title: Dexmedetomidine prevents post-ischemic LTP via presynaptic and postsynaptic mechanisms.
abstract: 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 plasticity caused by ischemia in the hippocampal CA1 neurons. To address this issue, we 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 postsynaptic roles of DEX were investigated. The activation of the α2 receptors of DEX decreased the frequency spontaneous mEPSCs, which exerted its presynaptic mechanisms. In addition, DEX also decreased the amplitude of mEPSCs and prevented the depolarization of postsynaptic membranes during OGD treatment, which exerted its postsynaptic mechanisms. More importantly, our results indicate that postsynaptic β receptors, not α1 receptors, participated in i-LTP. Therefore, these results demonstrated that decreasing β receptors activation by DEX-medicated pre- and post-synaptic α2 receptors activation is responsible for i-LTP. Because of the NMDARs required for i-LTP, we further examined the critical roles of postsynaptic β receptors downstream PKA regulation of NMDA receptor-mediated EPSCs (NMDA EPSC). We clarified that it is attributable to the direct effect of DEX on NMDA EPSC as mediated by PKA inactivation. These findings suggest that DEX can protect neurons from functional damage caused by a relatively mild degree of transient cerebral ischemia, and this effect is mediated by both presynaptic reduction of NE and glutamate release and postsynaptic suppression of NMDAR activation by β receptors and downstream PKA regulation.
authors.affiliation: Department of Anaesthesiology, The Affiliated Hospital of XuZhou Medical College, XuZhou 221002, Jiangsu, China; Key Laboratory for Anesthesiology of Jiangsu Province Xuzhou, XuZhou 221004, Jiangsu, China.
authors.forename: Li
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Department of Pharmacology, Xuzhou Medical College, Jiangsu Key Laboratory of Target Drug and Clinical Application, XuZhou 221004, Jiangsu, China.
authors.forename: Shou-Jun
authors.initials: SJ
authors.lastname: Qin
authors.affiliation: Department of Pharmacology, Xuzhou Medical College, Jiangsu Key Laboratory of Target Drug and Clinical Application, XuZhou 221004, Jiangsu, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Gao
authors.affiliation: Department of Pharmacology, Xuzhou Medical College, Jiangsu Key Laboratory of Target Drug and Clinical Application, XuZhou 221004, Jiangsu, China.
authors.forename: Jun-Ping
authors.initials: JP
authors.lastname: Han
authors.affiliation: Department of Pharmacology, Xuzhou Medical College, Jiangsu Key Laboratory of Target Drug and Clinical Application, XuZhou 221004, Jiangsu, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Hu
authors.affiliation: Department of Pharmacology, Xuzhou Medical College, Jiangsu Key Laboratory of Target Drug and Clinical Application, XuZhou 221004, Jiangsu, China.
authors.forename: Mei
authors.initials: M
authors.lastname: Li
authors.affiliation: Key Laboratory for Anesthesiology of Jiangsu Province Xuzhou, XuZhou 221004, Jiangsu, China.
authors.forename: Yu-Qing
authors.initials: YQ
authors.lastname: Wu
authors.affiliation: Department of Pharmacology, Xuzhou Medical College, Jiangsu Key Laboratory of Target Drug and Clinical Application, XuZhou 221004, Jiangsu, China.
authors.forename: Xing
authors.initials: X
authors.lastname: Ma
authors.affiliation: Department of Pharmacology, Xuzhou Medical College, Jiangsu Key Laboratory of Target Drug and Clinical Application, XuZhou 221004, Jiangsu, China.
authors.forename: Shu-Ling
authors.initials: SL
authors.lastname: Gu
authors.affiliation: Department of Pharmacology, Xuzhou Medical College, Jiangsu Key Laboratory of Target Drug and Clinical Application, XuZhou 221004, Jiangsu, China. Electronic address: tengfeimtf@gmail.com.
authors.forename: Teng-Fei
authors.initials: TF
authors.lastname: Ma
mesh_terms: D058647:Adrenergic alpha-2 Receptor Agonists / Q000494:pharmacology; D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy* / Q000503:physiopathology; D056547:CA1 Region, Hippocampal / Q000187:drug effects* / Q000503:physiopathology; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D020927:Dexmedetomidine / Q000494:pharmacology*; D004195:Disease Models, Animal; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D005947:Glucose / Q000172:deficiency; D018698:Glutamic Acid / Q000378:metabolism; D017774:Long-Term Potentiation / Q000187:drug effects* / Q000502:physiology; D055369:Miniature Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009638:Norepinephrine / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D013569:Synapses / Q000187:drug effects* / Q000502:physiology; D046509:Tissue Culture Techniques
chemical_list: D058647:Adrenergic alpha-2 Receptor Agonists; D018696:Neuroprotective Agents; D047428:Protein Kinase Inhibitors; D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid; D020927:Dexmedetomidine; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D005947:Glucose; D009638:Norepinephrine
keywords: Dexmedetomidine; Hippocampus; Ischemia; LTP; NMDARs