5‐HT(1A) receptor antagonist improves behavior performance of delirium rats through inhibiting PI3K/Akt/mTOR activation‐induced NLRP3 activity

• Published in: IUBMB life 2016-04, Vol.68 (4), p.311-319
• Main Authors: Qiu, Yimin, Huang, Xiaojing, Huang, Lina, Tang, Liang, Jiang, Jihong, Chen, Lianhua, Li, Shitong
• Format: Article
• Language: English
• Subjects: 3,4-Dihydroxyphenylacetic Acid - cerebrospinal fluid; 5‐HT(1A) receptor antagonist; amygdala; Animals; Basolateral Nuclear Complex - drug effects; Basolateral Nuclear Complex - metabolism; Basolateral Nuclear Complex - physiopathology; Emergence Delirium - cerebrospinal fluid; Emergence Delirium - chemically induced; Emergence Delirium - physiopathology; Emergence Delirium - prevention & control; Gene Expression Regulation; hippocampus; Hippocampus - drug effects; Hippocampus - metabolism; Hippocampus - physiopathology; Homovanillic Acid - cerebrospinal fluid; Humans; Hydroxyindoleacetic Acid - cerebrospinal fluid; Injections, Intraventricular; Interleukin-1beta - antagonists & inhibitors; Interleukin-1beta - cerebrospinal fluid; Interleukin-1beta - genetics; Male; Maze Learning - drug effects; neuroinflammation; neurotransmitter; NLR Family, Pyrin Domain-Containing 3 Protein - antagonists & inhibitors; NLR Family, Pyrin Domain-Containing 3 Protein - cerebrospinal fluid; NLR Family, Pyrin Domain-Containing 3 Protein - genetics; Phosphatidylinositol 3-Kinase - antagonists & inhibitors; Phosphatidylinositol 3-Kinase - cerebrospinal fluid; Phosphatidylinositol 3-Kinase - genetics; Piperazines - pharmacology; Proto-Oncogene Proteins c-akt - antagonists & inhibitors; Proto-Oncogene Proteins c-akt - cerebrospinal fluid; Proto-Oncogene Proteins c-akt - genetics; Pyridines - pharmacology; Rats; Rats, Wistar; Receptor, Serotonin, 5-HT1A - genetics; Receptor, Serotonin, 5-HT1A - metabolism; Scopolamine Hydrobromide; Serotonin - cerebrospinal fluid; Serotonin Antagonists - pharmacology; Signal Transduction; Stereotaxic Techniques; TOR Serine-Threonine Kinases - antagonists & inhibitors; TOR Serine-Threonine Kinases - cerebrospinal fluid; TOR Serine-Threonine Kinases - genetics
• ISSN: 1521-6543; 1521-6551
• DOI: 10.1002/iub.1491

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. © 2016 IUBMB Life, 68(4):311–319, 2016