Neuroprotective effect of ketamine and sevoflurane against TNF‐α induced cognitive impairment

Abstract In the present study, neuroprotective effect of sevoflurane in combination with ketamine was investigated on TNF‐α induced necroptosis of neurons and cognitive impairment in the rat model. The results demonstrated that exposure to TNF‐α/z‐VAD led to a significant decrease in viability of HT‐22 neuronal cells. However, incubation of HT‐22 cells with ketamine plus sevoflurane inhibited decrease in viability induced by TNF‐α/z‐VAD exposure. The increase in production of ROS by TNF‐α/z‐VAD exposure in HT‐22 cells was effectively suppressed on pre‐treatment with ketamine plus sevoflurane. Moreover, suppression of TNF‐α/z‐VAD induced ROS production in HT‐22 cells by ketamine plus sevoflurane pretreatment was higher in comparison to ketamine or sevoflurane treatment alone. Treatment of HT‐22 cells with ketamine plus sevoflurane suppressed TNF‐α/z‐VAD induced increase in RIP1 and p‐MLKL protein expression. Ketamine plus sevoflurane treatment effectively reversed decrease in movement speed as well as total distance traveled in TNF‐α injected rats. The number of neurons in rat hippocampus injected with TNF‐α showed a significant decrease more specifically in carbonic anhydrase‐3 region. However, no significant change in the density of neurons was observed in the hippocampus of rats pretreated with ketamine plus sevoflurane by TNF‐α injection. The increase in expression of p‐MLKL and p‐RIP3 by TNF‐α injection was effectively reversed in rats on treatment with ketamine plus sevoflurane. In silico studies revealed that ketamine interacts with p‐MLKL protein in different confirmations with the binding affinities ranging from −9.7 to −8.4 kcal/mol. It was found that ketamine binds to p‐MLKL protein by interacting with alanine (ALA A:295), proline (PRO A:306), glutamine (GLN A: 307) and isoleucine (ILE A:293) amino acid residues. In summary, ketamine plus sevoflurane combination alleviates TNF‐α/z‐VAD induced decrease in viability of HT‐22 cells in vitro and rat hippocampus neurons in vivo. Moreover, ketamine plus sevoflurane combination prevented TNF‐α injection induced cognitive impairment in rats. Therefore, sevoflurane plus ketamine combination can be developed as a potential therapeutic regimen for treatment of isoflurone induced cognitive impairment.