Dexmedetomidine is neuroprotective in an in vitro model for traumatic brain injury

Department of Anesthesiology, University Hospital of the RWTH Aachen, Pauwelsstraße 30, 52074 Aachen, Germany.
BMC Neurology (Impact Factor: 2.04). 04/2012; 12(1):20. DOI: 10.1186/1471-2377-12-20
Source: PubMed


The α2-adrenoreceptor agonist dexmedetomidine is known to provide neuroprotection under ischemic conditions. In this study we investigated whether dexmedetomidine has a protective effect in an in vitro model for traumatic brain injury.
Organotypic hippocampal slice cultures were subjected to a focal mechanical trauma and then exposed to varying concentrations of dexmedetomidine. After 72 h cell injury was assessed using propidium iodide. In addition, the effects of delayed dexmedetomidine application, of hypothermia and canonical signalling pathway inhibitors were examined.
Dexmedetomidine showed a protective effect on traumatically injured hippocampal cells with a maximum effect at a dosage of 1 μM. This effect was partially reversed by the simultaneous administration of the ERK inhibitor PD98059.
In this TBI model dexmedetomidine had a significant neuroprotective effect. Our results indicate that activation of ERK might be involved in mediating this effect.

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    • ", nonessential amino acids, and 10% fetal bovine serum) or growth medium alone (control) for 24 hours at 37 C. The Dex concentrations used in this study were based on those previously used in neuronal cell culture studies (Sanders et al., 2010) as well as concentrations previously demonstrated to be neuroprotective in an organotypic hippocampal slice culture model of traumatic brain injury (Schoeler et al., 2012). At the end of the exposure period, the media were removed by aspiration, and each well was rinsed twice with 1 mL of phosphate-buffered saline warmed to 37 C. "
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    ABSTRACT: There is developing interest in the potential association between anesthesia and the onset and progression of Alzheimer's disease. Several anesthetics have, thus, been demonstrated to induce tau hyperphosphorylation, an effect mostly mediated by anesthesia-induced hypothermia. Here, we tested the hypothesis that acute normothermic administration of dexmedetomidine (Dex), an intravenous sedative used in intensive care units, would result in tau hyperphosphorylation in vivo and in vitro. When administered to nontransgenic mice, Dex-induced tau hyperphosphorylation persisting up to 6 hours in the hippocampus for the AT8 epitope. Pretreatment with atipamezole, a highly specific α2-adrenergic receptor antagonist, blocked Dex-induced tau hyperphosphorylation. Furthermore, Dex dose-dependently increased tau phosphorylation at AT8 in SH-SY5Y cells, impaired mice spatial memory in the Barnes maze and promoted tau hyperphosphorylation and aggregation in transgenic hTau mice. These findings suggest that Dex: (1) increases tau phosphorylation, in vivo and in vitro, in the absence of anesthetic-induced hypothermia and through α2-adrenergic receptor activation, (2) promotes tau aggregation in a mouse model of tauopathy, and (3) impacts spatial reference memory. Copyright © 2015 Elsevier Inc. All rights reserved.
    Neurobiology of Aging 05/2015; 36(8). DOI:10.1016/j.neurobiolaging.2015.05.002 · 5.01 Impact Factor
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    • "In conclusion, nerve cell apoptosis was apparent in the ventricular fluid impact model, and the reason for the apoptosis was closely associated with the impact of the ventricular liquid on the periventricular structures. The results of this study may be beneficial in the further development of new understandings of the pathological mechanism of clinical craniocerebral injury and its pathological changes (20–23). "
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    ABSTRACT: The aim of this study was to investigate the apoptosis of nerve cells in the hippocampal and thalamencephalon regions using a rabbit model of ventricular fluid impact. The results for the study demonstrated a variety of pathophysiological changes in the rabbit model, while changes in the hippocampal and thalamencephalon regions were observed under a light microscope following hematoxylin and eosin (H&E)/terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining. Among the mild, moderate and severe injury groups, there were significant differences in the mortality rate and in the changes in vital signs and consciousness recovery time following trauma. Furthermore, H&E staining showed that pathological changes, such as hemorrhage and necrosis, occurred in the hippocampal and thalamencephalon regions at an early stage subsequent to trauma, while TUNEL staining showed that neuronal apoptosis occurred in the various injury groups. In traumatic brain injuries, the impact caused by cerebrospinal fluid moving with a certain energy results in marked damage to the contralateral periventricular structures and may generate a series of pathophysiological changes.
    Experimental and therapeutic medicine 12/2013; 6(6):1463-1468. DOI:10.3892/etm.2013.1342 · 1.27 Impact Factor
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    • "Of all the JAK/STAT pathways, JAK2 signaling through STAT1 and STAT3 are the best studied in diseases affecting the kidney. An in vitro study has shown that dexmedetomidine may exert a significant neuroprotective effect by involving the activation of extracellular regulated protein kinases (ERK) [25]. Interference with ERK and STAT signaling pathways may also play a role in myocardial I/R injury [20]. "
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    ABSTRACT: Background The α2-adrenoreceptor agonist dexmedetomidine is known to provide renoprotection against ischemia and reperfusion (I/R) injury. However the underlying molecular mechanisms remain unclear. The purpose of this study was to investigate whether the Janus kinase and signal transducer and activator of transcription (JAK/STAT) signaling pathway plays a role in dexmedetomidine’s renoprotection. Methods I/R model was induced by bilateral renal pedicle clamping for 45 min followed by 48 h of reperfusion in male Wistar rat. Sham laparotomy served as controls. Animals received dexmedetomidine (50 μg/kg, i.p.) in the absence or presence of atipamezole (250 μg/kg, i.p.), or vehicle (DMSO) in the absence or presence of selective JAK2 inhibitor tyrphostin AG490 (10 mg/kg, i.p.) before ischemia. Renal function, histology, apoptosis, expression of cleaved caspase 3 protein, intercellular adhesion molecule-1 (ICAM-1), monocyte chemoattractant protein-1 (MCP-1) and phosphorylations of JAK2, STAT1 and STAT3 were assessed. Results The animals treated with either dexmedetomidine or AG490 exhibited an improved renal functional recovery, attenuated histological lesions and reduced number of apoptotic tubular epithelial cells. Either dexmedetomidine or AG490 inhibited the phosphorylations of JAK2 and its downstream molecule STAT1 and STAT3, accompanied by down-regulation the expression of cleaved caspase 3, ICAM-1 and MCP-1 proteins, and significantly ameliorated renal I/R injury. Conclusions Dexmedetomidine protects kidney against I/R injury, at least in part, through its inhibitory effects on injury-induced activation of JAK/STAT signaling pathway. If our data can be extrapolated to clinical setting, then dexmedetomidine may therefore serve as a clinical strategy to treat/prevent perioperative renal I/R injury.
    Journal of Translational Medicine 06/2013; 11(1):141. DOI:10.1186/1479-5876-11-141 · 3.93 Impact Factor
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