Neonatal exposure to sevoflurane in mice causes deficits in maternal behavior later in adulthood.

BACKGROUND: In animal models, exposure to general anesthetics induces widespread increases in neuronal apoptosis in the developing brain. Subsequently, abnormalities in brain functioning are found in adulthood, long after the anesthetic exposure. These abnormalities include not only reduced learning abilities but also impaired social behaviors, suggesting pervasive deficits in brain functioning. But the underlying features of these deficits are still largely unknown. METHODS: Six-day-old C57BL/6 female mice were exposed to 3% sevoflurane for 6 h with or without hydrogen (1.3%) as part of the carrier gas mixture. At 7-9 weeks of age, they were mated with healthy males. The first day after parturition, the maternal behaviors of dams were evaluated. The survival rate of newborn pups was recorded for 6 days after birth. RESULTS: Female mice that received neonatal exposure to sevoflurane could mate normally and deliver healthy pups similar to controls. But these dams often left the pups scattered in the cage and nurtured them very little, so that about half of the pups died within a couple of days. Yet, these dams did not show any deficits in olfactory or exploratory behaviors. Notably, pups born to sevoflurane-treated dams were successfully fostered when nursed by control dams. Mice coadministered of hydrogen gas with sevoflurane did not exhibit the deficits of maternal behaviors. CONCLUSION: In an animal model, sevoflurane exposure in the developing brain caused serious impairment of maternal behaviors when fostering their pups, suggesting pervasive impairment of brain functions including innate behavior essential to species survival.

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.

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 anesthetic-induced 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 long-term 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.

Neonatal desflurane exposure induces more robust neuroapoptosis than do isoflurane and sevoflurane and impairs working memory.

BACKGROUND: In animal models, neonatal exposure to volatile anesthetics induces neuroapoptosis, leading to memory deficits in adulthood. However, effects of neonatal exposure to desflurane are largely unknown. METHODS: Six-day-old C57BL/6 mice were exposed to equivalent doses of desflurane, sevoflurane, or isoflurane for 3 or 6 h. Minimum alveolar concentration was determined by the tail-clamp method as a function of anesthesia duration. Apoptosis was evaluated by immunohistochemical staining for activated caspase-3, and by TUNEL. Western blot analysis for cleaved poly-(adenosine diphosphate-ribose) polymerase was performed to examine apoptosis comparatively. The open-field, elevated plus-maze, Y-maze, and fear conditioning tests were performed to evaluate general activity, anxiety-related behavior, working memory, and long-term memory, respectively. RESULTS: Minimum alveolar concentrations at 1 h were determined to be 11.5% for desflurane, 3.8% for sevoflurane, and 2.7% for isoflurane in 6-day-old mice. Neonatal exposure to desflurane (8%) induced neuroapoptosis with an anatomic pattern similar to that of sevoflurane or isoflurane; however, desflurane induced significantly greater levels of neuroapoptosis than almost equivalent doses of sevoflurane (3%) or isoflurane (2%). In adulthood, mice treated with these anesthetics had impaired long-term memory, whereas no significant anomalies were detected in the open-field and the elevated plus-maze tests. Although performance in a working memory task was normal in mice exposed neonatally to sevoflurane or isoflurane, mice exposed to desflurane had significantly impaired working memory. CONCLUSIONS: In an animal model, neonatal desflurane exposure induced more neuroapoptosis than did sevoflurane or isoflurane and impaired working memory, suggesting that desflurane is more neurotoxic than sevoflurane or isoflurane.

Mechanical allodynia but not thermal hyperalgesia is impaired in mice deficient for ERK2 in the central nervous system.

Extracellular signal-regulated kinase (ERK) plays critical roles in pain plasticity. However, the specific contribution of ERK2 isoforms to pain plasticity is not necessarily elucidated. Here we investigate the function of ERK2 in mouse pain models. We used the Cre-loxP system to cause a conditional, region-specific, genetic deletion of Erk2. To induce recombination in the central nervous system, Erk2-floxed mice were crossed with nestin promoter-driven cre transgenic mice. In the spinal cord of resultant Erk2 conditional knockout (CKO) mice, ERK2 expression was abrogated in neurons and astrocytes, but indistinguishable in microglia compared to controls. Although Erk2 CKO mice showed a normal baseline paw withdrawal threshold to mechanical stimuli, these mice had a reduced nociceptive response following a formalin injection to the hind paw. In a partial sciatic nerve ligation model, Erk2 CKO mice showed partially restored mechanical allodynia compared to control mice. Interestingly, thermal hyperalgesia was indistinguishable between Erk2 CKO and control mice in this model. In contrast to Erk2 CKO mice, mice with a targeted deletion of ERK1 did not exhibit prominent anomalies in these pain models. In Erk2 CKO mice, compensatory hyperphosphorylation of ERK1 was detected in the spinal cord. However, ERK1 did not appear to influence nociceptive processing because the additional inhibition of ERK1 phosphorylation using MEK (MAPK/ERK kinase) inhibitor SL327 did not produce additional changes in formalin-induced spontaneous behaviors in Erk2 CKO mice. Together, these results indicate that ERK2 plays a predominant and/or specific role in pain plasticity, while the contribution of ERK1 is limited.

Repeated deflation of a gas-barrier cuff to stabilize cuff pressure during nitrous oxide anesthesia.

UNLABELLED: Although a nitrous oxide (N(2)O) gas-barrier cuff effectively limits the increase of cuff pressure during N(2)O anesthesia, there are few data assessing whether an N(2)O gas-barrier cuff is more beneficial for stabilizing intracuff pressure than standard endotracheal tubes when cuffs are repeatedly deflated to stabilize pressure during N(2)O anesthesia. In the present study, the pressure of air-filled standard-type cuffs (Trachelon; Terumo, Tokyo, Japan) and N(2)O gas-barrier type endotracheal tube cuffs (Profile Soft-Seal Cuff [PSSC]; Sims Portex, Kent, UK) was measured during 67% N(2)O anesthesia (n = 8 in each), during which the cuffs were repeatedly deflated every 30 min (Trachelon) or 60 min (PSSC) for the first 3 or 4 h. After aspirating the cuffs for 3 h, the cuff pressure exceeded 22 mm Hg in more than half of the patients in both groups. However, aspiration of the cuffs for 4 h decreased the maximal cuff pressure between deflation intervals in both groups (P < 0.01 for each), and increased the intracuff N(2)O concentration (P < 0.0001 for each). After deflating the cuffs over 4 h, the cuff pressure in both groups never exceeded 22 mm Hg during the subsequent 3 h, and intracuff N(2)O concentrations did not significantly change. Therefore, deflation of cuffs for 4 h during N(2)O anesthesia sufficiently stabilized cuff pressure and equilibrated the intracuff N(2)O concentrations in both groups. The use of the PSSC endotracheal tube might be more practical because of the smaller number of cuff deflations required, but the PSSC does not reduce the duration of cuff deflations to stabilize the pressure. IMPLICATIONS: We demonstrated that the N(2)O concentration and pressure in the N(2)O-barrier Profile Soft-Seal Cuff stabilized when the cuff was aspirated once an hour for 4 h during N(2)O anesthesia. The Profile Soft-Seal Cuff might be easier to use in clinical practice than standard endotracheal tubes because of the smaller number of cuff deflations required.