Lipoxin A4 methyl ester attenuated ketamine-induced neurotoxicity in SH-SY5Y cells via regulating leptin pathway.

Ketamine, the widely used intravenous anesthetic, has been reported to cause neurotoxicity and disturbs normal neurogenesis. However, the efficacy of current treatment strategies targeting ketamine's neurotoxicity remains limited. Lipoxin A4 methyl ester (LXA4 ME) is relatively stable lipoxin analog, which serves an important role in protecting against early brain injury. The purpose of this study was to investigate the protective effect of LXA4 ME on ketamine-caused cytotoxicity in SH-SY5Y cells, as well as the underlying mechanisms. Cell viability, apoptosis and endoplasmic reticulum stress (ER stress) were detected by adopting experimental techniques including CCK-8 assay, flow cytometry, western blotting and transmission electron microscope. Furthermore, examining the expression of leptin and its receptor (LepRb), we also measured the levels of activation of the leptin signaling pathway. Our results showed that LXA4 ME intervention promoted the cell viability, inhibited cell apoptosis, and reduced the expression of ER stress related protein and morphological changes induced by ketamine. In addition, inhibition of leptin signaling pathway caused by ketamine could be reversed by LXA4 ME. However, as the specific inhibitor of leptin pathway, leptin antagonist triple mutant human recombinant (leptin tA) attenuated the cytoprotective effect of LXA4 ME against ketamine-induced neurotoxicity. In conclusion, our findings demonstrated LXA4 ME could exert a neuroprotective effect on ketamine-induced neuronal injury via activation of the leptin signaling pathway.

Lipoxin A4 methyl ester protects PC12 cells from ketamine-induced neurotoxicity via the miR-22/BAG5 pathway.

OBJECTIVE: Ketamine is an anesthetic that induces neurotoxicity when administered at high doses. In this work, we explored the protective effects of lipoxin A4 methyl ester (LXA4 ME) against ketamine-induced neurotoxicity and the underlying protective mechanism in pheochromocytoma (PC12) cells. METHODS: PC12 cells were treated with 50 µM of ketamine and different LXA4 ME concentrations of LXA4 ME (5-50 nM) for 24 h, and their viability, apoptosis, and oxidative status were assessed. RESULTS: Quantitative real-time polymerase chain reaction experiments showed that ketamine downregulated miR-22 expression and upregulated Bcl-2-associated athanogene 5 (BAG5) in PC12 cells in a concentration-dependent manner. LXA4 ME induced the opposite effects, thus attenuating ketamine-induced neurotoxicity. Further in vitro assays showed that miR-22 directly targeted BAG5, thus promoting cell viability by suppressing cell apoptosis and oxidative stress. Under expression miR-22 or upregulation of BAG5 antagonized the effects of LXA4 ME. CONCLUSION: LXA4 ME can protect PC12 cells from ketamine-induced neurotoxicity by activating the miR-22/BAG5 signaling pathway. Thus, LXA4 ME can be used as a protective drug against ketamine-induced neural damage.

Lipoxin A4 methyl ester ameliorates cognitive deficits induced by chronic cerebral hypoperfusion through activating ERK/Nrf2 signaling pathway in rats.

Lipoxin A4 (LXA4) is known for its powerful anti-inflammatory function. Current studies in vitro suggest that LXA4 possesses novel antioxidant effect. The aim of this study is to examine whether Lipoxin A4 methyl ester (LXA4 ME) has neuroprotective effects against chronic cerebral hypoperfusion, and if so, whether the effects of LXA4 ME are associated with its potential antioxidant property. Adult male Sprague-Dawley rats were subjected to permanent bilateral common carotid artery occlusion (BCCAO) and randomly assigned into four groups: sham (sham-operated) group, vehicle (BCCAO+normal saline) group, LXA4 ME10 (BCCAO+LXA4 ME 10 ng per day) group and LXA4 ME100 (BCCAO+LXA4 ME 100 ng per day) group. LXA4 ME was administered through intracerebroventricular injection for 2 consecutive weeks. LXA4 ME significantly alleviated spatial learning and memory impairments, as assessed by Morris water maze and inhibited the loss of neurons in the CA1 region of the hippocampus. Biochemically, LXA4 ME phosphorylated extracellular signal regulated kinase (ERK) 1/2 and enhanced nuclear factor erythroid 2-related factor 2 (Nrf2) expression and its nuclear translocation, as well as NAD(P)H: quinone oxidoreductase 1 (NQO1) expression. LXA4 ME reduced lipid peroxidative production in the hippocampus, as measured by immunohistochemical staining for 4-Hydroxynonenal (4-HNE). In addition, LXA4 ME significantly elevated the ratio of Bcl-2/Bax and decreased cleaved caspase-3 expression in the hippocampus. Therefore, these data suggest that LXA4 ME exerts beneficial effects on the cognitive impairment induced by chronic cerebral hypoperfusion through attenuating oxidative injury and reducing neuronal apoptosis in the hippocampus, which is most likely associated with the activation of ERK/Nrf2 signaling pathway.