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Excitotoxicity is one of the main mechanisms related to hypoxia/reoxygenation (H/R) injury. Excitatory amino acid transporter (EAAT)2 mainly distributes on astrocytes and plays an important role on glutamate reuptake and glutamate homeostasis. Midazolam has a neuroprotective effect in some neuropathological conditions. The present study aimed to detect the role of EAAT2 in the neuroprotective effect of midazolam in neonatal rat brain subjected to H/R. Pretreatment with midazolam reversed H/R-induced apoptosis and downregulation of EAAT2 mRNA and protein expression in the hippocampus. Pretreatment with dihydrokainic acid (a selective inhibitor of EAAT2) exacerbated apoptosis, and thus inhibited the neuroprotective effect of midazolam against H/R injury. We demonstrated for the first time that dysregulation of EAAT2 expression may be related to the neural injury induced by H/R in rat pups, and pretreatment with midazolam attenuated apoptosis and improved learning and memory partly due to regulating EAAT2 expression., Competing Interests: Declaration of Competing Interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2020. Published by Elsevier Inc.)

Background: Exploring the effective therapy for neonatal hypoxic-ischemic brain injury is an important goal. This study was designed to investigate how dexmedetomidine (DEX) contribute to hypoxic brain injury. Methods: Developing Sprague-Dawley rat models of hypoxia/reoxygenation (H/R) injury were constructed to simulate neonatal hypoxic brain injury for DEX treatment. Immunohistochemistry and western blot were performed to measure neuroglobin (Ngb) protein expression in hippocampal tissues. Hippocampal neuron injury and apoptosis were detected by Nissl staining and TUNEL assay, respectively. A Morris water maze (MWM) test was performed to evaluate the long-term learning and memory function. Results: The expression of Ngb was increased following H/R model establishment and up-regulated by medium and high doses of DEX, but not up-regulated by low doses of DEX. Medium and high doses of DEX alleviated the H/R injury as well as induced the reduction of Nissl bodies and apoptosis. Besides, medium and high doses of DEX down-regulated cytosolic Cyt-c, Apaf-1, and caspase-3 in H/R injury model. MWM test showed that medium and high doses of DEX significantly shortened the escape latency and enhanced the number of platform crossings. However, low doses of DEX have no effect on Nissl bodies, mitochondrial apoptosis, expression of apoptosis-related proteins and long-term learning functions. Conclusions: DEX induced Ngb expression in H/R rat models. The neuroprotection of DEX-mediated Ngb up-regulation may be achieved by inhibiting neuronal apoptosis through the mitochondrial pathway. Findings indicated that DEX may be useful as an effective therapy for neonatal hypoxic brain injury. [ABSTRACT FROM AUTHOR]

To observe the effect of dexmedetomidine (DEX) on mitochondrial apoptosis of hippocampal neurons in hypoxia/reoxygenation (H/R) brain injury in developing rats, and to investigate its regulatory mechanism on HIF-1α/p53 signaling pathway. Hypoxia/reoxygenation model was used in this study. TUNEL assay was performed to detect cell apoptosis. Immunohistochemical analysis and Western-blotting analysis were conducted to detect Cytochrome-C (Cyt-c), APAF-1, Caspase-3, Neuroglobin (Ngb), HIF-1α and p53 expression. After 28 days, Morris water maze (MWM) was performed. 50 μg/kg DEX improved H/R-induced brain injury and inhibited mitochondrial apoptosis in rats. Western-blotting and Immunohistochemical results demonstrated that DEX could up-regulate Ngb through α 2 receptor to inhibit H/R-induced mitochondrial apoptosis. In addition, by adding inhibitors yohimbine and 2-methoxyestradiol (2ME2), we found that DEX could activate HIF-1α/p53 signaling pathway. MWM test showed that DEX could enhance long-term learning and memory of H/R brain injury rats. DEX alleviates H/R-induced brain injury and mitochondrial apoptosis in developing rats through α 2 receptor, which may be related to activation of HIF-1α/p53 signaling pathway to up-regulate the expression of Ngb. [ABSTRACT FROM AUTHOR]