Levetiracetam: antiepileptic properties and protective effects on mitochondrial dysfunction in experimental status epilepticus

PURPOSE: To assess the anticonvulsant activity of the novel antiepileptic drug, levetiracetam (LEV) in a model of self-sustaining limbic status epilepticus, and to measure the consequence of LEV treatment on the pattern of mitochondrial dysfunction known to occur after status epilepticus (SE). METHODS: The rat perforant pathway was stimulated for 2 h to induce self-sustaining status epilepticus (SSSE). Stimulated rats were assigned to one of three treatment groups, receiving intraperitoneal injections of saline, 200 mg/kg LEV, or 1,000 mg/kg LEV, 15 min into SSSE and at 3 times over the next 44-h period. All animals received diazepam after 3-h SSSE to terminate seizures. Forty-four hours later, the hippocampi were extracted and prepared for electrochemical high-performance liquid chromatography (HPLC), to measure reduced glutathione levels, and for spectrophotometric assays to measure activities of mitochondrial enzymes (aconitase, alpha-ketoglutarate dehydrogenase, citrate synthase, complex I, and complex II/III). These parameters were compared between treatment groups and with sham-operated rats. RESULTS: LEV administration did not terminate seizures or have any significant effect on spike frequency, although rats that received 1,000 mg/kg LEV did exhibit improved behavioral seizure parameters. Significant biochemical changes occurred in saline-treated stimulated rats compared with shams: with reductions in glutathione, alpha-ketoglutarate dehydrogenase, aconitase, citrate synthase, and complex I activities. Complex II/III activities were unchanged throughout. Rats that received 1,000 mg/kg LEV had significantly improved biochemical parameters, in many instances, comparable to sham control levels. CONCLUSIONS: Despite continuing seizures, administration of LEV (1,000 mg/kg) protects against mitochondrial dysfunction, indicating that in addition to its antiepileptic actions, LEV may have neuroprotective effects.     

During 3 years treatment of primary progressive multiple sclerosis with glatiramer acetate, specific antibodies switch from IgG1 to IgG4

In this study we analyzed the humoral immune response to glatiramer acetate in 16 GA-treated primary progressive MS patients and 9 placebo patients from the PROMiSe study. We have demonstrated that all multiple sclerosis patients (n=16) continuously treated with GA for 3 years developed anti-GA antibodies that peaked at month 3 and remained elevated during the whole study. We have also demonstrated that initially GA-reactive antibodies of the IgG1 subclass predominate, peaking at month 9 of therapy, but after 9 months IgG1 decreases while anti-GA antibodies of the IgG4 subclass increase and remain high for the 3 years of follow-up. These results support a shift from Th1 to Th2 in the antibody response to glatiramer acetate treatment.     

Awake Renal Transplantation; A Realistic Alternative to General Anesthesia

A 63-year-old man with profound phobia of general anesthesia recently underwent successful renal transplantation in our unit under combined spinal-epidural anesthesia (CSEA). We believe that although this is not a novel technique, it is a realistic option for renal transplantation in patients in whom general anesthesia is not feasible. The use of CSEA for surgery below the umbilicus and its postoperative pain management has increased in popularity in recent years. Its use in renal transplantation is not widely reported; however, available articles suggest that it is a safe and useful alternative to general anesthesia, with no significant difference in anesthesia or surgical time, surgical conditions, hemodynamic stability, or early postoperative renal function. The procedure was performed with no alteration to the surgical technique usually adopted by the surgeon. The patient had a largely uneventful postoperative recovery, with good pain control and no significant complications. He has achieved good stable renal function, with a serum creatinine concentration of 105 μmol/L at 6 months (preoperative serum creatinine concentration, 832 μmol/L). We believe this case demonstrates that CSEA is a practical option for renal transplantation in the United Kingdom, and would recommend CSEA as a useful alternative to general anesthesia in patients with this type of phobia. Careful preoperative planning, patient selection, and consideration of a contingency plan meant that surgically the procedure proceeded as standard, with good results. Because of the success of this case, a second patient with phobia of general anesthesia has recently been placed on the regional transplantation waiting list.     

Lung cancer cell lines harboring MET gene amplification are dependent on Met for growth and survival

Recent clinical successes of small-molecule epidermal growth factor receptor (EGFR) inhibitors in treating advanced non-small cell lung cancer (NSCLC) have raised hopes that the identification of other deregulated growth factor pathways in NSCLC will lead to new therapeutic options for NSCLC. Met, the receptor for hepatocyte growth factor, has been implicated in growth, invasion, and metastasis of many tumors including NSCLC. To assess the functional role for Met in NSCLC, we evaluated a panel of nine lung cancer cell lines for Met gene amplification, Met expression, Met pathway activation, and the sensitivity of the cell lines to short hairpin RNA (shRNA)-mediated Met knockdown. Two cell lines, EBC-1 and H1993, showed significant Met gene amplification and overexpressed Met receptors which were constitutively phosphorylated. The other seven lines did not exhibit Met amplification and expressed much lower levels of Met, which was phosphorylated only on addition of hepatocyte growth factor. We also found a strong up-regulation of tyrosine phosphorylation in beta-catenin and p120/delta-catenin in the Met-amplified EBC-1 and H1993 cell lines. ShRNA-mediated Met knockdown induced significant growth inhibition, G(1)-S arrest, and apoptosis in EBC-1 and H1993 cells, whereas it had little or no effect on the cell lines that do not have Met amplification. These results strongly suggest that Met amplification identifies a subset of NSCLC likely to respond to new molecular therapies targeting Met.     

Pulmonary alveolar proteinosis caused by deletion of the GM-CSFRalpha gene in the X chromosome pseudoautosomal region 1

Pulmonary alveolar proteinosis (PAP) is a rare lung disorder in which surfactant-derived lipoproteins accumulate excessively within pulmonary alveoli, causing severe respiratory distress. The importance of granulocyte/macrophage colony-stimulating factor (GM-CSF) in the pathogenesis of PAP has been confirmed in humans and mice, wherein GM-CSF signaling is required for pulmonary alveolar macrophage catabolism of surfactant. PAP is caused by disruption of GM-CSF signaling in these cells, and is usually caused by neutralizing autoantibodies to GM-CSF or is secondary to other underlying diseases. Rarely, genetic defects in surfactant proteins or the common β chain for the GM-CSF receptor (GM-CSFR) are causal. Using a combination of cellular, molecular, and genomic approaches, we provide the first evidence that PAP can result from a genetic deficiency of the GM-CSFR α chain, encoded in the X-chromosome pseudoautosomal region 1.     

Astrocytic involvement in learning and memory consolidation

Astrocytes play fundamental roles in brain function, interacting with neurons and other astrocytes, yet their role in learning is not widely recognized. This review focuses on astrocytic involvement in memory consolidation following bead discrimination learning in day-old chick and draws parallels to mammalian learning, providing strong empirical support for the conclusion that the described neuronal-astrocytic interactions are universally valid. It identifies specific mechanisms whereby astrocytes support memory consolidation. Uptake of glucose, stimulated in astrocytes by beta(3)-noradrenergic receptor activation, provides energy by glycolytic/oxidative metabolism. Unlike neurons, astrocytes carry out net synthesis of tricarboxylic acid cycle intermediates needed for synthesis of transmitter glutamate formed by rapid degradation of glucose-derived glycogen and stimulated by beta(2)-noradrenergic receptor activation. This makes learning dependent on glycogenolysis and its stimulation by noradrenaline. Astrocytes take up most synaptically released glutamate, terminating transmitter activity and returning glutamate to neurons in a glutamate-glutamine cycle, interference with which abolishes learning. The various astrocytic activities follow a rigidly controlled time schedule, easily determined after bead discrimination learning but also detectable in other paradigms.