Available online at www.sciencedirect.com
Dexmedetomidine p via presynaptic and
Li Zhoub,c,1, Shou-Jun Qina,1,
Yu-Qing Wuc, Xing Maa, Shu aDepartment of Pharmacology, Xuzhou Medica
XuZhou 221004, Jiangsu, China bDepartment of Anaesthesiology, The Affiliate
Jiangsu the depolarization its postsynaptic β receptors, not α1 that decreasing β ptors activation is ther examined the f NMDA receptormediated EPSCs (NMDA EPSC). We clarified that it is attributable to the direct effect of DEX est that DEX can egree of transient uction of NE and y β receptors and b r a i n r e s e a r c h 1 6 2 2 ( 2 0 1 5 ) 3 0 8 – 3 2 0These two authors contributed equally to this work.http://dx.doi.org/10.1016/j.brainres.2015.06.040 0006-8993/& 2015 Elsevier B.V. All rights reserved. nCorresponding authors at: Department of Pharmacology, Xuzhou Medical College, No. 209, TongShan Road, Xuzhou 221004,
Jiangsu Province, China. Fax: þ86 516 83262251.
E-mail address: firstname.lastname@example.org (T.-F. Ma). 1downstream PKA regulation. & 2015 Elsevier B.V. All rights reserved.on NMDA EPSC as mediated by PKA inactivation. These findings sugg protect neurons from functional damage caused by a relatively mild d cerebral ischemia, and this effect is mediated by both presynaptic red glutamate release and postsynaptic suppression of NMDAR activation bHippocampus decreased the frequency spontaneous mEPSCs, which exerted its presyna
In addition, DEX also decreased the amplitude of mEPSCs and prevented of postsynaptic membranes during OGD treatment, which exerted mechanisms. More importantly, our results indicate that postsynaptic receptors, participated in i-LTP. Therefore, these results demonstrated receptors activation by DEX-medicated pre- and post-synaptic α2 rece responsible for i-LTP. Because of the NMDARs required for i-LTP, we fur critical roles of postsynaptic β receptors downstream PKA regulation oLTP
NMDARs postsynaptic roles of DEX were investigated. The activation of the α2 receptors of DEX ptic mechanisms.Keywords:
IschemiaAvailable online 10 July 2015 plasticity caused by ischemia in the hippocampal CA1 neurons. To address this issue, wecKey Laboratory for Anesthesiology of a r t i c l e i n f o
Accepted 24 June 2015revents post-ischemic LTP postsynaptic mechanisms
Xin Gaoa, Jun-Ping Hana, Bin Hua, Mei Lia, -Ling Gua,n, Teng-Fei Maa,n l College, Jiangsu Key Laboratory of Target Drug and Clinical Application, d Hospital of XuZhou Medical College, XuZhou 221002, Jiangsu, China
Province Xuzhou, XuZhou 221004, Jiangsu, China a b s t r a c t
Increasing evidence indicates that dexmedetomidine (DEX), a selective α2-adrenergic receptor agonist, has a neuroprotective effect against cerebral injury. However, it remains unknown whether and how DEX functionally prevents the pathological form of synaptic analyzed the role of DEX using a model of brain ischemia (oxygen and glucose deprivation,
OGD) referred to as post-ischemic LTP (i-LTP). We found that DEX could reduce i-LTP by selectively activating α2 receptors. To clarify its detailed mechanisms, the presynaptic and 1. Introduction
Dexmedetomidine (DEX) is a potent, highly selective α2 adrenergic agonist that is widely used in the perioperative period for its major sedative and analgesic effects (Blaudszun et al., 2012; Zhang et al., 2013). In preoperative anesthesia, neuroapoptosis is often induced by the administration of anesthetic agents to patients, especially children (Sanders et al., 2010). However, different from other anesthetic agents, the neuroprotective role of DEX (Sanders et al., 2009; Yuen, 2010r) is increasingly being considered in clinical research (Hori et al., 2010; Jeon et al., 2013). In addition, animal studies have reported that DEX effectively prevents the delayed neuronal death of hippocampal neurons after cerebral ischemia (Dahmani et al., 2005; Engelhard et al., 2002; Engelhard et al., 2003; Kuhmonen et al., 1997; Maier et al., 1993).
Recently, a study demonstrated that DEX may have potential beneficial value in patients with stroke in clinical applications (Whalin et al., 2014), and therefore, it is of great importance to clarify the precise mechanisms of effects of DEX in ischemic injury.
Cerebral ischemia induces a massive release of norepinephrine (NE) associated with neuronal death in the brain (Walter et al., 2013; Wei et al., 2012). Preventing NE release may be provide a neuroprotective therapeutic effect against ischemic insult. Kuhmonen et al. (1997) suggested that DEX activates presynaptic α2-adrenergic receptors and can thereby reduce ischemic damage by inhibiting NE or glutamate release, whereas Engelhard et al. (2002) reported that
DEX suppressed the circulating NE concentrations and did not inhibit presynaptic NE or glutamate release in vivo. It is
LTP ndi lM
The er ar b r a i n r e s e a r c h 1 6 2 2 ( 2 0 1 5 ) 3 0 8 – 3 2 0 309Fig. 1 – DEX selectively activated α2 receptors and reduced ishowing AMPA EPSC under OGD, DEX and DEX with YOH co magnitude of the AMPA EPSC (n¼7). Application of DEX (0.2 potentiation (n¼7). The a2 antagonist yohimbine (YOH) (10 l magnitude of potentiation compared with DEX group (n¼7). treatments. (B) The histogram summarizes the data from exp means7SEMs (the error bars show the SEMs). ** Po0.01, comp
Compared with baseline, there is no obvious changes during and timing of the NE treatment. (D) Summary of data showing the eff means7SEMs. ** Po0.01, compared with OGD group.. (A) The effects of DEX on AMPA EPSC i-LTP. Sample traces tions. OGD treatment induced i-LTP by increasing the ) reduced i-LTP (n¼7) by decreasing the magnitude of abolished the effects DEX on i-LTP by increasing the horizontal bars represent the timing of the OGD and drugs iments shown in A. All values are expressed as the ed with OGD group. (C) The effects of DEX on the AMPA EPSC. after NE treatment (n¼6). The horizontal bars represent theects of NE on the AMPA EPSC. All values are expressed as the 10079% n¼6; compared with before DEX, P40.05, Fig. 1C and 6 2possible that the different results between the two studies are related to differences in the regions of interest or the use of different ischemia models. Within in vitro hippocampal rat brain slices, DEX suppressed excessive glutamate release during hypoxic stress (Talke and Bickler, 1996). It is well known that excessive glutamate release-mediated pathological synaptic plasticity in vitro ischemic models, referred to as post-ischemic LTP (i-LTP), is dependent on the overactivation of ionotropic NMDA receptors. Although numerous studies have reported the effects of DEX on ischemic cerebral stroke (Dahmani et al., 2005; Degos et al., 2013; Engelhard et al., 2003; Ma et al., 2004a; Rajakumaraswamy et al., 2006), the functional prevention of i-LTP by DEX is not yet fully understood. In physiology, NMDA receptors is required for the induction of synaptic plasticity and several modulating transmitters, such as adrenergic transmitters (NE), which can modulate its induction (Katsuki et al., 1997). The hippocampus receives major adrenergic input from the locus coeruleus.