In vivo modulatory action of extracellular glutamate on the anticonvulsant effects of hippocampal dopamine and serotonin

Purpose: Our recent work (Clinckers et al., J Neurochem 2004;89:834-43) demonstrated that intrahippocampal perfusion of 2 nM dopamine or serotonin via a microdialysis probe offered complete protection against focal pilocarpine-induced limbic seizures and did not influence basal extracellular hippocampal glutamate levels. Ten nanomolar dopamine or serotonin perfusion, however, worsened seizures and was accompanied by significant extracellular glutamate increases to similar to 200%. The significance of these glutamate elevations in seizure generation remains unclear. The present microdialysis study investigated the modulatory role of extracellular hippocampal glutamate levels in these monoaminergic protective and proconvulsant effects. Methods: A first group of male Wistar albino rats was perfused intrahippocampally for 240 min with 6.25 mu M glutamate alone to increase extracellular levels by 200%. Other animals were perfused with anticonvulsant concentrations of monoamines throughout the experiments while receiving continuous coperfusions of 6.25 mu M glutamate either before, during, and after (240 min) or only after (100 min) pilocarpine perfusion (40 min). Rats were scored for epileptic behavior, and the mean scores were compared with those of the control group. Microdialysates were analyzed for monoamine and glutamate content with microbore liquid chromatography. Results: No convulsions occurred during glutamate perfusion alone. When monoamines and glutamate were coperfused before pilocarpine administration, the anticonvulsant effect of the monoamines was lost. Glutamate addition after pilocarpine administration did not affect monoaminergic seizure protection. Conclusions: These results indicate that extracellular glutamate increases per se do not necessarily induce seizures but that they can modulate the anticonvulsant effects exerted by hippocampal monoamines

Data from: Nusinersen in later-onset spinal muscular atrophy: long-term results from the phase 1/2 studies

Objective: Report results of intrathecal nusinersen in children with later-onset spinal muscular atrophy (SMA). Methods: Analyses included children from the phase 1b/2a study (ISIS-396443-CS2; NCT01703988) who first received nusinersen during that study and were eligible to continue treatment in the extension study (ISIS-396443-CS12; NCT02052791). The phase 1b/2a study was a 253-day, ascending dose (3, 6, 9, 12 mg), multiple-dose, open-label, multicenter study that enrolled children with SMA aged 2 to 15 years. The extension study was a 715-day, single-dose level (12 mg) study. Time between studies varied by participant (196–413 days). Assessments included the Hammersmith Functional Motor Scale–Expanded (HFMSE), Upper Limb Module (ULM), Six-Minute Walk Test (6MWT), compound muscle action potential (CMAP), and quantitative multipoint incremental motor unit number estimation. Safety also was assessed. Results: Twenty-eight children were included (SMA Type II, n = 11; SMA Type III, n = 17). Mean HFMSE scores, ULM scores, and 6MWT distances improved by the day 1150 visit (HFMSE: SMA Type II, +10.8 points; SMA Type III, +1.8 points; ULM: SMA Type II, +4.0 points; 6MWT: SMA Type III, +92.0 meters). Mean CMAP values remained relatively stable. No children discontinued treatment due to adverse events. Conclusions: Nusinersen treatment over ~3 years resulted in motor function improvements and disease activity stabilization not observed in natural history cohorts. These results document the long-term benefit of nusinersen in later-onset SMA, including SMA Type III. Classification of evidence: This study provides Class IV evidence that nusinersen improves motor function in children with later-onset SMA

Darras et al. NEUROLOGY/2018/918938 Supplementary appendix

Supplementary appendix containing additional methodological details for the manuscript titled "Nusinersen in later-onset spinal muscular atrophy: long-term results from the phase 1/2 studies