Isoflurane induces c-Fos expression in the area postrema of the rat.

INTRODUCTION: Volatile anesthetics are speculated to cause postoperative nausea and vomiting via stimulation of the chemoreceptor trigger zone (CTZ). However, the precise mechanism underlying the emetic action of these drugs is not well understood. In this study, we assessed whether isoflurane induced the expression of c-Fos, a neuronal activation marker, in the area postrema (AP), the locus of the CTZ, in rats, which do not have vomiting action. MATERIALS AND METHODS: Male rats were exposed to 1.3% isoflurane for 0-240 min, or to various concentrations of isoflurane (0, 1.3%, or 2.6%) for 120 min. Finally, the rats were exposed to 1.3% isoflurane for 120 min after ondansetron administration. After the treatments, immunohistochemistry of the rat AP was performed using c-Fos antibody staining. RESULTS: One-way analysis of variance showed that isoflurane exposure significantly increased c-Fos expression in the AP; however, the rats pretreated with 4 mg/kg ondansetron showed significantly decreased c-Fos expression. Moreover, we evaluated the effect of the anesthetic on inducing pica in the rats, and found that kaolin intake was not influenced by isoflurane exposure. CONCLUSION: Overall, these results suggest that isoflurane activates AP neurons and may be involved in the emetic mechanism of isoflurane. This study further suggests the feasibility of using rats as a model for studying emetic mechanisms of drugs, despite their lack of vomit action.

The incidence of and risk factors for developing atypical femoral fractures in Japan.

The long-term treatment with anti-resorptive drugs for osteoporotic patients is suggested to be associated with an increase in atypical femoral fractures (AFFs). However, their incidence, patient characteristics, and risk factors have not been fully elucidated especially in Asian countries. This retrospective observational cohort study found fourteen AFFs in ten patients (four bilateral fractures) among 2,238 hip and femoral shaft fractures treated in our associated hospitals between 2005 and 2010; this incidence (0.63%) was similar to Caucasians. Of the ten patients with AFFs, nine (90%) and six (60%) were using bisphosphonates (BPs) and glucocorticoids (GCs), respectively, compared to 14.3 and 8.6% for patients with typical femoral fractures who were using these agents. As comorbid conditions, five patients had collagen disease (CD) and two had diabetes. A fracture location-, age- and gender-matched (1:3) case-control study revealed that administration of BPs, GCs, and suffering from collagen disease (CD) were significant risk factors for developing AFFs [odds ratios 36.0 (95% confidence intervals 3.8-342.2), 13.0 (2.3-74.1) and 9.0 (1.6-50.3), respectively]. Interestingly, all of the patients with atypical subtrochanteric femoral fractures, defined as those within 5 cm of the lesser trochanter, were taking GCs due to CD, and the age of these patients (average of 54.8 years) was significantly younger than those with atypical diaphyseal femoral fractures (average of 77.2 years, p < 0.05). In conclusion, the incidence of AFFs in the Japanese population was similar to that of Caucasians, and taking BPs and GCs and suffering from CD were risk factors for developing AFFs.

[A Case of Repetitive Cardiac Arrest due to Coronary Vasospasm after Sugammadex Administration].

A 58-year-old man with no history of cardiac disease was scheduled for a cerebral aneurysm clipping surgery. Anesthesia was administered with propofol, rocuronium, fentanyl, and remifentanil. At the end of the surgery, extubation was performed 3 min after the administration of 200 mg sugammadex, along with a simultaneous blood-pressure decrease with ST elevation on lead II. Cardiopulmonary resuscitation was per- formed owing to the occurrence of lethal arrhythmia, and the patient was successfully resuscitated. Subsequent emergent coronary angiography revealed normal coronary arteries. Twelve days after the first surgery, a tracheostomy was performed owing to persistent disturbance of consciousness. Anesthesia was administered with sevoflurane, fentanyl, and rocuronium. Sugammadex 200 mg was administered after the insertion of a tracheal cannula, and 5 min later, the blood pressure were gradually decreased with ST depression on lead V5. Finally, cardiopulmonary resuscitation was required, and the patient recovered again. An acetylcholine provocation test performed later showed positive results. We suspect sugammadex to be the cause of coronary vasospasm, because the time courses of the two cardiac arrest episodes after sugammadex administration were very similar. Therefore, clinicians should consider sugammadex as one of the causative agents of cardiac arrest in the operating room.

Identification of Keratinocyte Cytoprotectants against Toxicity by the Multikinase Inhibitor Sorafenib Using Drug Repositioning.

Hand-foot skin reaction is the most common adverse event of multikinase inhibitors, such as sorafenib. Although hand-foot skin reaction is not life threatening, severe cases impair quality of life because of pain and reduced activities of daily living. However, the pathological mechanisms of hand-foot skin reaction have not yet been elucidated in detail, and there is currently no effective treatment. We aimed to identify keratinocyte cytoprotectants against sorafenib toxicity. The screening of cytoprotectants against sorafenib toxicity was performed using cultured normal human epidermal keratinocytes or a reconstructed human epidermis model and off-patent approved drugs in the Prestwick Chemical library. Among 1273 drugs in the chemical library, 8 dose-dependently increased cell viability by >200% in the presence of sorafenib. In the presence of sorafenib, the number of proliferating cell nuclear antigen-positive cells was significantly higher in clofazimine-, cyclosporin A-, and itraconazole-treated reconstructed human epidermis models than in sorafenib-treated models, and candidate drugs suppressed sorafenib-induced apoptosis in normal human epidermal keratinocytes. In addition, clofazimine, itraconazole, and pyrvinium pamoate significantly recovered the phosphorylation of extracellular signal-regulated kinase 1/2 in the presence of sorafenib. Collectively, hit drugs promoted cell viability and normalized keratinocyte proliferation in the presence of sorafenib. These candidate drugs have potential as treatments for multikinase inhibitor-induced hand-foot skin reaction.

Neonatal exposure to sevoflurane causes significant suppression of hippocampal long-term potentiation in postgrowth rats.

BACKGROUND: The inhaled anesthetic sevoflurane is commonly used for neonates in the clinical setting. Recent studies have indicated that exposure of neonatal rodents to sevoflurane causes acute widespread neurodegeneration and long-lasting neurocognitive dysfunction. Although acute toxic effects of sevoflurane on cellular viability in the hippocampus have been reported in some studies, little is known about the effects of neonatal sevoflurane exposure on long-term hippocampal synaptic plasticity, which has been implicated in the processes of learning and memory formation. Our study is the first to examine the long-term electrophysiological impact of neonatal exposure to a clinically relevant concentration of sevoflurane. METHODS: On postnatal day 7, rats were exposed to sevoflurane (1% or 2% for 2 hours) with oxygen. To eliminate the influence of blood gas abnormalities caused by sevoflurane-induced respiratory suppression, a group of rats were exposed to a high concentration of carbon dioxide (8% for 2 hours) to duplicate respiratory disturbances caused by 2% sevoflurane exposure. RESULTS: Exposure of neonatal rats to 2% sevoflurane for 2 hours caused significant suppression of long-term potentiation (LTP) induction in the postgrowth period. There was no significant difference between the control group and the CO2-exposed group in LTP induction, indicating that sevoflurane-induced LTP suppression was not caused by blood gas abnormalities. CONCLUSION: Our present findings indicate that neonatal exposure to sevoflurane at a higher concentration can cause alterations in the hippocampal synaptic plasticity that persists into adulthood.

Neonatal administration with dexmedetomidine does not impair the rat hippocampal synaptic plasticity later in adulthood.

BACKGROUND AND OBJECTIVE: The use of dexmedetomidine (DEX), a selective alpha-2 agonist, in pediatric practice is expanding as a result of its desirable properties. To clarify the long-term neurological consequences of neonatal administration of DEX, we investigated the long-term effects of neonatal administration of DEX on hippocampal synaptic activity. METHODS: The rat pups received a bolus intraperitoneal injection of either 5 or 10 µg·kg(-1) DEX, or an equivalent volume of vehicle on postnatal day 7 (P7). Nine weeks after administration, evoked potentials (population spike, PS) and long-term potentiation (LTP) in the hippocampal CA1 region of rats were studied in vivo. RESULTS: Dexmedetomidine had a considerable sedative effect at these doses with little respiratory depression on P7. Nine weeks after administration of DEX, the amplitude of PS in the two treated groups was similar to that in the control group. DEX-treated rats showed no impairment in the induction of LTP. Furthermore, the response in PS to the paired stimuli was not impaired by neonatal administration of DEX. CONCLUSION: These findings demonstrate that a single administration of DEX to rats on P7 preserves hippocampal synaptic plasticity as well as synaptic transmission later in life. In view of the some evidence that have demonstrated the permanent detrimental impact of commonly used anesthetics on neurological outcomes after neonatal exposure, our findings may suggest the relative safety of DEX administered as a sedative agent to neonatal animals with regard to the development of hippocampal synaptic functions.

Influence of nitrous oxide on granule cell migration in the dentate gyrus of the neonatal rat.

For several decades, the neurotoxicities of anesthetics to the developing brain have been reported by many researchers focusing on various phenomena such as apoptosis, neurodegeneration, electrophysiological aberrations, and behavioral abnormalities. According to these reports, signals via N-methyl-D-aspartate receptors (NMDA-r) and/or γ-aminobutyric acid type A receptors (GABAA-r) are implicated in the anesthetic neurotoxicity. On the other hand, during brain development, NMDA-r and GABAA-r are also recognized to play primary roles in neural cell migration. Therefore, anesthetics exposed in this period may influence the neural cell migration of neonates, and increase the number of hilar ectopic granule cells, which are reported to be a cause of continuous neurological deficits. To examine this hypothesis, we investigated immunohistochemically granule cell distribution in the hippocampal dentate gyrus of Wistar/ST rats after nitrous oxide (N2O) exposure. At postnatal day (P) 6, 5-bromo-2'-deoxyuridine (BrdU) was administered to label newly generated cells. Then, rats were divided into groups (n = 6 each group), exposed to 50% N2O at P7, and evaluated at P21. As a result, we found that ectopic ratios (ratio of hilar/total granule cells generated at P6) were decreased in rats at P21 compared with those at P7, and increased in N2O exposed rats for over 120 min compared with the other groups. These results suggest that 50% N2O exposure for over 120 min increases the ratios of ectopic granule cells in the rat dentate gyrus.

Plantar injection of formalin in rats reduces the expression of a potassium chroride cotransporter KCC2 in the spinal cord and a kinase inhibitor suppresses this reduction.

Brain-derived neurotrophic factor (BDNF) is released from activated microglia during neuropathic pain and is hypothesized to downregulate the expression of the potassium chloride cotransporter 2 (KCC2) via the TrkB receptor. Previous studies reported that KCC2 is downregulated 5 min after the plantar injection of formalin in rats; however, the mechanism behind this decrease in KCC2 expression during acute inflammatory pain remains unknown. In this study, we determined whether the TrkB receptor contributes to the expression of KCC2 during the acute pain. Five minutes after the plantar injection of formalin in rats, the ratio of KCC2-immunoreactive area in layer II of the spinal cord significantly decreased on the stimulated side compared to the unaffected side. On the other hand, this response was inhibited by the injection of a kinase inhibitor, K252a, in the subarachnoid space 15 min before the formalin injection. These findings suggest that in acute pain, the TrkB receptor may contribute to the decrease in the expression of KCC2.

The fracture sites of atypical femoral fractures are associated with the weight-bearing lower limb alignment.

PURPOSE: Atypical femoral fractures (AFFs) are stress-related fractures that are speculated to associate with long-term treatment with bisphosphonates for osteoporosis. A history of AFF is a high risk factor for the development of a subsequent AFF in the same location of the contralateral femur, suggesting that a patient's individual anatomical factor(s) are related to the fracture site of AFFs. In this study, we investigated the radiographs of fourteen AFFs (four bilateral fractures among ten patients) treated at six hospitals associated with our university between 2005 and 2010. The fracture site and standing femorotibial angle (FTA), which reflects the mechanical axis of the lower limb, were measured on weight-bearing lower limb radiographs. The fracture site and FTA of patients with typical femoral fractures (TFF) were compared to those of patients with AFFs. The correlations were examined using Spearman's rank correlation coefficients. The fracture locations in the femora were almost the same in the patients with bilateral AFFs. There was a positive correlation between the fracture site and the standing FTA in the patients with AFFs (r=0.82, 95% confidence interval; 0.49 to 0.94), indicating that the larger the standing FTA (varus alignment), the more distal the site of the fracture in the femur. The FTA of the patients with atypical diaphyseal femoral fracture were significantly larger compared to that of those with not only atypical subtrochanteric fractures but also TFFs. In conclusion, the fracture sites of AFFs are associated with the standing lower limb alignment, while those of TFFs are not.

Neonatal exposure to high concentration of carbon dioxide produces persistent learning deficits with impaired hippocampal synaptic plasticity.

Although respiratory complications with blood gas abnormalities contribute significantly to neurodevelopment in the immature brain, little is known about the mechanisms via which blood gas abnormalities, such as hypoxic hypercapnia, impair neurocognitive outcomes. To investigate the possible long-term consequences of neonatal exposure to hypoxic hypercapnia regarding learning ability, we investigated the effect of neonatal hypoxic hypercapnia on later functions in the hippocampus, which is a structure that has been implicated in many learning and memory processes. Neonatal rat pups (postnatal day 7; P7) were exposed to a high concentration of carbon dioxide (CO2; 13%) for 2 or 4h. Exposure to CO2 in P7 rat pups caused blood gas abnormalities, including hypercapnia, hypoxia, and acidosis, and disrupted later learning acquisition, as assessed in 10-week-old adult rats subjected to a Morris water maze test. Induction of long-term potentiation (LTP) in the synapses of the hippocampal CA1 area was also impaired, whereas the paired-pulse responses of population spikes exhibited a significant increase, in CO2-exposed rats, suggesting decreased recurrent inhibition in the hippocampus. Such long-lasting modifications in hippocampal synaptic plasticity may contribute to the learning impairments associated with perinatal hypoxic hypercapnia and acidosis.

Long-lasting effects of neonatal pentobarbital administration on spatial learning and hippocampal synaptic plasticity.

Exposure of newborn rats to antiepileptics such as barbiturates has long-lasting detrimental effects on the hippocampus and hippocampus-dependent behavior. However, the long-term consequences of neonatal administration with barbiturates on the hippocampal synaptic plasticity remain unresolved. In this study, we investigated the long-lasting effects of a neonatal administration of pentobarbital on spatial memory, paired-pulse plasticity in the population spikes, and long-term potentiation (LTP) in the hippocampal CA1 region of rats in vivo. Eight weeks after administration of pentobarbital (10 or 20mg/kg) on the seventh postnatal day (P7), rats showed impaired induction in LTP. During paired-pulse stimulation, pentobarbital-treated rats exhibited a greater facilitation of the test pulse population spike, suggesting a disruption in the inhibitory GABAergic synaptic transmission. Spatial learning in hidden platform task of the Morris water maze was impaired in pentobarbital-treated rats. Our present findings indicate that neonatal treatment with pentobarbital causes alterations in function of the hippocampal inhibitory synaptic transmission that persist into adulthood, likely contributing to the long-lasting abnormalities in the hippocampal LTP as well as learning ability. We also demonstrated significant respiratory disturbances, i.e., severe hypoxia, hypercapnia, and extracellular acidosis, in rats treated with pentobarbital on P7. Given that extracellular acidosis can also modulate synaptic transmission in the developing hippocampus, this finding led us to speculate regarding the influence of respiratory disturbances in pentobarbital-induced long-lasting hippocampal dysfunctions.

Altered synaptic transmission in rat anterior cingulate cortex following peripheral nerve injury.

BACKGROUND: Patients with neuropathic pain present not only with persistent pain but also a complex set of additional symptoms, including mood disorders and cognitive disturbance. Given the important roles of the anterior thalamic nuclei (ATN) and anterior cingulate cortex (ACC) in the cognitive and emotional aspects of pain, investigation of the properties of ATN-ACC synapses will help us to understand the mechanisms underlying neuropathic pain. METHODS: We studied changes in ATN-evoked ACC excitatory postsynaptic potentials (EPSPs) induced by neuropathic pain in a rat model under halothane anaesthesia. RESULTS: Neuropathic pain caused significant suppression of EPSPs in the ACC compared with rats subjected to sham surgery. Similar to previous evidence, acute inflammatory pain induced by formalin injection into the hind paw significantly increased synaptic efficacy in the ACC compared with naive rats. Neither of the pain paradigms altered the paired-pulse responses. CONCLUSIONS: A possible explanation for the neuropathic pain-related suppression of EPSPs is that the ACC was already sufficiently active at baseline as a result of neuropathic pain, and ATN stimulation could not further increase the already elevated level of ACC activity. This abnormal excitability of the ATN-ACC synapse may be important in understanding the mechanism underlying neuropathic pain, particularly with respect to the affective and cognitive aspects.