Pentobarbital and other anesthetic agents induce opposite regulations of MAP kinases p-MEK and p-ERK, and upregulate p-FADD/FADD neuroplastic index in brain during hypnotic states in mice

• Published in: Neurochemistry international 2019-01, Vol.122, p.59-72
• Main Authors: Salort, Glòria, Álvaro-Bartolomé, María, García-Sevilla, Jesús A.
• Format: Article
• Language: English
• Subjects: Anesthetics - pharmacology; Animals; Brain - drug effects; Brain - metabolism; Fas-Associated Death Domain Protein - metabolism; Hypnotics and Sedatives - pharmacology; Isoflurane; Ketamine - pharmacology; Male; MAP Kinase Kinase Kinases - drug effects; MEK-ERK; Mice; Mouse brain; Neuronal Plasticity - drug effects; Other anesthetic agents; p-FADD/FADD; Pentobarbital; Pentobarbital - pharmacology; Transcriptional Activation - drug effects; Up-Regulation - drug effects
• ISSN: 0197-0186; 1872-9754
• DOI: 10.1016/j.neuint.2018.11.008

Midazolam and ketamine-induced anesthesia were recently shown to induce a disruption of MEK/ERK sequential phosphorylation with parallel upregulation of p-FADD in the mouse brain. The present study was designed to assess whether other structurally diverse anesthetic agents (pentobarbital, ethanol, chloral hydrate, isoflurane) also impair brain p-MEK to p-ERK signal and increase p-FADD during the particular time course of ‘sleep’ in mice. Pentobarbital (50 mg/kg)-, ethanol (4000 mg/kg)-, chloral hydrate (400 mg/kg)-, and isoflurane (2% in O2)-induced anesthesia (range: 24–60 min) were associated with unaltered or increased p-MEK1/2 (up to +155%) and decreased p-ERK1/2 (up to −60%) contents, revealing disruption of MEK to ERK activation in mouse brain cortex. These anesthetic agents also upregulated cortical p-FADD (up to +110%), but not total FADD (moderately decreased), which resulted in increased neuroplastic/survival p-FADD/FADD ratios (up to +2.8 fold). The inhibition of pentobarbital metabolism with SKF525-A (a cytochrome P450 inhibitor) augmented barbiturate anesthesia (2.6 times) and induced a greater and sustained upregulation of p-MEK with p-ERK downregulation, as well as prolonged increases of p-FADD content and p-FADD/FADD ratio (effects lasting for more than 240 min). Pentobarbital also upregulated significantly the cortical contents of other markers of neuroplasticity such as the ERK inhibitor p-PEA-15 (up to +46%), the transcription factor NF-κB (up to +27%) and the synaptic density protein PSD-95 (up to +20%) during ‘sleep’. The results reveal a paradoxical stimulation of p-MEK without the concomitant (canonical) activation of p-ERK (e.g. with pentobarbital and isoflurane), for which various molecular mechanisms are discussed. The downregulation of brain p-ERK may participate in the manifestations of adverse effects displayed by most hypnotic/anesthetic agents in clinical use (e.g. amnesia). •MEK-ERK disruption in brain by pentobarbital and other hypnotics in mice.•Upregulation of neuroplastic/survival p-FADD by hypnotic agents during sleep.•Upregulation of neuroplastic markers by pentobarbital.•SKF525-A modulating pentobarbital effects on MEK-ERK and p-FADD.