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

Abstract

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.

Allopurinol and Febuxostat Equally Attenuate Methotrexate-Induced Testicular Injury In Rats Via Activation Of EGF/ ERK1/2/HO‐1 Signaling Pathway.

“…In current work, p-ERK 1/2 increased in the testicular tissue exposed to MTX + ALL and increased in MTX + FEB groups when compared with MTX intoxicated rats. Interestingly, recent studies demonstrated that several drugs provide protective effect through activating ERK signaling cascade [40][41][42]. Surprisingly, the current results are supported by reports exhibited the link between activation of EGF and induction of ERK 1/2 [43].…”

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

“…However, when the phosphorylation of erK1/2 was inhibited by Pd98059, the protective effects of dex appeared to be largely weakened. The neuroprotective role of dex against cerebral ischemic injury may function via phosphorylation of erK1/2 or the MaPK/erK pathway (34,35). Similarly, the present study indicated that dex pretreatment may protect alveolar epithelial cells against Vili-mediated effects through erK1/2 activation.…”

Mechanisms of Dexmedetomidine in Neuropathic Pain

“…Therefore, in future clinical research, it is necessary to consider the influence of various drug factors on various aspects of neuronal injury and to conduct a large number of preclinical experiments to accurately assess the safety and effectiveness of dexmedetomidine on the neuroprotective effects of the human body Wang et al, 2019). Moreover, in lieu of the neuroprotective effect of dexmedetomidine, the drug has begun to be studied in clinical neuropathic pain diseases (Kim et al, 2017;Shi et al, 2018). Thus, we have also summarized many studies on the application of dexmedetomidine in neuropathic pain in this review.…”

“…In the CNS, astrocytes connect capillaries and neurons through perivascular limbs, which can transport nutrients and eliminate metabolites to neurons (Zuchero and Barres, 2015). It has been found that dexmedetomidine can inhibit the astrocyte-induced overactivation caused by ischemia-reperfusion and can reduce the expression of glial fibrillary acidic protein and inflammatory factor TNF-α, which suggests that dexmedetomidine has neuroprotective effects on cerebral ischemia-reperfusion injury in rats (Freeman et al, 2015;Shi et al, 2018).…”