Mechanisms of propofol attenuation of ketamine-induced neonatal brain injury

OBJECTIVE: We studied the mechanisms of protective effects of propofol on ketamine-induced damage to neonatal cognitive function.

MATERIALS AND METHODS: We utilized a rat model of ketamine anaesthesia. Eighty neonatal rats (7 days after birth) were divided into four groups: normal saline group, ketamine group, and low- and high-dose propofol combined with ketamine groups. Six hours after anaesthesia, we obtained hippocampal tissue, and quantified apoptotic index and total protein concentration, and assessed global proteomics changes induced by two tested drugs. The latter changes were documented by two-dimensional electrophoresis and matrix-assisted laser desorption/ ionization time of flight mass spectrometry. To evaluate cognitive functions, water maze test was applied after animals grew for 21 days. We further repeated proteomics studies at 21 days post-anaesthesia.

RESULTS: Ketamine markedly up-regulated apoptotic index and decreased total protein concentration. Propofol dose-dependently reverted these adverse changes. Six hours post-anaesthesia, combined propofol and ketamine administration up-regulated the following proteins in the hippocampus: PD1A3, NDUFB10, HSPA8, ATP5JD, and PSMA1. Furthermore, the following proteins were down-regulated: PPIA, PKM2, GFAP, NSE, PPIA, PKM2, and GFAP. After 21 days, animals treated with ketamine showed marked disturbances in cognitive function as demonstrated by increased time of the water maze test, whereas propofol diminished these changes. In addition, expression of proteins largely normalized in propofol-treated animals, with only two up-regulated proteins (FUBP3 and PRDX5) and three down-regulated proteins (GAPDH, AKR1A1, and VCP).

CONCLUSIONS: Adverse effects of ketamine on cognitive function are reverted by propofol, also through beneficial effects on protein expression in the hippocampus.

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