General Anesthesia Causes Long-term Impairment of Mitochondrial Morphogenesis and Synaptic Transmission in Developing Rat Brain

Abstract

Background Clinically used general anesthetics, alone or in combination, are damaging to the developing mammalian brain. In addition to causing widespread apoptotic neurodegeneration in vulnerable brain regions, exposure to general anesthesia at the peak of synaptogenesis causes learning and memory deficiencies later in life. Our in-vivo rodent studies have suggested that activation of the intrinsic (mitochondria-dependent) apoptotic pathway is the earliest warning sign of neuronal damage, suggesting that a disturbance in mitochondrial integrity and function could be the earliest triggering events. Methods Since proper and timely mitochondrial morphogenesis is critical for brain development, we examined the long-term effects of a commonly used anesthesia combination (isoflurane, nitrous oxide, and midazolam) on the regional distribution, ultrastructural properties, and electron transport chain function of mitochondria, as well as synaptic neurotransmission, in the subiculum of rat pups. Results This anesthesia, administered at the peak of synaptogenesis, causes protracted injury to mitochondria, including significant enlargement of mitochondria (over 30%, p < 0.05), impairment of their structural integrity, about 28% increase in their complex IV activity (p < 0.05) and two-fold decrease in their regional distribution in presynaptic neuronal profiles (p < 0.05) where their presence is crucially important for the normal development and functioning of synapses. Consequently, we showed that impaired mitochondrial morphogenesis is accompanied by heightened autophagic activity, decrease in mitochondrial density (about 27%, p < 0.05) and long-lasting disturbances in inhibitory synaptic neurotransmission. The interrelation of these phenomena remains to be established. Conclusion Developing mitochondria are exquisitely vulnerable to general anesthesia and may be important early target of anesthesia-induced developmental neurodegeneration.

Persistent neuronal apoptosis and synaptic loss induced by multiple but not single exposure of propofol contribute to long-term cognitive dysfunction in neonatal rats

“…Second, the effect of propofol on synaptic function was not studied. In addition to synaptic density, synaptic plasticity and synaptic neurotransmissions play an important role in learning and memory as well (Jevtovic-Todorovic et al, 2003;Kato et al, 2013;Sanchez et al, 2011). Further studies are needed to determine whether propofol of different exposure times can affect synaptic function at different time points with brain development.…”

Anesthesia and Apoptosis in the Developing Brain: An Update

“…Altered neurogenesis and abnormal re-entry into the cell cycle has also been observed [29,30]. Lastly, anesthetics have been shown to impair mitochondrial function [31]. It is unknown if all these observed effects are linked with a common mechanism.…”

Coadministration of Hydrogen Gas as Part of the Carrier Gas Mixture Suppresses Neuronal Apoptosis and Subsequent Behavioral Deficits Caused by Neonatal Exposure to Sevoflurane in Mice

“…11 Complex IV, which controls the final step of the mitochondrial electron transport chain, is acutely sensitive to neonatal anesthesia. 11 Dysfunction of complex IV is thought to cause electron leakage from the mitochondrial electron transport chain, thereby increasing ROS production. 20 It is well known that oxygen radicals easily react with macromolecules, including DNA, lipids, and protein, causing cellular injury.…”

“…11 Because dysfunctional mitochondria could be a source of excess reactive oxygen species (ROS), oxidative stress may contribute to anesthetic-induced neurotoxicity in the developing brain. Thus, it is tempting to speculate that antioxidants may be able to protect against neurotoxicity caused by anesthetic Hydrogen Reduces Neonatal Anesthesia Toxicity exposure to neonate.…”