P-Retigabine: An <i>N</i>-Propargyled Retigabine with Improved Brain Distribution and Enhanced Antiepileptic Activity

Retigabine (RTG, [ethyl N-[2-amino-4-[(4-fluorophenyl)methyl] amino] phenyl] carbamate]) is a first-in-class antiepileptic drug that acts by potentiating neuronal KCNQ potassium channels; however, it has less than optimal brain distribution. In this study, we report that P-RTG (ethyl N-[2-amino-4-((4-fluorobenzyl) (prop-2-ynyl)amino)phenyl]carbamate), an RTG derivative that incorporates a propargyl group at the N position of the RTG linker, exhibits an inverted brain distribution compared with RTG. The brain-to-plasma concentration ratio of P-RTG in-creased to 2.30 compared with 0.16 for RTG. However, the structural modification did not change the drug’s potentiation potency, subtype selectivity, or RTG molecular determinants on KCNQ channels. In addition, in cultured hippocampal neurons, P-RTG exhibited a similar capability as RTG for suppressing both induced and spontaneous action potential firing. Notably, P-RTG antiepileptic activity in the maximal electroshock (MES)-induced mouse seizure model was significantly en-hanced to a value 2.5 times greater than that of RTG. Additionally, the neurotoxicity of P-RTG in the rotarod test was comparable with that of RTG. Collectively, our results indicate that the incorporation of a propargyl group signifi-cantly improves the RTG brain distribution, supporting P-RTG as a promising antiepileptic drug candidate. The strategy for improving brain-to-plasma distribution of RTG might be applicable for the drug development of other central nervous system diseases

Distinct Molecular Mechanisms Underlying Potassium Efflux for NLRP3 Inflammasome Activation

The NLRP3 inflammasome is a core component of innate immunity, and dysregulation of NLRP3 inflammasome involves developing autoimmune, metabolic, and neurodegenerative diseases. Potassium efflux has been reported to be essential for NLRP3 inflammasome activation by structurally diverse pathogen-associated molecular patterns (PAMPs) or danger-associated molecular patterns (DAMPs). Thus, the molecular mechanisms underlying potassium efflux to activate NLRP3 inflammasome are under extensive investigation. Here, we review current knowledge about the distinction channels or pore-forming proteins underlying potassium efflux for NLRP3 inflammasome activation with canonical/non-canonical signaling or following caspase-8 induced pyroptosis. Ion channels and pore-forming proteins, including P2X7 receptor, Gasdermin D, pannexin-1, and K2P channels involved present viable therapeutic targets for NLRP3 inflammasome related diseases.</jats:p

Prefiltered Striation-Based Beamforming for Range Estimation of Multiple Sources

The element&ndash;frequency acoustic intensity of a horizontal line array with a sufficient aperture exhibits interference striation patterns, which can be used for source range estimation without prior environmental information. Under multisource scenarios, the interference striations of the sources overlap with each other, leading to great difficulty in utilizing the information of striations. In this paper, the wavenumber filtering method is applied to each sensor of the horizontal line array to extract the surface-reflected&ndash;bottom-reflected modes and reconstruct the recognizable interference spectrogram for each source. Then, via beamforming along the striations, the source ranges can be estimated individually with little prior environmental information and without the long-time observation of moving sources. The required sensor spacing is analyzed, and the spatial filtering capabilities for a single source from different bearings and two sources for which azimuth angles are close to each other have also been investigated. The simulation results indicate that the proposed algorithm can estimate ranges of multiple sources within 25 km, with relative errors of less than 4%