al, 2017a).…”

Silencing of TCTN1 inhibits proliferation, induces cell cycle arrest and apoptosis in human thyroid cancer

“…To illuminate the molecular mechanisms by which TCTN1 affected thyroid cancer apoptosis, we detected some molecules associated with cell survival in CAL62 cells after TCTN1 knockdown. The anti-apoptotic protein Bcl-2 plays a pivotal role in regulating cell apoptosis under many adverse conditions, while pro-apoptotic Bad is essential for inducing apoptosis ( 22 ). In our results, reduced Bcl-2 and increased Bad expression suggested silencing TCTN1 might serve as a promoter of cell apoptosis.…”