N-acetylserotonin Derivative Exerts a Neuroprotective Effect by Inhibiting the NLRP3 Inflammasome and Activating the PI3K/Akt/Nrf2 Pathway in the Model of Hypoxic-Ischemic Brain Damage

• Published in: Neurochemical research Vol. 46; no. 2; pp. 337 - 348
• Main Authors: Luo, Xing, Zeng, Honglan, Fang, Chengzhi, Zhang, Bing-Hong
• Format: Journal Article
• Language: English
• Published: New York Springer US 01.02.2021; Springer Nature B.V
• Subjects: 1-Phosphatidylinositol 3-kinase; AKT protein; Animals; Apoptosis; Apoptosis - drug effects; Biochemistry; Biomedical and Life Sciences; Biomedicine; Blood-brain barrier; Brain damage; Brain injury; Cell Biology; Cerebral Cortex - drug effects; Cerebral Cortex - pathology; Cerebral infarction; Edema; Encephalopathy; Hippocampus - drug effects; Hippocampus - pathology; Hypoxia; Hypoxia-Ischemia, Brain - drug therapy; Hypoxia-Ischemia, Brain - pathology; Immunofluorescence; Infarction; Inflammasomes; Inflammasomes - antagonists & inhibitors; Ischemia; Kinases; N-Acetylserotonin; Neonates; Neurochemistry; Neurology; Neurons - drug effects; Neuroprotection; Neuroprotective Agents - therapeutic use; Neurosciences; NF-E2-Related Factor 2; NLR Family, Pyrin Domain-Containing 3 Protein - antagonists & inhibitors; Nuclear transport; Original Paper; Phosphatidylinositol 3-Kinases - metabolism; Polymerase chain reaction; Proto-Oncogene Proteins c-akt - metabolism; Rats; Rats, Sprague-Dawley; Serotonin - analogs & derivatives; Serotonin - therapeutic use; Signal Transduction - drug effects; Translocation; Western blotting; N-[2-(5-hydroxy-1H-indol-3-yl) ethyl]-2-oxopiperidine-3-carboxamide; NLRP3 inflammasome; Nrf2; Hypoxic-ischemic encephalopathy
• ISSN: 0364-3190; 1573-6903
• DOI: 10.1007/s11064-020-03169-x

Neonatal hypoxic-ischemic encephalopathy (HIE) is one of the main causes of neonatal disability and death. As a derivative of N-acetylserotonin, N-[2-(5-hydroxy-1H-indol-3-yl) ethyl]-2-oxopiperidine-3-carboxamide (HIOC) can easily cross the blood–brain barrier and have a long half-life in the brain. In this study, the hypothesis was verified that HIOC plays a neuroprotective role in the HIE model and its potential mechanism was evaluated. Firstly, an HIE rat model was established to deliver HIOC, revealing that it can reduce cerebral infarction volume, cerebral edema, and neuronal apoptosis. The results of immunofluorescence staining, Western blots and RT-PCR further showed that HIOC could inhibit the activation of the NLRP3 inflammasome and the expression of related proteins. Finally, the activation of the phosphatidylinositol-3-kinase (PI3K)/Akt/nuclear factor erythroid 2-related factor 2 (Nrf2) pathway by HIOC was verified in vitro and in vivo . It was discovered that HIOC could increase the nuclear translocation of Nrf2, and that this induction can be reversed by the PI3K/Akt pathway inhibitor LY294002. In general terms, the neuroprotective effect of HIOC was confirmed in the HIE model, which is related to the activation of the Pi3k/Akt/Nrf2 signal pathway and the inhibition of the NLRP3 inflammasome.