ABSTRACT
Introduction: Dravet syndrome (DS) is an intractable epilepsy syndrome concomitant with neurodevelopmental disorder that begins in infancy. DS is dominantly caused by mutations in the SCN1A gene, which encodes the α subunit of a voltage-gated Na channel. Pre-synaptic inhibitory dysfunction is regarded as the pathophysiological mechanism, but an effective strategy for ameliorating seizures and behavioral problems is still under development. Here, we evaluated the effects of KRM-II-81, a newly developed positive allosteric modulator for α 2/3 subunit containing GABAA receptors (α2/3-GABAAR) in a mice model of DS both in vivo and at the neuronal level. Methods: We used knock-in mice carrying a heterozygous, clinically relevant SCN1A mutation (background strain: C57BL/6 J) as a model of the DS (Scn1a WT/A1783V mice), knock-in mouse strain carrying a heterozygous, clinically relevant SCN1A mutation (A1783V). Seizure threshold and locomotor activity was evaluated by using the hyperthermia-induced seizure paradigm and open filed test, respectively. Anxiety-like behavior was assessed by avoidance of the center region in locomotor activity. We estimated a sedative effect by the total distance traveled in locomotor activity and grip strength. Inhibitory post synaptic currents (IPSCs) were recorded from a hippocampal CA1 pyramidal neuron in an acutely prepared brain slice. Results: KRM-II-81 significantly increased the seizure threshold of Scn1a WT/A1783V mice in a dose-dependent manner. A low dose of KRM-II-81 specifically improved anxiety-like behavior of Scn1a WT/A1783V mice. A sedative effect was induced by relatively high dose of KRM-II-81 in Scn1a WT/A1783V mice, the dose of which was not sedative for WT mice. KRM-II-81 potentiated IPSCs by increasing its decay time kinetics. This effect was more prominent in Scn1a WT/A1783V mice. Discussion: Higher activation of α2/3-GABAAR by KRM-II-81 suggests a compensatory modification of post synaptic inhibitory function against presynaptic inhibitory dysfunction in Scn1a WT/A1783V. The increased sensitivity for KRM-II-81 may be relevant to the distinct dose-dependent effect in each paradigm of Scn1a WT/A1783V mice. Conclusion: Selective activation for α2/3-GABAAR by KRM-II-81 could be potential therapeutic strategy for treating seizures and behavioral problems in DS.
ABSTRACT
The changes in dose distribution caused by backscatter radiation from a common commercial dental alloy (Au-Ag-Pd dental alloy; DA) were investigated to identify the optimal material and thicknesses of a dental device (DD) for effective prevention of mucositis. To this end, 1 cm3 of DA was irradiated with a 6-MV X-ray beam (100 MU) in a field size of 10 × 10 cm2 using a Novalis TX linear accelerator. Ethylene vinyl acetate copolymer, polyolefin elastomer, and polyethylene terephthalate (PET) were selected as DD materials. The depth dose along the central axis was determined with respect to the presence/absence of DA and DDs at thicknesses of 1-10 mm using a parallel-plate ionization chamber. The dose in the absence of DDs showed the lowest value at a distance of 5 mm from the DA surface and gradually increased with distance between the measurement point and the DA surface for distances of ≥5 mm. Except for PET, no significant difference between the DA dose curves for the presence and absence of DDs was observed. In the dose curve, PET showed a slightly higher dose for DA with DD than for DA without DD for thicknesses of ≥4 mm. The findings herein suggest that the optimal DD material for preventing local dose enhancement of the mucosa caused by DA backscatter radiation should have a relatively low atomic number and physical density and that optimal DD thickness should be chosen considering backscatter radiation and percentage depth dose.
