In the hippocampus, BK channels are preferentially localized in presynaptic glutamatergic terminals including mossy fibers where they are thought to play an important role regulating excessive glutamate release during hyperactive states. Large conductance calcium-activated potassium channels (BK, MaxiK, Slo) have recently been implicated in the pathogenesis of genetic epilepsy. However, the role of BK channels in acquired mesial temporal lobe epilepsy (MTLE) remains unknown. Here we used immunohistochemistry, laser scanning confocal microscopy (LSCM), western immunoblotting and RT-PCR to investigate the expression pattern of the alpha-pore forming subunit of BK channels in the hippocampus and cortex of chronically epileptic rats obtained by the pilocarpine model of MTLE. All epileptic rats experiencing recurrent spontaneous seizures exhibited a significant down-regulation of BK channel immunostaining in the mossy fibers at the hilus and stratum lucidum of the CA3 area. Quantitative analysis of immunofluorescence signals by LSCM revealed a significant 47% reduction in BK channel in epileptic rats when compared to age-matched non-epileptic control rats. These data correlate with a similar reduction in BK channel protein levels and transcripts in the cortex and hippocampus. Our data indicate a seizure-related down-regulation of BK channels in chronically epileptic rats. Further functional assays are necessary to determine whether altered BK channel expression is an acquired channelopathy or a compensatory mechanism affecting the network excitability in MTLE. Moreover, seizure-mediated BK down-regulation may disturb neuronal excitability and presynaptic control at glutamatergic terminals triggering exaggerated glutamate release and seizures.
Group II metabotropic (mGlu II) receptor subtypes mGlu2 and mGlu3 are important modulators of synaptic plasticity and glutamate release in the brain. Accordingly, several pharmacological ligands have been designed to target these receptors for the treatment of neurological disorders characterized by anomalous glutamate regulation including epilepsy. In this study, we examine whether the expression level and function of mGlu2 and mGlu3 are altered in experimental epilepsy by using immunohistochemistry, Western blot analysis, RT-PCR and extracellular recordings. A downregulation of mGlu2/3 protein expression at the mossy fiber pathway was associated with a significant reduction in mGlu2/3 protein expression in the hippocampus and cortex of chronically epileptic rats. Moreover, a reduction in mGlu2 and mGlu3 transcripts levels was noticed as early as 24h after pilocarpine-induced status epilepticus (SE) and persisted during subsequent "latent" and chronic periods. In addition, a significant impairment of mGlu II-mediated depression of field excitatory postsynaptic potentials at mossy fiber-CA3 synapses was detected in chronically epileptic rats. Application of mGlu II agonists (2S,2'R,3'R)-2-(2',3'-dicarboxycyclopropyl)glycine (DCG-IV) induced a significant reduction of the fEPSP amplitude in control rats, but not in chronic epileptic rats. These data indicate a long-lasting impairment of mGlu2/3 expression that may contribute to abnormal presynaptic plasticity, exaggerate glutamate release and hyperexcitability in temporal lobe epilepsy. Classification terms: THEME J: DISORDERS OF THE NERVOUS SYSTEMEpilepsy: basic mechanisms; Epilepsy: human studies and animal models
BackgroundAccording to the latest NICE Guidelines for the management of type 2 diabetes, glucagon-like peptide 1 analogues (GLP-1) are indicated after failure of other therapies and should be considered ineffective in the absence of a metabolic response after 6 months of treatment.PurposeTo analyse the adequacy and effectiveness of liraglutide use in type 2 diabetes management in clinical practice.Material and methodsA retrospective study was conducted in diabetic patients who started treatment with liraglutide in 2013 in a health area comprising 450 000 inhabitants. Prescription data were obtained from the official prescription database (Microstrategy). Clinical data for assessing adequacy and effectiveness were obtained from medical records. It was considered appropriate to use liraglutide when basal HbA1c was ≥7.5%. Treatment was considered effective when HbA1c reduction was ≥1% 6 months after the start of therapy. The absence of HbA1c data was considered an inadequacy criterion. Effectiveness was evaluated only for those patients with analytical results. The percentage of patients in which the treatment was adequate, percentage of patients in which the treatment was effective and percentage of patients in which the treatment was withdrawn following lack of effectiveness were determined.ResultsDuring 2013, 82 patients began treatment with liraglutide. It was a suitable treatment in 55% of patients (n=45). Lack of analytical results for HbA1c led to the inadequacy criterion in 25 patients. Only 51 patients had analytical data to assess effectiveness. 45% (n=23) of patients had a reduction ≥1%, with a mean HbA1c reduction of 0.85% (95% CI 0.31 to 1.37). Treatment was continued for a year later despite being ineffective in 22 patients (79%).ConclusionLiraglutide use did not meet the criteria for adequacy for the indication in half of the patients. In more than half of the patients, liraglutide was ineffective in the metabolic control of type 2 diabetes. Despite the lack of effectiveness, liraglutide was continued in most patients.No conflict of interest
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