Felbamate (FBM) is a potent nonsedative anticonvulsant whose clinical effect may be related to the inhibition of N-methyl-Daspartate (NMDA) currents, but the exact molecular action remains unclear. Using whole-cell patch-clamp recording in rat hippocampal neurons, we found that submillimolar FBM effectively modifies the gating process of NMDA channels. During a single high-concentration (1 mM) NMDA pulse, FBM significantly inhibits the late sustained current but not the early peak current. However, if the 1 mM NMDA pulse is preceded by a low-concentration (10 M) NMDA prepulse, then FBM significantly inhibits both the peak and the sustained currents in the 1 mM pulse. In sharp contrast, the NMDA currents elicited by micromolar NMDA are only negligibly inhibited or even enhanced by FBM. These findings indicate that the inhibitory effect of FBM on NMDA currents is stronger with both higher NMDA concentration and longer NMDA exposure, and is thus "use-dependent". FBM also slows recovery of the desensitized NMDA channel, and quantitative analyses of FBM effects on the activation kinetics and the desensitization curve of the NMDA currents further disclose dissociation constants of ϳ200, ϳ110, and ϳ55 M for FBM binding to the resting, activated, and desensitized NMDA channels, respectively. We conclude that therapeutic concentrations (50 -300 M) of FBM could bind to and modify a significant proportion of the resting NMDA channel even when NMDA or other glutamatergic ligand is not present and then decrease the NMDA currents at subsequent NMDA pulses by stabilization of the desensitized channels. Because the inhibitory effect is apparent only when there is excessive NMDA exposure, FBM may effectively inhibit many seizure discharges but preserve most normal neuronal firings.Felbamate (FBM; 2-phenyl-1,3-propanediol dicarbamate) is a potent new-generation anticonvulsant that is effective against many different types of epilepsy (Pellock and Brodie, 1997). In addition to clinical cases, the broad-spectrum antiepileptic effect is also well documented in experimental seizures. For example, FBM is effective against both supramaximal extension seizures induced by maximal electroshock and threshold seizures induced by pentylenetetrazol (Swinyard et al., 1986). Although serious complications such as aplastic anemia and hepatotoxicity have limited its use, FBM is an anticonvulsant which is too important to discard. With informed consent of the patients, FBM has remained as a useful anticonvulsant for Lennox-Gastaut syndrome in children and for a variety of complex partial seizures that are refractory to the other anticonvulsants in adults (Kaufman et al., 1997;Pellock, 1999).The intriguing pharmacological profile of FBM implies a unique mechanism of action. Just as for the other nonsedative anticonvulsants, any proposed mechanism underlying FBM action preferably should explain why seizure discharges are effectively inhibited but normal neuronal firings are relatively preserved. FBM has been reported to have multiple pharmac...

Intermittent hypoxia (IH), characterized as cyclic episodes of short-period hypoxia followed by normoxia, occurs in many physiological and pathophysiological conditions such as pregnancy, athlete, obstructive sleep apnea, and asthma. Hypoxia can induce autophagy, which is activated in response to protein aggregates, in the proteotoxic forms of cardiac diseases. Previous studies suggested that autophagy can protect cells by avoiding accumulation of misfolded proteins, which can be generated in response to ischemia/reperfusion (I/R) injury. The objective of the present study was to determine whether IH-induced autophagy can attenuate endoplasmic reticulum (ER) stress and cell death. In this study, H9c2 cell line, rat primary cultured cardiomyocytes, and C57BL/6 male mice underwent IH with an oscillating O 2 concentration between 4 and 20% every 30 min for 1–4 days in an incubator. The levels of LC3, an autophagy indicator protein and CHOP and GRP78 (ER stress-related proteins) were measured by Western blotting analyses. Our data demonstrated that the autophagy-related proteins were upregulated in days 1–3, while the ER stress-related proteins were downregulated on the second day after IH. Treatment with H 2 O 2 (100 μM) for 24 h caused ER stress and increased the level of ER stress-related proteins, and these effects were abolished by pre-treatment with IH condition. In response to the autophagy inhibitor, the level of ER stress-related proteins was upregulated again. Taken together, our data suggested that IH could increase myocardial autophagy as an adaptive response to prevent the ER stress and apoptosis.

BackgroundMetabolic syndrome has been shown to be associated with lower levels of plasma N-terminal pro-B-type natriuretic peptide (Nt-proBNP) in the general population. We sought to elucidate the relationship between Nt-proBNP and components of metabolic syndrome in patients with congestive heart failure (CHF).MethodsFasting blood samples were obtained from 93 patients in our institution. Plasma levels of Nt-proBNP and other biochemical data were measured. The New York Heart Association (NYHA) classification system (I-IV) was used to define the functional capacity of CHF. Metabolic syndrome and its components were defined using diagnostic criteria from the International Diabetes Federation.ResultsForty-nine patients (52.7%) had CHF. There was a positive correlation between plasma Nt-proBNP levels and NYHA functional capacity in CHF patients. Plasma Nt-proBNP levels increased significantly with each increasing NYHA class of the disease. The prevalence of metabolic syndrome in CHF patients was higher than that in patients without CHF. Most importantly, we found that plasma Nt-proBNP levels were lower in CHF patients with metabolic syndrome attributable to inverse relationships between plasma Nt-proBNP and body mass index (β = −0.297), plasma triglyceride (β = −0.286) and homeostasis model assessment of insulin resistance (HOMA-IR; β = −0.346). Fasting glucose to insulin ratio (FGIR, an insulin sensitivity index) was positively associated with plasma Nt-proBNP levels (β = 0.491), and was the independent predictor of plasma Nt-proBNP levels in CHF patients.ConclusionsPlasma Nt-proBNP levels are inversely associated with metabolic syndrome in CHF patients. Reduced plasma Nt-proBNP levels in CHF patients may lead to impaired lipolysis and metabolic function, and may contribute to the development of metabolic syndrome in CHF patients.