Sodium channels x GABA receptor

Rhythmic eupneic breathing in mammals depends on the coordinated activities of the neural system that sends cranial and spinal motor outputs to respiratory muscles. These outputs modulate lung ventilation and adjust respiratory airflow, which depends on the upper airway patency and venti- latory musculature. Anesthetics are widely used in clinical practice worldwide. In addition to clinically necessary pharmacological effects, respiratory depression is a critical side effect induced by most gen- eral anesthetics. Therefore, understanding how general anesthetics modulate the respiratory system is important for the development of safer general anesthetics. Currently used volatile anesthetics and most intravenous anesthetics induce inhibitory effects on respiratory outputs. Various general anes- thetics produce differential effects on respiratory characteristics, including the respiratory rate, tidalvolume, airway resistance, and ventilatory response. At the cellular and molecular levels, the mechanisms underlying anesthetic-induced breathing depression mainly include modulation of synaptictransmission of ligand-gated ionotropic receptors (e.g., γ-aminobutyric acid, N-methyl-D-aspartate,and nicotinic acetylcholine receptors) and ion channels (e.g., voltage-gated sodium, calcium, and po-tassium channels, two-pore domain potassium channels, and sodium leak channels), which affect neu-ronal firing in brainstem respiratory and peripheral chemoreceptor areas. The present review compre-hensively summarizes the modulation of the respiratory system by clinically used general anesthetics,including the effects at the molecular, cellular, anatomic, and behavioral levels. Specifically, analgesics, such as opioids, which cause respiratory depression and the "opioid crisis", are discussed. Finally, underlying strategies of respiratory stimulation that target general anesthetics and/or analgesics aresummarized.

The present study used a binding assay to identify novel target biomolecules of l -menthol ([-]-menthol) that promote mouse ambulation. Among 88 different ligands to specific biomolecules examined, 0.1 mM l -menthol inhibited the binding of 13 ligands with relatively high inhibition rates. The assays showed that l -menthol acts on calcium channels, sodium channels, γ-aminobutyric acid type A (GABA _A ) receptor, GABA transporter, dopamine transporter, dopamine D4 receptor, adenosine A2a receptor, α2A-adrenergic receptor, histamine H2 receptor, bombesin receptor, angiotensin AT1 receptor, vasopressin V2 receptor, and leukotriene B4 receptor over a similar concentration range. The inhibition constant (K _i ) for l -menthol inhibition of binding of [ ³ H]-WIN35,428 to the human recombinant dopamine transporter was 6.15 × 10 ^-4 mol/L. The K _i for l -menthol inhibition of binding of [ ³ H]-ethynylbicycloorthobenzoate (EBOB), a ligand of GABA _A receptor picrotoxin site, was 2.88 × 10 ^-4 mol/L. These results should aid future research by providing clues for investigating the mechanisms underlying l -menthol activities, including the ambulation-promoting effect. The present results suggest that the dopamine transporter, adenosine A2a receptor, dopamine D4 receptor, α2A-adrenergic receptor, and GABA _A receptor are promising candidate molecules that are involved in the mechanisms underlying the psychostimulant-like effect of l -menthol.

In searching for more effective and safer antiepileptic drugs, a series of 2,5-disubstituted [1,2,4]-triazolo[1,5-a]pyrimidine-7(4H)-one derivatives were designed and synthesized. Spontaneous Ca ²⁺ oscillations (SCOs) of cortical neurons were used for in vitro phenotypic screening. Maximal electroshock test (MES) and pentylenetetrazole (PTZ) test were used to access their anticonvulsant activity, and rotarod test was used to estimate their neurotoxicity. The active compounds in in vitro model are specifically effective in pentylenetetrazole (PTZ)-induced epilepsy model but not maximal electroshock (MES) model, more importantly with lower neurotoxicity as compared to commonly used drugs. Among them, compound 5c and 5e showed significant anticonvulsant activities in PTZ-induced epilepsy model with ED ₅₀ values at 31.81 mg/kg and 40.95 mg/kg, respectively. These compounds have improved neurotoxicity with protective index (PI = TD ₅₀ /ED ₅₀ ) values at 17.22 and 9.09, respectively. Finally we demonstrated that compound 5c and 5e mainly acted on GABA _A receptor as positive modulators but not sodium channels. Thus the present study has provided potential candidates for further investigation in epilepsy.