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.

Sugammadex-Enhanced Neuronal Apoptosis following Neonatal Sevoflurane Exposure in Mice

“…In this study, we confirmed disruption of the BBB ultrastructure in neonatal mice exposed to sevoflurane. This study indicated that sugammadex passed through the BBB, which was disrupted by neonatal sevoflurane exposure, and that sugammadex induced neuronal apoptosis as seen in primary culture [4]. …”

“…Palanca et al [4] reported that sugammadex altered cholesterol homeostasis. Long-term memory impairment must be examined in a future study because we previously showed that high levels of apoptosis soon after anesthesia cause long-term memory impairment in adults [14, 19].…”

“…Sugammadex is used by anesthesiologists to achieve immediate reversal of an NMB with few side adverse effects. Recently, sugammadex was shown to induce neuronal apoptosis in primary cultures [4]. …”

Effects of Intracerebroventricular Sugammadex Administration on Central Nervous System in Rats

“…In a study of Palanca it was stated that SUG causes neuronal apoptosis in primary cultures [25]. Primary cultures of cortical neurons were prepared from the cerebral cortex of 14-15 day old rat fetuses (5 female rats to obtain fetuses).…”

Safety and Efficacy of Sugammadex for Neuromuscular Blockade Reversal

“…However, one safety issue has been raised by Palanca et al who found that clinically relevant sugammadex concentrations in primary culture was associated with cortical neuron necrosis and cell death. 169 This may have potential implications for sugammadex use if used in patients where the blood brain barrier has been disrupted (trauma, ischemia, infections) or immature (neonates) and warrants further investigation.…”