In Vitro Effects of Paclitaxel and Cremophor EL on Human Riboflavin Transporter SLC52A2.

Paclitaxel, a mitotic inhibitor with anti-cancer effects, is dissolved in Cremophor EL (CrEL). However, peripheral neuropathy is a known side effect. As one of the mechanisms of the neuropathy, mitochondrial dysfunction has been proposed, while peroxidation products are involved in the cause of CrEL-induced neurotoxicity. Riboflavin is an essential nutrient required for ATP production in mitochondria and has an antioxidant role as a coenzyme for glutathione. Therefore, riboflavin transporters might play a key role to mitigate neuropathy. However, it is unclear whether paclitaxel and CrEL affect these transporters. In this study, human riboflavin transporter SLC52A2 was used to analyze the effects of paclitaxel and CrEL. CrEL, but not paclitaxel, inhibited uptake of riboflavin in human embryonic kidney 293 cells transfected with the SLC52A2 expression vector, suggesting that altered riboflavin disposition may be involved in the pathogenesis of paclitaxel/CrEL toxicity.

Biphasic cuirass ventilation for treatment of an air leak after pneumothorax in a patient with nemaline myopathy: a case report.

We describe an 11-year-old boy with nemaline myopathy who developed tension pneumothorax while undergoing noninvasive positive-pressure ventilation (NIPPV). The patient developed a persistent air leak after pleurodesis with minocycline hydrochloride and lowering of the NIPPV inspiratory pressure. He required additional respiratory support without the high airway pressures that may aggravate pneumothorax. We provided adequate respiratory support without increasing the positive airway pressure using biphasic cuirass ventilation (BCV), which moved the patient's chest wall by negative pressure. The air leak was resolved without any additional treatment. We should provide BCV for patients in whom surgery may have a risk of both extubation failure and postoperative complications before deciding on surgery.

Adenosine A1 receptor blockage mediates theophylline-associated seizures.

Theophylline-associated seizures (TAS) often progress to prolonged or treatment-resistant convulsions. Theophylline is a nonselective adenosine receptor antagonist. Adenosine is an endogenous anticonvulsant that can terminate seizures. Fever and young age have been reported to be risk factors for TAS. To elucidate the mechanism of TAS, we investigated the effect of theophylline and adenosine receptor ligands on hyperthermia-induced seizures in juvenile rats. The treatment dose of theophylline or control saline was injected intraperitoneally 1 h before hyperthermia-induced seizures. The seizure threshold in the theophylline group was significantly lower and seizure duration was significantly longer than those in the control group. The addition of a selective adenosine A(1) receptor agonist and an adenosine kinase inhibitor completely counteracted the effects of theophylline. Moreover, a selective A(1) antagonist caused a significantly longer seizure duration compared with the control. These findings suggest that blockage of the adenosine A(1) receptor is the main cause of TAS.

Interleukin-1beta enhances susceptibility to hyperthermia-induced seizures in developing rats.

Cytokines have been shown to influence susceptibility to febrile seizures and epilepsy. In this study, the role of interleukin-1beta (IL-1beta) was examined in developing rats. IL-1beta and interleukin-1 receptor antagonist (IL-1ra) were administered to developing rats, and seizures were induced by moist warm air. Twenty male Lewis rats (21-23 days old) were divided into two groups (IL-1beta and saline control groups) and two holes were made in the skull for EEG electrodes. We applied human recombinant IL-1beta intra-nasally 1h before seizures induced by moist warm air. The brain temperature at the appearance of seizure discharges on EEG, and the latency time from the hyperthermia onset until the appearance of seizure discharges on EEG were measured. And the same study using IL-1ra was performed. The median brain temperature for the IL-1beta group, 42.6 degrees C (range: 41.8-43.0), was significantly lower than that for the control, 42.9 (42.3-43.4) (P=0.043). The brain temperature for the IL-1ra group, 43.3 (42.8-43.7), was significantly higher than that for the control, 42.9 (42.2-43.5) (P=0.011), and the latency time for the IL-1ra group, 398s (270-561), was significantly longer than that for the control, 325 (252-462) (P=0.035). These results demonstrate that IL-1beta promotes hyperthermia-induced seizures in developing rats.

Postnatal interleukin-1ß enhances adulthood seizure susceptibility and neuronal cell death after prolonged experimental febrile seizures in infantile rats.

Febrile seizures (FS) are recognized as an antecedent to the development of temporal lobe epilepsy with hippocampal sclerosis (TLE-HS), but it is unclear whether prolonged FS are a direct cause of TLE-HS. Here, we used a rat model of infantile FS to study the effects of inflammatory cytokines on seizure susceptibility and neuronal death in adults. Prolonged hyperthermia-induced seizures (pHS) were induced in male Lewis rats at post natal day (P) 10. Cytokines were administered twice intranasally, once immediately after pHS and once the following day. The effects of intranasal interleukin (IL)-1ß or tumor necrosis factor (TNF) α were tested in rats undergoing a single episode of pHS (P10) and in rats undergoing repeated pHS (P10 and P12). Seizure susceptibility was tested at P70-73 by quantifying the seizure onset time (SOT) after kainic acid administration, and neuronal cell injury and gliosis in adulthood. SOT significantly reduced in rats receiving IL-1ß together with repeated pHS, whereas no significant effects were seen in rats receiving IL-1ß after a single pHS episode, or in rats receiving TNFα. Hippocampal neuronal cell loss was observed in the CA3 region of rats receiving IL-1ß together with repeated pHS; however, there was no significant change in gliosis among each group. Our results are consistent with the hypothesis that excessive production of IL-1ß after repeated prolonged FS can enhance adult seizure susceptibility and neuronal cell death, and might contribute to the development of TLE-HS.

Anticonvulsive effect of paeoniflorin on experimental febrile seizures in immature rats: possible application for febrile seizures in children.

Febrile seizures (FS) is the most common convulsive disorder in children, but there have been no clinical and experimental studies of the possible treatment of FS with herbal medicines, which are widely used in Asian countries. Paeoniflorin (PF) is a major bioactive component of Radix Paeoniae alba, and PF-containing herbal medicines have been used for neuromuscular, neuropsychiatric, and neurodegenerative disorders. In this study, we analyzed the anticonvulsive effect of PF and Keishikashakuyaku-to (KS; a PF-containing herbal medicine) for hyperthermia-induced seizures in immature rats as a model of human FS. When immature (P5) male rats were administered PF or KS for 10 days, hyperthermia-induced seizures were significantly suppressed compared to control rats. In cultured hippocampal neurons, PF suppressed glutamate-induced elevation of intracellular Ca(2+) ([Ca(2+)](i)), glutamate receptor-mediated membrane depolarization, and glutamate-induced neuronal death. In addition, PF partially suppressed the elevation in [Ca(2+)](i) induced by activation of the metabotropic glutamate receptor 5 (mGluR5), but not that mediated by α-amino-3-hydroxy-5-methyl-4-isoxazolpropionic acid (AMPA) or N-methyl-D-aspartate (NMDA) receptors. However, PF did not affect production or release of γ-aminobutyric acid (GABA) in hippocampal neurons. These results suggest that PF or PF-containing herbal medicines exert anticonvulsive effects at least in part by preventing mGluR5-dependent [Ca(2+)](i) elevations. Thus, it could be a possible candidate for the treatment of FS in children.

Activation of central adenosine A(2A) receptors lowers the seizure threshold of hyperthermia-induced seizure in childhood rats.

Adenosine is a potent neuromodulator in the central nervous system (CNS). The functional deterioration of adenosine A(1) receptors in the CNS was reported to cause a failure of termination of seizures and to a lower seizure threshold of hyperthermia-induced seizures (HS) in childhood rats, which may contribute to adenosine-related convulsive disorders such as theophylline-associated seizures in childhood patients. In contrast to the inhibitory effect of adenosine A(1) receptors, the function of adenosine A(2A) receptors remains controversial. To clarify the function of adenosine A(2A) receptors in childhood convulsive disorders associated to hyperthermia, we investigated the in vivo interaction between adenosine A(2A) receptors and their ligands in HS in childhood rats. Adenosine selective A(2A) receptor ligands were injected intraperitoneally before HS. We measured brain temperature at the onset of seizures and the mortality rate after HS. We found that brain temperature at seizure onset was significantly higher in the A(2A) receptor antagonist group compared with that in the control group (p<0.05), and there was no significant difference in mortality among the groups. In contrast, brain temperature at seizure onset was significantly lower in the A(2A) receptor agonist group compared with that in the control group (p<0.05), and mortality was significantly higher in the A(2A) agonist group compared with that in the control group (p<0.001). The activation of the adenosine A(2A) receptor might enhance seizures associated to hyperthermia in the childhood human brain, and be involved in the pathogenesis of sudden unexpected death in epilepsy (SUDEP) in childhood patients with convulsive disorders.

Nonketotic hyperglycinemia: proposal of a diagnostic and treatment strategy.

Early myoclonic encephalopathy presents neonatally with fragmented myoclonus and a suppression-burst electroencephalography pattern. We describe a newborn boy with early myoclonic encephalopathy caused by nonketotic hyperglycinemia. He presented with severe hypotonia, progressive apneic episodes, and erratic myoclonus. Screening of deletions in GLDC, using the multiplex ligation-dependent probe amplification method, and a (13)C breath test confirmed the diagnosis of nonketotic hyperglycinemia. Treatment with the N-methyl-d-aspartate receptor antagonist ketamine exerted dramatic suppressive effects on his seizures, and ameliorated his clinical status.

Beta-hydroxybutyrate alters GABA-transaminase activity in cultured astrocytes.

The ketogenic diet has long been recognized as an effective treatment for medically refractory epilepsy. Despite nearly a century of use, the mechanisms underlying its clinical efficacy remain unknown. One of the proposed hypotheses for its anti-epileptic actions involves increased GABA concentration in the brain due to ketone bodies that become elevated with a ketogenic diet. In recent years, the notion that astrocytes could play a role in the evolution of abnormal cortical excitability in chronic neurological disorders, such as epilepsy, has received renewed attention. The present study examined the effects of beta-hydroxybutyrate, a ketone body, on GABA metabolism in rat primary cultured astrocytes. When beta-hydroxybutyrate was added to culture medium, GABA-transaminase (GABA-T) mRNA expression was significantly suppressed in time- and dose-dependent manners. GABA-T enzymatic activity in beta-hydroxybutyrate-treated astrocytes was also suppressed, in accordance with its gene expression. These effects were evident after 3 days of culture, which might coincide with depleted intracellular glycogen. GABA transporter, GAT-1, gene expression was strongly suppressed in cultured astrocytes after 5 days of culture with beta-hydroxybutyrate, although other type of GABA transporters did not display significant changes. These results suggest that beta-hydroxybutyrate induced by ketogenic diet may increase GABA concentration in the epileptic brain by suppressing astrocytic GABA degradation, leading to antiepileptic effects.