Membrane nanodomains homeostasis during propofol anesthesia as function of dosage and temperature

Abstract

Some anesthetics bind and potentiate g-aminobutyric-acid-type receptors, but no universal mechanism for general anesthesia is known. Furthermore, often encountered complications such as anesthesia induced amnesia are not understood. General anesthetics are hydrophobic molecules easily dissolving into lipid bilayers. Recently, it was shown that general anesthetics perturb phase separation in vesicles extracted from fixed cells. Unclear is whether under physiological conditions general anesthetics induce perturbation of the lipid bilayer, and whether this contributes to the transient loss of consciousness or anesthesia side effects. Here we show that propofol perturbs lipid nanodomains in the outer and inner leaflet of the plasma membrane in intact cells, affecting membrane nanodomains in a concentration dependent manner: 1 μM to 5 μM propofol destabilize nanodomains; however, propofol concentrations higher than 5 μM stabilize nanodomains with time. Stabilization occurs only at physiological temperature and in intact cells. This process requires ARP2/3 mediated actin nucleation and Myosin II activity. The rate of nanodomain stabilization is potentiated by GABA receptor activity. Our results show that active nanodomain homeostasis counteracts the initial disruption causing large changes in cortical actin. Significance Statement General anesthesia is a routine medical procedure with few complications, yet a small number of patients experience side-effects that persist for weeks and months. Very young children are at risk for effects on brain development. Elderly patients often exhibit subsequent amnesia. Here, we show that the general anesthetic propofol perturbs the ultrastructure of the lipid bilayer of the cell membrane in intact cells. Initially propofol destabilized lipid nanodomains. However, with increasing incubation time and propofol concentration, the effect is reversed and nanodomains are further stabilized. We show that this stabilization is caused by the activation of the actin cortex under the membrane. These perturbations of membrane bilayer and cortical actin may explain how propofol affects neuronal plasticity at synapses.

Mechanistic Understanding from Molecular Dynamics in Pharmaceutical Research 2: Lipid Membrane in Drug Design

“…Pain medication Paracetamol [283][284][285] Pain medication, opioid receptors Morphine [132], Fentanyl [132], Fentanyl and its analogues [286], Codeine [287] Local anesthetics Benzocaine [288][289][290], KP-23 [147], Dibucaine [291], Lidocaine [289,292,293], Articaine [289], Tetracaine [294,295], Prilocaine [296], Dyclonine, Butamben [290] General anesthetic Xenon [124,125], Chloroform [292,[297][298][299][300][301], Halothane [146,298,302,303], Isoflurane [297,299,304,305], Phenyl-ethanol [306], Desflurane [305,307], Sevoflurane [305,308], Propofol [305,309,310], Diethyl ether [298,308], Enflurane…”

“…Recent studies performed using multiple experimental techniques (Super-Resolution Microscopy dSTORM, Patch-Clamp, Fluorescence Resonance Energy Transfer) have demonstrated that both chloroform and isoflurane disrupt lipid domains (rafts) that contain the ganglioside GM1 [299]. Another anesthetic, propofol, at concentrations in the range 1 µM to 5 µM, has also been found to destabilize nanodomains in cellular membranes via Binned Imaging Fluorescence Correlation Spectroscopy [309]. Thus, the significant perturbations of the structure of bilayers in the liquid ordered phase, observed in MD simulation studies [271,308], are in agreement with experimental observations.…”

Adpative Neuro-Fuzzy Inference System Estimation Propofol dose in the induction phase during anesthesia; case study

“…Observing the effect of drug on the patient, the variation of BIS values may depend on the effective Ce, drug concentration by the experimental non-linear Eq. (5) [6][7][8], named the Hill-Curve in the PD model. In the Hill equation, Ce (t) is the concentration of propofol (μg/ml) in the brain.…”

“…A current review of pharmacokinetics and pharmacodynamics approaches to optimize the anesthetic drug administration was performed [3,4]. In this pursuit, advanced mathematical techniques can be of superb value, for instance, robust PID control [5], fuzzy-type I/II [6,7], propofol injection robot-assistant [8,9] and target control infusion [10]. Some of the auto-drug delivery systems have widely used bispectral index monitoring [11,12], as variables of control modeling to administer the propofol dose during the anesthesia.…”

Heptanol-mediated phase separation determines phase preference of molecules in live cell membranes

“…Previous work demonstrated that benzyl alcohol (BA), a routinely used anesthetic, hyperfluidizes the membrane and induces the reorganization of domains 46 . A recent work showed that propofol also reorganizes cholesterol-dependent domains in cell membranes 47 .…”