Status epilepticus (SE) remains a significant cause of morbidity and mortality and often is refractory to standard first-line treatments. A rapid loss of synaptic inhibition and development of pharmacoresistance to benzodiazepines (BZDs) occurs early during SE, while NMDA and AMPA receptor antagonists remain effective treatments after BZDs have failed. Multimodal and subunit-selective receptor trafficking within minutes to an hour of SE involves GABA-A, NMDA, and AMPA receptors and contributes to shifts in the number and subunit composition of surface receptors with differential impacts on the physiology, pharmacology, and strength of GABAergic and glutamatergic currents at synaptic and extrasynaptic sites.
View Article and Find Full Text PDFEnzyme replacement therapy with laronidase (recombinant human alpha-l-iduronidase) is successfully used to treat patients with mucopolysaccharidosis type I (MPS I). However, the intravenously-administered enzyme is not expected to treat or prevent neurological deterioration. As MPS I patients suffer from spinal cord compression due in part to thickened spinal meninges, we undertook a phase I clinical trial of lumbar intrathecal laronidase in MPS I subjects age 8 years and older with symptomatic (primarily cervical) spinal cord compression.
View Article and Find Full Text PDFEpileptic Disord
October 2014
Several clinical trials have shown improved seizure control and outcome by early initiation of treatment with benzodiazepines, before arrival in the emergency department and before intravenous access can be established. Here, evidence is provided and reviewed for rapid treatment of acute seizures in order to avoid the development of benzodiazepine pharmacoresistance and the emergence of self-sustaining status epilepticus. Alterations in the physiology, pharmacology, and postsynaptic level of GABA-A receptors can develop within minutes to an hour and hinder the ability of synaptic inhibition to stop seizures while also impairing the efficacy of GABAergic agents, such as benzodiazepines, to boost impaired inhibition.
View Article and Find Full Text PDFWe used a model of severe cholinergic status epilepticus (SE) to study polytherapy aimed at reversing the effects of seizure-induced loss of synaptic GABA(A) receptors and seizure-induced gain of synaptic NMDA receptors. Combinations of a benzodiazepine with ketamine and valproate, or with ketamine and brivaracetam, were more effective and less toxic than benzodiazepine monotherapy in this model of SE.
View Article and Find Full Text PDFSeizures rapidly become self-sustaining and pharmacoresistant to benzodiazepines during status epilepticus (SE). A decrease in the number of postsynaptic gamma-aminobutyric acid (GABA)(A) receptors with SE causes a loss of synaptic inhibition, whereas increases in postsynaptic glutamatergic receptors further upset the balance between excitation and inhibition. Although extracellular GABA levels may increase during SE and contribute to postsynaptic GABA(A) receptor desensitization, other pathways involving glutamatergic activation ultimately may be responsible for the persistent down-regulation of postsynaptic GABA(A) receptors and erosion of synaptic inhibition.
View Article and Find Full Text PDFDuring status epilepticus (SE), GABAergic mechanisms fail and seizures become self-sustaining and pharmacoresistant. During lithiumpilocarpine-induced SE, our studies of postsynaptic GABA(A) receptors in dentate gyrus granule cells show a reduction in the amplitude of miniature IPSCs (mIPSCs). Anatomical studies show a reduction in the colocalization of the beta2/beta3 and gamma2 subunits of GABA(A) receptors with the presynaptic marker synaptophysin and an increase in the proportion of those subunits in the interior of dentate granule cells and other hippocampal neurons with SE.
View Article and Find Full Text PDFPurpose: To study the pharmacologic and synaptic basis for the early loss of paired-pulse inhibition that occurs in the perforant-path stimulation model of status epilepticus.
Methods: Hippocampal slices were prepared from male Wistar rats. Test paired pulses (20- to 50-ms interstimulus interval) of the perforant path were used before and after an abbreviated period of perforant-path stimulation (1-5 min; 2-Hz continuous with 20 Hz of 10 s/min pulses) while either recording field potentials from the dentate gyrus granule cell layer or directly measuring whole-cell patch-clamp currents from granule cells.