title: Sugammadex, a neuromuscular blockade reversal agent, causes neuronal apoptosis in primary cultures.
abstract: Sugammadex, a γ-cyclodextrin that encapsulates selectively steroidal neuromuscular blocking agents, such as rocuronium or vecuronium, has changed the face of clinical neuromuscular pharmacology. Sugammadex allows a rapid reversal of muscle paralysis. Sugammadex appears to be safe and well tolerated. Its blood-brain barrier penetration is poor (< 3% in rats), and thus no relevant central nervous toxicity is expected. However the blood brain barrier permeability can be altered under different conditions (i.e. neurodegenerative diseases, trauma, ischemia, infections, or immature nervous system). Using MTT, confocal microscopy, caspase-3 activity, cholesterol quantification and Western-blot we determine toxicity of Sugammadex in neurons in primary culture. Here we show that clinically relevant sugammadex concentrations cause apoptotic/necrosis neuron death in primary cultures. Studies on the underlying mechanism revealed that sugammadex-induced activation of mitochondria-dependent apoptosis associates with depletion of neuronal cholesterol levels. Furthermore SUG increase CytC, AIF, Smac/Diablo and CASP-3 protein expression in cells in culture. Potential association of SUG-induced alteration in cholesterol homeostasis with oxidative stress and apoptosis activation occurs. Furthermore, resistance/sensitivity to oxidative stress differs between neuronal cell types.
authors: Department of Surgery/Anaesthesiology, School of Medicine and Odontology, University of Valencia, Spain.
authors: José M
authors: JM
authors: Palanca
authors: Diana
authors: D
authors: Aguirre-Rueda
authors: Manuel V
authors: MV
authors: Granell
authors: Martin
authors: M
authors: Aldasoro
authors: Alma
authors: A
authors: Garcia
authors: Antonio
authors: A
authors: Iradi
authors: Elena
authors: E
authors: Obrador
authors: Maria Dolores
authors: MD
authors: Mauricio
authors: Jose
authors: J
authors: Vila
authors: Anna
authors: A
authors: Gil-Bisquert
authors: Soraya L
authors: SL
authors: Valles
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002478:Cells, Cultured; D019148:Neuromuscular Blockade; D009474:Neurons / Q000166:cytology / Q000187:drug effects*; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D000077122:Sugammadex; D047408:gamma-Cyclodextrins / Q000494:pharmacology*
chemical_list: D047408:gamma-Cyclodextrins; D000077122:Sugammadex
keywords: AIF; CytC; Smac/Diablo and CASP-3.; Sugammadex; apoptosis
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