title: Sevoflurane prevents stroke-induced depressive and anxiety behaviors by promoting cannabinoid receptor subtype I-dependent interaction between β-arrestin 2 and extracellular signal-regulated kinases 1/2 in the rat hippocampus.
abstract: One of the most frequent psychological consequences of stroke is depression. Previous animal studies have demonstrated that post-conditioning with sevoflurane protects against focal cerebral ischemia and reperfusion injury. Thus, we hypothesized that repeated exposure to sevoflurane after transient ischemia can prevent the development of depressive-like behavior. To test this hypothesis, we induced transient cerebral ischemia via transient occlusion of bilateral common carotid arteries and examined the effects of subsequent repeated exposure to sevoflurane on sucrose preference, locomotor activity, and rearing activity in rats. To explore the putative neurobiological mechanisms, we further investigated the roles of hippocampal CB1 receptor in the behavioral effects of sevoflurane. We found that repeated sevoflurane exposures reversed ischemia-induced depressive-like behaviors. Furthermore, CB1 receptor inhibition in the dorsal hippocampus (DH) abolished the effects of sevoflurane exposures on ischemia-induced depressive-like behaviors. In addition, repeated sevoflurane exposures increased CB1 receptor expression and endocannabinoids levels in the DH of ischemic rats. Moreover, repeated sevoflurane exposures enhanced the expression of β-arrestin 2, increased the activation of extracellular signal-regulated kinases (ERK)1/2, and promoted the interaction of β-arrestin 2 and ERK1/2 in the DH, and such effects were reversed by CB1 receptor antagonism in the DH. Finally, β-arrestin 2 expression and ERK1/2 activation in the DH were critical for the preventative effects of sevoflurane exposures on ischemia-induced depressive-like behaviors. Taken together, our results suggested that sevoflurane exposure after brain ischemia may prevent the development of depression, and such preventative effects of sevoflurane are likely ascribed to the activation of CB1 receptor-mediated β-arrestin 2-ERK1/2 signaling pathways. We propose that the following mechanisms are critical for the preventative effects of sevoflurane against post-stroke depressive and anxiety behaviors: repeated sevoflurane exposure after transient brain ischemia enhances N-arachidonoylethanolamine (AEA) and 2-Arachidonoylglycerol (2-AG) levels and normalize cannabinoid receptor type 1 (CB1) receptor expression in the dorsal hippocampus, which results in enhanced interaction of β-arrestin 2 and extracellular signal-regulated kinases (ERK1/2) and increased ERK1/2 activation, leading to decreased depressive and anxiety behaviors. We think these findings should provide a new strategy for treatment of post-stroke depression.
authors.affiliation: Department of Anesthesiology, The Second Hospital of Jilin University, Changchun, China.
authors.forename: Houzhong
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Anesthesiology, The Obstetrics and Gynecology Hospital of Changchun, Changchun, China.
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Anesthesiology, The People's Hospital of Changchun City, Changchun, China.
authors.forename: Yanli
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Department of Thoracic Surgery, The Second Hospital of Jilin University, Changchun, China.
authors.forename: Xingyi
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Thoracic Surgery, The Second Hospital of Jilin University, Changchun, China.
authors.forename: Yifan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Anesthesiology, The Second Hospital of Jilin University, Changchun, China.
authors.forename: Shuang
authors.initials: S
authors.lastname: Xu
authors.affiliation: Department of Anesthesiology, The Second Hospital of Jilin University, Changchun, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Zhao
authors.affiliation: Department of Anesthesiology, The Second Hospital of Jilin University, Changchun, China.
authors.forename: Tiecheng
authors.initials: T
authors.lastname: Liu
mesh_terms: D018685:Anesthetics, Inhalation / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D001007:Anxiety / Q000209:etiology / Q000378:metabolism* / Q000517:prevention & control; D003863:Depression / Q000209:etiology / Q000378:metabolism* / Q000517:prevention & control; D004305:Dose-Response Relationship, Drug; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D008297:Male; D008738:Methyl Ethers / Q000494:pharmacology / Q000627:therapeutic use*; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000378:metabolism*; D000077149:Sevoflurane; D020521:Stroke / Q000150:complications / Q000188:drug therapy / Q000378:metabolism*; D000071560:beta-Arrestin 2 / Q000378:metabolism*
chemical_list: D018685:Anesthetics, Inhalation; D008738:Methyl Ethers; D043884:Receptor, Cannabinoid, CB1; D000071560:beta-Arrestin 2; D000077149:Sevoflurane
keywords: ERK1/2; cannabinoid receptor; hippocampus; post-stroke depression; sevoflurane; β-arrestin 2