title: 5-HT(1A) receptor antagonist improves behavior performance of delirium rats through inhibiting PI3K/Akt/mTOR activation-induced NLRP3 activity.
abstract: Postoperative delirium is a common complication that often results in poor outcomes in surgical and elderly patients. Accumulating evidences suggest that the pathophysiology of delirium results from multiple neurotransmitter system dysfunctions. To further clarify the effects of the selective serotonin (5-HT) (1A) antagonist WAY-100635 on the behaviors in scopolamine induced-delirium rats and to explore the molecular mechanism, in this study, we investigated the change of monoamine levels in the cerebrospinal fluid (CSF) and different brain regions using high-performance liquid chromatography and assessed the behavioral retrieval of delirium rats treated with WAY-100635. It was found that 5-hydroxy-3-indoleacetic acid (5-HIAA), 3,4-dihydroxyphenylacetic acid, and homovanillic acid concentrations in the CSF of scopolamine-induced delirium rats were significantly increased, among which 5-HIAA was also increased in hippocampus and basolateral amygdala (BLA), and 5-HT(1A) receptor was significantly higher in the hippocampuses and BLA than other brain regions. Furthermore, intrahippocampus and intra-BLA stereotactic injection of WAY-100635 improved the delirium-like behavior of rats. Mechanistically, after WAY-100635 treatment, significant reduction of IL-1β release into CSF and NOD-like receptor family, pyrin domain containing 3 (NLRP3) expression, phosphorylated phosphatidylinositol-3-kinase (PI3K), protein kinase B (AKT), and S6K was observed. Altogether, these results suggest that delirium rats induced by scopolamine may be correlated with an increased cerebral concentration of 5-HT and dopamine neurotransmitters system; the selective 5-HT(1A) antagoniszts can reverse the delirium symptoms at some extent through tendering PI3K/Akt/mammalian target of rapamycin complex 1 (mTOR) activation-induced NLRP3 activity and then reducing IL-1β release.
authors.affiliation: Department of Anesthesiology, Shanghai General Hospital, Shanghai Jiaotong University, Shanghai, China.
authors.forename: Yimin
authors.initials: Y
authors.lastname: Qiu
authors.affiliation: Department of Pain Management, Shanghai General Hospital, Shanghai Jiaotong University, Shanghai, China.
authors.forename: Xiaojing
authors.initials: X
authors.lastname: Huang
authors.affiliation: Department of Anesthesiology, Shanghai General Hospital, Shanghai Jiaotong University, Shanghai, China.
authors.forename: Lina
authors.initials: L
authors.lastname: Huang
authors.affiliation: Department of Anesthesiology, Shanghai General Hospital, Shanghai Jiaotong University, Shanghai, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Tang
authors.affiliation: Department of Pain Management, Shanghai General Hospital, Shanghai Jiaotong University, Shanghai, China.
authors.forename: Jihong
authors.initials: J
authors.lastname: Jiang
authors.affiliation: Department of Anesthesiology, Shanghai General Hospital, Shanghai Jiaotong University, Shanghai, China.
authors.forename: Lianhua
authors.initials: L
authors.lastname: Chen
authors.affiliation: Department of Anesthesiology and Pain Management, Shanghai General Hospital, Shanghai Jiaotong University, Shanghai, China.
authors.forename: Shitong
authors.initials: S
authors.lastname: Li
mesh_terms: D015102:3,4-Dihydroxyphenylacetic Acid / Q000134:cerebrospinal fluid; D000818:Animals; D066272:Basolateral Nuclear Complex / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D000071257:Emergence Delirium / Q000134:cerebrospinal fluid / Q000139:chemically induced / Q000503:physiopathology / Q000517:prevention & control*; D005786:Gene Expression Regulation; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D006719:Homovanillic Acid / Q000134:cerebrospinal fluid; D006801:Humans; D006897:Hydroxyindoleacetic Acid / Q000134:cerebrospinal fluid; D007276:Injections, Intraventricular; D053583:Interleukin-1beta / Q000037:antagonists & inhibitors* / Q000134:cerebrospinal fluid / Q000235:genetics; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000037:antagonists & inhibitors* / Q000134:cerebrospinal fluid / Q000235:genetics; D058539:Phosphatidylinositol 3-Kinase / Q000134:cerebrospinal fluid / Q000235:genetics; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010879:Piperazines / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000134:cerebrospinal fluid / Q000235:genetics; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D044282:Receptor, Serotonin, 5-HT1A / Q000235:genetics / Q000378:metabolism*; D012601:Scopolamine; D012701:Serotonin / Q000134:cerebrospinal fluid; D012702:Serotonin Antagonists / Q000494:pharmacology*; D015398:Signal Transduction; D013238:Stereotaxic Techniques; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000134:cerebrospinal fluid / Q000235:genetics
chemical_list: C000594089:IL1B protein, rat; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C573346:Nlrp3 protein, rat; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010879:Piperazines; D011725:Pyridines; D012702:Serotonin Antagonists; D015102:3,4-Dihydroxyphenylacetic Acid; D044282:Receptor, Serotonin, 5-HT1A; D012701:Serotonin; D006897:Hydroxyindoleacetic Acid; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide; D012601:Scopolamine; C546845:mTOR protein, rat; D058539:Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D006719:Homovanillic Acid
keywords: 5-HT(1A) receptor antagonist; amygdala; hippocampus; neuroinflammation; neurotransmitter