Neuroprotective effects of dexmedetomidine conditioning strategies: Evidences from an in vitro model of cerebral ischemia

Rodríguez-González, Raquel; Sobrino, Tomás; Veiga, Sonia; Lopez, Pablo; Rodrı́guez-Garcı́a, Javier; Río, Sonia Veiras Del; Baluja, Aurora; Castillo, José; Álvarez, Julián

doi:10.1016/j.lfs.2015.12.007

Cited by 30 publications

(21 citation statements)

References 32 publications

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“…The protective effects of Dex in cerebral ischemia were achieved presently with pre- and post-conditioning (drug administration prior to and following the ischemic episode), which is important in a clinical context, since its ability to protect brain tissue even after the onset of ischemia may increase its therapeutic potential as a neuroprotective agent ( 34 , 35 ). The present results indicated that Dex decreased the inflammatory response of brain cells to ischemia, even when administrated 90 min after the H/R period, which indicated that it appeared to be a suitable and reasonable choice that Dex was administrated within 90 min after stoke.…”

Section: Discussionmentioning

confidence: 99%

Neuroprotective role of dexmedetomidine pretreatment in cerebral ischemia injury via ADRA2A‑mediated phosphorylation of ERK1/2 in adult rats

Shi

Peng

et al. 2018

Exp Ther Med

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Neuroprotective effects of dexmedetomidine (Dex) have been reported in various models of brain injury. However, to our knowledge, the neuroprotective mechanism of Dex pretreatment in rats remains unknown. The aim of the present study was to detect the expression of the α2A adrenergic receptor (ADRA2A) in focal ischemic brain tissues and to investigate the protective role and corresponding mechanism of Dex pretreatment in cerebral ischemia in rats. A hypoxia/reoxygenation (H/R) cell model in primary cultured astrocytes and a focal cerebral ischemia/reperfusion (I/R) model in adult rats were used. The expression of ADRA2A and extracellular signal-regulated kinases 1 and 2 (ERK1/2) in the primary cultured astrocytes and rat brain ischemic tissues was detected in the different conditions prior to and following Dex pretreatment using western blotting. The H/R model of primary cultured astrocytes and the focal cerebral I/R model in adult rats were successfully constructed. Under the normal oxygen conditions, 500 ng/ml Dex pretreatment increased the expression of ADRA2A and phosphorylated (p)-ERK1/2 in the astrocytes compared with in the control group. Hypoxic culture for 6 h and then reoxygenation for 24 h decreased the levels of p-ERK1/2 in the astrocytes compared with those in control group. This decrease was prevented by Dex pretreatment for 3 h. The hypoxic culture and then reoxygenation increased the expression of ADRA2A. Similarly, compared with those prior to Dex treatment, the levels of ADRA2A and p-ERK1/2 in the brain ischemic tissues following Dex treatment were increased. The levels of ADRA2A and p-ERK1/2 were 0.72±0.23 and 0.66±0.25 following Dex treatment, compared with 0.76±0.22 and 0.31±0.18, respectively, prior to Dex treatment. The effect of Dex pretreatment increasing p-ERK1/2 expression was attenuated by AG1478 pretreatment. In summary, Dex appeared to promote phosphorylation of ERK1/2 in astrocytes under H/R. As a specific agonist of ADRA2A, Dex may activate phosphorylation of ERK1/2 via ADRA2A in astrocytes. Thus, the neuroprotective role of Dex pretreatment against cerebral ischemic injury may function via ADRA2A-mediated phosphorylation of ERK1/2.

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Section: Discussionmentioning

confidence: 99%

Neuroprotective role of dexmedetomidine pretreatment in cerebral ischemia injury via ADRA2A‑mediated phosphorylation of ERK1/2 in adult rats

Shi

Peng

et al. 2018

Exp Ther Med

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“…Primary mixed cortical cells were isolated from neonatal (P0–P2) C57BL/6J mice and cultured as described previously (Rodriguez-Gonzalez et al, 2016). Briefly, astrocytes were collected and seeded in multiwell plates in DMEM.…”

Section: Methodsmentioning

confidence: 99%

The Potassium Channel KCa3.1 Represents a Valid Pharmacological Target for Astrogliosis-Induced Neuronal Impairment in a Mouse Model of Alzheimer’s Disease

Wei

et al. 2017

Front. Pharmacol.

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Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by progressive decline of cognitive function. Astrogliosis plays a critical role in AD by instigating neuroinflammation, which leads ultimately to cognition decline. We previously showed that the intermediate-conductance Ca2+-activated potassium channel (KCa3.1) is involved in astrogliosis-induced by TGF-β in vitro. In the present study, we investigated the contribution of KCa3.1 channels to astrogliosis-mediated neuroinflammation, using TgAPP/PS1 mice as a model for AD. We found that KCa3.1 expression was increased in reactive astrocytes as well as in neurons in the brains of both TgAPP/PS1 mice and AD patients. Pharmacological blockade of KCa3.1 significantly reduced astrogliosis, microglial activation, neuronal loss, and memory deficits. KCa3.1 blockade inhibited astrocyte activation and reduced brain levels of IL-1β, TNF-α, iNOS, and COX-2. Furthermore, we used primary co-cultures of cortical neurons and astrocytes to demonstrate an important role for KCa3.1 in the process of astrogliosis-induced neuroinflammatory responses during amyloid-β (Aβ)-induced neuronal loss. KCa3.1 was found to be involved in the Aβ-induced activated biochemical profile of reactive astrocytes, which included activation of JNK MAPK and production of reactive oxygen species. Pharmacological blockade of KCa3.1 attenuated Aβ-induced reactive astrocytes and indirect, astrogliosis-mediated damage to neurons. Our data clearly indicate a role for astrogliosis in AD pathogenesis and suggest that KCa3.1 inhibition might represent a good therapeutic target for the treatment of AD.Highlights:(1) Blockade of KCa3.1 in APP/PS1 transgenic mice attenuated astrogliosis and neuron loss, and an attenuation of memory deficits. (2) Blockade of KCa3.1 attenuated Aβ-induced indirect, astrogliosis-mediated damage to neurons in vitro via activation of JNK and ROS.

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“… 12 , 13 Moreover, it has also produced neuroprotective effects by attenuating inflammation and oxidative stress. 32 In the present retrospective analysis, >50% of the patients who underwent PCNL received intraoperative administration of DEX, which was associated with a lower incidence of postoperative SIRS and fever after PCNL compared with those who did not receive DEX. Furthermore, as commonly reported about the inflammation and neuropathic pain after PCNL, the results of our study supported the analgesic benefit of DEX.…”

Section: Discussionmentioning

confidence: 64%

Intraoperative dexmedetomidine attenuates postoperative systemic inflammatory response syndrome in patients who underwent percutaneous nephrolithotomy: a retrospective cohort study

Tan

Gan

Deng

et al. 2018

TCRM

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PurposeDexmedetomidine (DEX) has been reported to attenuate inflammation in rats. The present retrospective cohort study aimed to investigate whether intraoperative administration with DEX could reduce the incidence of postoperative systemic inflammatory response syndrome (SIRS) in patients following percutaneous nephrolithotomy (PCNL).Patients and methodsA total of 251 patients were included in the analysis. Among these patients, 175 received intravenous DEX infusion during the intraoperative period and 76 did not. The primary outcome measures were the incidences of postoperative SIRS and fever. Secondary outcomes included patient-controlled analgesia (tramadol) requirements, length of postoperative hospitalization stay, serum creatinine (Scr) and serum blood urea nitrogen (BUN) concentration, and adverse events (bradycardia, hypotension, renal artery thrombosis).ResultsAdministration of DEX not only significantly attenuated the incidence of SIRS and fever (P=0.029, P=0.042, respectively), but also reduced analgesia requirements (P=0.028). The length of postoperative hospitalization stay, Scr and BUN concentration, and adverse events did not differ significantly between the two groups. Further univariate and multivariate logistic regression analysis indicated that intraoperative DEX administration was a protective factor against SIRS after PCNL (OR 0.476 [95% CI: 0.257–0.835]; P=0.019).ConclusionIntraoperative administration of DEX might be associated with reductions in the incidences of SIRS and fever after PCNL.

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Neuroprotective effects of dexmedetomidine conditioning strategies: Evidences from an in vitro model of cerebral ischemia

Cited by 30 publications

References 32 publications

Neuroprotective role of dexmedetomidine pretreatment in cerebral ischemia injury via ADRA2A‑mediated phosphorylation of ERK1/2 in adult rats

Neuroprotective role of dexmedetomidine pretreatment in cerebral ischemia injury via ADRA2A‑mediated phosphorylation of ERK1/2 in adult rats

The Potassium Channel KCa3.1 Represents a Valid Pharmacological Target for Astrogliosis-Induced Neuronal Impairment in a Mouse Model of Alzheimer’s Disease

Intraoperative dexmedetomidine attenuates postoperative systemic inflammatory response syndrome in patients who underwent percutaneous nephrolithotomy: a retrospective cohort study

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