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

Abstract

Background:In animal models, several anesthetics induce widespread increases in neuronal apoptosis in the developing brain with subsequent neurologic deficits. Although the mechanisms are largely unknown, the neurotoxicity may, at least in part, be due to elevated oxidative stress caused by mitochondrial dysfunction. In an investigation of potential therapies that could protect against this type of damage, we studied the effects of molecular hydrogen on anestheticinduced neurotoxicity in the developing mouse brain. Methods: Six-day-old C57BL/6 mice were exposed to 3% sevoflurane for 6 h with or without hydrogen (< 1.3%) as part of the carrier gas mixture. Apoptosis was evaluated by immunohistochemical staining for cleaved caspase-3 (n = 8-10/ group). Western blot analysis for cleaved poly-(adenosine diphosphate-ribose) polymerase was also performed to examine apoptosis (n = 3-6/group). Oxidative stress was assessed by immunohistochemical staining for 4-hydroxy-2-nonenal (n = 8/group). Long-term memory and social behavior were examined using the fear conditioning test and the sociability test, respectively (n = 18-20/group). Results: Western blot analysis showed that coadministration of 1.3% hydrogen gas significantly (P < 0.001) reduced the level of neuronal apoptosis to approximately 40% compared with sevoflurane exposure alone. Immunohistochemical analysis showed that hydrogen reduced oxidative stress induced by neonatal sevoflurane exposure. Although neonatal sevoflurane exposure caused impairment in longterm memory and abnormal social behaviors in adulthood, mice coadministered hydrogen gas with sevoflurane did not exhibit these deficits. Conclusions: Inhalation of hydrogen gas robustly decreased neuronal apoptosis and subsequent cognitive impairments caused by neonatal exposure to sevoflurane.

Pre-administration of curcumin prevents neonatal sevoflurane exposure-induced neurobehavioral abnormalities in mice

“…The developing brain is particularly susceptible to oxidative stress damage due to its high oxygen consumption, high polyunsaturated fatty acid content, and low antioxidant defenses (Morrison et al, 2013;Tiwari and Chopra, 2012). Accumulating evidence implies that the deleterious effects of general anesthetics on neuronal cells have been related to enhanced oxidative stress (Boscolo et al, 2012;Sanchez et al, 2011;Yonamine et al, 2013). It is well established that oxygen radicals can easily react with macromolecules, including DNA, lipids, and protein, and ultimately leading to cellular injury (Luo et al, 2013;Tiwari and Chopra, 2012).…”

“…Mounting evidence from animal studies shows that anesthetic exposure in early life leads to neuroapoptosis in the developing nervous system, where loss of neurons is associated with behavioral deficiencies later in life (Shen et al, 2013a,b;Yonamine et al, 2013). We examined cleaved caspase-3 expression to represent apoptosis in the prefrontal cortex and hippocampus, two key brain regions involved in the memory processes, and we confirmed that anesthesia with 3% sevoflurane for 2 h daily for 3 days in P6 mice increased caspase-3 activity, while preadministration of curcumin decreased neuroapoptosis and alleviated the cognitive impairment.…”

“…It is well established that oxygen radicals can easily react with macromolecules, including DNA, lipids, and protein, and ultimately leading to cellular injury (Luo et al, 2013;Tiwari and Chopra, 2012). Of note, it has been suggested that the developing mitochondria are extremely vulnerable to anesthetics, which in turn result in excess reactive oxygen species (ROS) and consequently contribute to anestheticinduced neurotoxicity in the developing brain (Boscolo et al, 2012;Sanchez et al, 2011;Yonamine et al, 2013). The role of oxidative stress in anesthesia-induced neurotoxicity is also supported by the study demonstrating the beneficial effects of antioxidant therapy, in which pretreatment with a synthetic ROS scavenger effectively inhibits the anesthesia-induced ROS production in an animal model (Boscolo et al, 2012).…”

“…In humans, anesthetics are often administered during the brain growth spurt period that occurs from the third trimester to the age of approximately 2 years, and this time period is equivalent to the first week after birth in mice and rats (Jevtovic-Todorovic et al, 2003;Yuede et al, 2010). It has been suggested that general anesthetics can induce neuronal apoptosis (Yonamine et al, 2013), disturb neurogenesis (Zhu et al, 2010), and impair long-term neurocognitive function in the infant rodent brain (Flick et al, 2011;Boscolo et al, 2012). Notably, children who have multiple exposures (e.g., three times) to anesthetics and surgery at an early age also are at an increased risk of developing learning disabilities (Flick et al, 2011;Shen et al, 2013a,b;Wilder et al, 2009).…”

Repeated Neonatal Sevoflurane Exposure-Induced Developmental Delays of Parvalbumin Interneurons and Cognitive Impairments Are Reversed by Environmental Enrichment

“…Accumulating evidence has suggested drugs that block Nmethyl-D-aspartate (NMDA) receptors and/or activation of gamma-aminobutyric acid receptors can cause widespread neuroapoptosis in the developing brain and result in subsequent long-term neurobehavioral abnormalities later in life [1,23]. Sevoflurane is an inhalation anesthetic commonly used in obstetric or pediatric surgery and has been shown as a NMDA receptor antagonist [1].…”