Veratrine

The delta opioid receptor agonist KNT-127 in the prelimbic medial prefrontal cortex attenuates veratrine-induced anxiety-like behaviors in mice.[Pubmed:28864205]

Behav Brain Res. 2018 Jan 15;336:77-84.

We previously reported that systemic administration of the selective delta opioid receptor (DOP) agonist KNT-127 produces potent anxiolytic-like effects in rats. Although a higher distribution pattern of DOPs was reported in the prelimbic medial prefrontal cortex (PL-PFC) of rodents, the role of DOPs in PL-PFC and in anxiolytic-like effects have not been well examined. Recently, we demonstrated that activation of PL-PFC with the sodium channel activator Veratrine increases glutamatergic neurotransmission and produces anxiety-like behaviors in mice. Therefore, we investigated the effects of co-perfusion with KNT-127 in PL-PFC on Veratrine-induced anxiety-like behaviors in mice. We also simultaneously measured extracellular glutamate and GABA levels. In addition, we assessed the effect of KNT-127 on the expression of c-Fos in sub-regions of the amygdala. Extracellular glutamate levels were measured in seven-week-old male C57BL/6N mice using an in vivo microdialysis-HPLC/ECD system, and behaviors were assessed simultaneously in an open field test. Basal levels of glutamate were measured by collecting samples every 10min for 60min. The drug-containing medium was perfused for 30min, and the open field test was performed during the last 10min of drug perfusion. After drug treatments, the perfusion was switched from drug-containing medium to control medium without drugs and samples were collected for another 90min. KNT-127 co-perfusion completely diminished Veratrine-induced anxiety-like behaviors and attenuated the Veratrine-induced increase in extracellular glutamate levels in PL-PFC. Interestingly, KNT-127 perfusion alone in PL-PFC did not affect anxiety-like behaviors. Local perfusion of Veratrine in PL-PFC induced c-Fos immunoreactivity in sub-regions of amygdala. Co-perfusion of KNT-127 diminished c-Fos expression. Here we demonstrate that the DOP agonist KNT-127 in PL-PFC attenuates Veratrine-induced anxiety-like behaviors in mice. These effects may be caused by the presynaptic suppression of activated glutamatergic transmission in PL-PFC, which projects to sub-regions of the amygdala. We propose that compounds like KNT-127, which inhibit glutamatergic transmission in PL-PFC, are candidates for novel anxiolytics.

Neural control of submucosal gland and apical membrane secretions in airways.[Pubmed:26059031]

Physiol Rep. 2015 Jun;3(6). pii: 3/6/e12398.

The mechanisms that lay behind the low-level secretions from airway submucosal glands and the surface epithelium in the absence of external innervation have been investigated in small areas (1.0-1.5 cm(2)) of mucosa from sheep tracheas, freshly collected from a local abattoir. Glandular secretion was measured by an optical method while short circuit current was used as a measure of surface secretion. Activation of neurones in the intrinsic nerve net by Veratrine alkaloids caused an immediate increase in both glandular secretion and short circuit current, both effects being blocked by the addition of tetrodotoxin. However, agents known to be acting directly on the glands, such as muscarinic agonists (e.g., carbachol) or adenylate cyclase activators (e.g., forskolin) were not influenced by tetrodotoxin. The toxin alone had no discernable effect on the low-level basal secretion shown by unstimulated glands. Calu-3 cell monolayers, generally agreed to be a surrogate for the secretory cells of submucosal glands, showed no sensitivity to Veratrine alkaloids, strengthening the view that the Veratrine-like drugs acted exclusively on the intrinsic nerve net. The data are discussed in relation way in which transplanted lungs can maintain mucociliary clearance and hence a sterile environment in the absence of external innervation, as in transplanted lungs.

Rational Design of Small Peptides for Optimal Inhibition of Cyclooxygenase-2: Development of a Highly Effective Anti-Inflammatory Agent.[Pubmed:27019010]

J Med Chem. 2016 Apr 28;59(8):3920-34.

Among the small peptides 2-31, (H)Gly-Gly-Phe-Leu(OMe) (30) reduced prostaglandin production of COX-2 with an IC50 of 60 nM relative to 6000 nM for COX-1. The 5 mg kg(-1) dose of compound 30 rescued albino mice by 80% from capsaicin-induced paw licking and recovered it by 60% from carrageenan-induced inflammation. The mode of action of compound 30 for targeting COX-2, iNOS, and VGSC was investigated by using substance P, l-arginine, and Veratrine, respectively, as biomarkers. The interactions of 30 with COX-2 were supported by isothermal calorimetry experiments showing a Ka of 6.10 +/- 1.10 x 10(4) M(-1) and DeltaG of -100.3 kJ mol(-1) in comparison to a Ka 0.41 x 10(3) +/- 0.09 M(-1) and DeltaG of -19.2 +/- 0.06 kJ mol(-1) for COX-1. Moreover, compound 30 did not show toxicity up to a 2000 mg kg(-1) dose. Hence, we suggest peptide 30 as a highly potent and promising candidate for further development into an anti-inflammatory drug.

The voltage-gated sodium channel activator veratrine induces anxiogenic-like behaviors in rats.[Pubmed:26099814]

Behav Brain Res. 2015 Oct 1;292:316-22.

In this study, we investigated the anxiogenic-like effects of systemically administered Veratrine in rat models of anxiety. In the light/dark test, Veratrine (0.6 mg/kg, s.c.) significantly and dose-dependently decreased the time rats spent in and the number of entries into a light box 30 min after administration, suggesting that Veratrine increases anxiety-like behaviors. These findings were also supported by results from the elevated-plus maze test and the tail-swing behavior test. In addition, Veratrine (0.6 mg/kg, s.c.) significantly increased the plasma concentration of corticosterone, an endogenous biomarker for anxiety, compared to vehicle. On the basis of these results, we conclude that Veratrine induces anxiogenic-like behaviors in rats. The anxiogenic-like behaviors induced by Veratrine (0.6 mg/kg, s.c.) were completely abolished by co-treatment with the typical benzodiazepine anxiolytic diazepam (1 mg/kg, s.c.), when assessed in the elevated-plus maze test. Similar results were obtained with co-treatment with riluzole (10 mg/kg, p.o.), which directly affects the glutamatergic system and has recently been suggested to have anxiolytic-like effects. In conclusion, this study provides evidence that systemically administered Veratrine induces anxiogenic-like behaviors in rats. We propose the Veratrine model as a novel pathological animal model to explore possible candidate drugs for anxiolytics.

The infralimbic and prelimbic medial prefrontal cortices have differential functions in the expression of anxiety-like behaviors in mice.[Pubmed:26802727]

Behav Brain Res. 2016 May 1;304:120-4.

The medial prefrontal cortex is a heterogeneous cortical structure composed of several nuclei, including the prelimbic (PL) and infralimbic (IL) cortices. We previously demonstrated in mice that PL activation with the sodium channel activator Veratrine induces anxiety-like behaviors. However, the role of IL in the regulation of anxiety-like behaviors remained unclear. Therefore, in the present study, we investigated the role of the IL in the regulation of anxiety-like behaviors using pharmacological activation model with Veratrine, and compared it with the role of the PL. Extracellular glutamate levels were measured by in vivo microdialysis-HPLC with an electrochemical detector, and behaviors were assessed using the open field test. In this study, extracellular glutamate levels rose significantly after perfusion of Veratrine in the IL and PL. Interestingly, the PL activation produced anxiety-like behaviors, whereas the activation of the IL produced no anxiety-like behavior in mice. Although the IL is adjacent to the PL, these two regions of the brain have differential functions in the expression of anxiety-like behaviors.

N-propyl-2,2-diphenyl-2-hydroxyacetamide, a novel alpha-hydroxyamide with anticonvulsant, anxiolytic and antidepressant-like effects that inhibits voltage-gated sodium channels.[Pubmed:29217174]

Eur J Pharmacol. 2018 Jan 15;819:270-280.

In patients with epilepsy, anxiety and depression are the most frequent psychiatric comorbidities but they often remain unrecognized and untreated. We report herein the antidepressant-like activity in two animal models, tail suspension and forced swimming tests, of six anticonvulsants alpha-hydroxyamides. From these, N-propyl-2,2-diphenyl-2-hydroxyacetamide (compound 5) emerged not only as the most active as anticonvulsant (ED50 = 2.5mg/kg, MES test), but it showed the most remarkable antidepressant-like effect in the tail suspension and forced swimming tests (0.3-30mg/kg, i.p.); and, also, anxiolytic-like action in the plus maze test (3-10mg/kg, i.p.) in mice. Studies of its mechanism of action, by means of its capacity to act via the GABAA receptor ([(3)H]-flunitrazepam binding assay); the 5-HT1A receptor ([(3)H]-8-OH-DPAT binding assay) and the voltage-gated sodium channels (either using the patch clamp technique in hNav 1.2 expressed in HEK293 cell line or using Veratrine, in vivo) were attempted. The results demonstrated that its effects are not likely related to 5-HT1A or GABAAergic receptors and that its anticonvulsant and antidepressant-like effect could be due to its voltage-gated sodium channel blocking properties.