The mitochondrial division inhibitor Mdivi-1 rescues mammalian neurons from anesthetic-induced cytotoxicity

Abstract

BackgroundConcerns have risen regarding the potential side effects of clinical exposure of the pediatric population to inhalational anesthetics, and how they might impact cognitive, learning, and memory functions. However, neither the mechanisms of anesthetic cytotoxicity, nor potential protective strategies, have yet been fully explored. In this study, we examined whether two of the most commonly used inhalational anesthetics, sevoflurane and desflurane, affect neuronal viability and synaptic network assembly between cultured rat cortical neurons.ResultsPrimary rat cortical neuron cultures were exposed to equipotent sevoflurane or desflurane for 1 hour. Neuron viability, synaptic protein expression, mitochondrial morphology, and neurite growth were assayed with immunostaining and confocal microscopy techniques. The effects of anesthetics on the functional development of neural networks were evaluated with whole-cell patch clamp recordings of spontaneous synaptic currents. Our results demonstrate that an acute exposure to sevoflurane and desflurane inhibits the development of neurite processes, impacts the mitochondria, and compromises synaptic proteins - concomitant with a reduction in synaptic function in mature networks. Interestingly, pretreatment of neurons with a mitochondrial division inhibitor (Mdivi-1) not only protected mitochondria integrity but also played a protective role against anesthetic-induced structural and functional neurotoxicity.ConclusionsWe show that Mdivi-1 likely plays a protective role against certain harmful effects of general anesthetics on primary rat neuronal cultures. In addition, Mdivi-1 alone plays a direct role in enhancing growth and modulating synaptic activity. This study highlights the importance of further study into possible protective agents against anesthetic neurotoxicity.

Mitochondrial division inhibitor 1 (mdivi‐1) increases oxidative capacity and contractile stress generated by engineered skeletal muscle

“…The effects of mdivi-1 are also controversial, especially in terms of its specificity in inhibiting Drp1. Although studies have shown that mdivi-1 inhibits mitochondrial fission, 32,[76][77][78][79][80][81] researchers have also reported that mdivi-1 inhibits complex I of the electron transport chain at concentrations greater than 25 μM. 52 A more recent study showed mdivi-1 is a Drp1 inhibitor that increased complex I, II, and IV enzymatic activities at a concentration of 25 μM.…”

Mechanisms of Anesthetic Action and Neurotoxicity: Lessons from Molluscs

“…For example, young rodents exposed to volatile anesthetics including sevoflurane and isoflurane were found to have deficits in long-term memory (Ramage et al, 2013 ). Rat cortical neurons exposed to either sevoflurane or desflurane demonstrated increased cell death, decreased neurite outgrowth and compromised mitochondrial integrity and synaptic function (Xu et al, 2016 ). Studies involving neonatal rodent exposure to intravenous anesthetics such as ketamine and propofol have also described detrimental effects on neuronal survival, dendritic spine density, and memory (Cattano et al, 2008 ; Pesić et al, 2009 ; Briner et al, 2011 ; Huang et al, 2012 ; Yu et al, 2013 ).…”

“…In addition, we systematically evaluate the subcellular impact of modern general anesthetics on neuronal excitability, viability, and connectivity between developing neurons. While many of the findings reviewed here emanate from research conducted on various molluscs, particularly the fresh water snail Lymnaea , these data have nevertheless stood the test of time as it pertains to vertebrates (Xu et al, 2016 ).…”

Molecular Mechanisms of Anesthetic Neurotoxicity: A Review of the Current Literature

“…While it is logical that the observed decrease in inhibitory synaptic neurotransmission may be due to the observed effects on the mitochondria, other explanations are not excluded by these data. Interestingly, in a recent paper, Xu showed that sevoflurane-induced apoptosis in primary cultured neurons could be prevented using a mitochondrial division inhibitor 98 . At this point, there is strong evidence to suggest that early anesthetic exposure strongly affects mitochondrial structure and function in neurons, and there is emerging evidence that mitochondrial disturbance may be associated with decreased synaptic transmission, a known inducer of apoptosis in developing neurons.…”