Potassium Channel Blocker Research Articles

POTENTIAL INTERACTIONS BETWEEN CARDIOVASCULAR AND COVID-19 MEDICATION REGIMENS AMONG PATIENTS WITH HEART FAILURE

Since December 2019, the COVID-19 pandemic has led to significant mortality in the world. Based on epidemiological data from China, 20% or more of COVID-19 patients had cardiovascular comorbidities. Life-threatening complications due to COVID-19 can develop in these patients. Meanwhile, the risk of complications may be higher in patients with heart failure (HF), who usually have older people and more comorbidities. COVID-19 can lead to myocardial injury and disease exacerbation in HF patients due to a cytokine storm-related hyper-inflammation syndrome.1 Hence, most studies only addressed the prevalence of the cardiovascular disease among COVID-19 patients and less specifically the prevalence of HF. A study in China found that 23% of COVID-19 patients had HF, of which 52% died.2 On the other hand, it has been suggested that COVID-19 may cause heart damage due to the specific condition of HF patients and the characteristics of this syndrome.3 Therefore, it is important to pay attention to the cardiovascular consequences of COVID-19. Despite, the effect of different drug therapies on the outcomes of COVID-19 patients with HF, management of potential interactions between cardiovascular and COVID-19 medication regimens among patients with HF remains an important and challenging clinical issue. In the early pandemic, antiviral drugs such as hydroxychloroquine were widely used to manage COVID-19 infection. Chloroquine and hydroxychloroquine are potassium channel blockers that can prolong QTc and play a role in sudden cardiac death. This process becomes especially dangerous when combined with other treatments, including the QTc prolonging azithromycin and lopinavir/ritonavir. Therefore, HF patients may be at particular risk for sudden cardiac death. In addition, in advanced treatments of HF patients, interactions may occur between COVID-19 and the cardiovascular medication regimen. For example, patients with left ventricular assist devices (LVAD) are usually treated with anticoagulation drugs such as warfarin. Warfarin is a vitamin k antagonist that can interact with some antiviral drugs in the treatment of COVID-19.4 Previous evidences have shown that chloroquine and hydroxychloroquine interactions with cardiovascular drugs such as digoxin and antiarrhythmic drugs are associated with the possibility of HF, QT prolongation, and cardiac arrhythmias.5,6 On the other hand, Remdesivir, which is made to treat Ebola, has shown little potential effect against SARS-CoV-2. Despite the lack of interaction of Remdesivir with HF drugs, it has been suggested that patients receiving Remdesivir be closely monitored due to the risk of QT prolongation and electrolyte disturbances. 1 In sum, previous evidence regarding the potential interactions between cardiovascular and COVID-19 medication regimens among patients with HF are limited and no strong evidence is available. Therefore, further studies are needed to identify these interactions. Given the increasing incidence of COVID-19 in HF patients, it is essential to better understand the interactions between this disease and SARS-CoV-2 in order to manage these patients. Also, a multidisciplinary approach including members of the HF team may lead to better management of HF patients in this pandemic.

The Role of Ionic Currents in Peripheral Nerve Regeneration

: Various factors may result in peripheral nerve injury leading to permanent functional loss. Here, we review the role of calcium and potassium ions in peripheral nerve regeneration and repair. This narrative review of the literature collected its data by searching Google Scholar, PubMed, Elsevier, Springer, Wiley, EBSCO, Scopus, and Science Direct. Publications were searched with no particular time restriction from 1997 to 2021, including all types of study. About 100 relevant papers were found from 1997, 77 of which were selected for this study. Both beta subunits of sodium channels are expressed in peripheral neurons, and drugs that affect those channels may facilitate nerve repair. Riluzole is a sodium/glutamate antagonist which has recently entered clinical trials for spinal cord injury. Riluzole's neuroprotective effects are due to sodium channel blockade and, subsequently, the prevention of Ca2+ overflow. Besides, 4-aminopyridine (4-AP) is a neurotransmitter of potassium channel blockers that increases the rate of functional improvement following peripheral nerve damage by promoting remyelination. Verapamil is a calcium channel blocker that stimulates an endogenous anti-inflammatory response and reduces pro-inflammatory processes, thus causing pain modulation. Inhibition of ROCKs accelerate the regeneration and functional restoration after spinal-cord damage in mammals, and inhibition of the Rho/ROCK pathway has been additionally proven efficacious in animal models of stroke, inflammatory and demyelinating diseases, Alzheimer’s disease, and neuropathic ache. Therefore, the neurite outgrowth of surviving neurons is necessary for nerve regeneration to reinnervate target tissue after nerve damage. One of the critical components of the damage response process is a local translation in axons, and it is critical for the regenerative outcome. On the other hand, it provides new axonal regrowth molecules and induces signals returning to the cell's soma to partake in regenerative pathways and survival.

Risk of out-of-hospital cardiac arrest in antidepressant drug users.

Conflicting results have been reported regarding the association between antidepressant use and out‐of‐hospital cardiac arrest (OHCA) risk. We investigated whether the use of antidepressants is associated with OHCA.MethodsWe conducted a nationwide nested case–control study to assess the association of individual antidepressant drugs within drug classes with the hazard of OHCA. Cases were defined as OHCA from presumed cardiac causes. Cox regression with time‐dependent exposure and time‐dependent covariates was conducted to calculate hazard ratios (HR) and 95% confidence intervals (95% CIs) overall and in subgroups defined by established cardiac disease and cardiovascular risk factors. Also, we studied antidepressants with and without sodium channel blocking or potassium channel blocking properties separately.ResultsDuring the study period from 2001 to 2015 we observed 10 987 OHCA cases, and found increased OHCA rate for high‐dose citalopram (>20 mg) and high‐dose escitalopram (>10 mg; HR:1.46 [95% CI:1.27–1.69], HR:1.43 [95% CI:1.16–1.75], respectively) among selective serotonin reuptake inhibitors (reference drug sertraline), and for high‐dose mirtazapine (>30; HR:1.59 [95% CI:1.18–2.14]) among the serotonin–norepinephrine reuptake inhibitors or noradrenergic and specific serotonergic antidepressants (reference drug duloxetine). Among tricyclic antidepressants (reference drug amitriptyline), no drug was associated with significantly increased OHCA rate. Increased OHCA rate was found for antidepressants with known potassium channel blocking properties (HR:1.14 [95% CI:1.05–1.23]), but for not those with sodium channel blocking properties. Citalopram, although not statistically significant, and mirtazapine were associated with increased OHCA rate in patients without cardiac disease and cardiovascular risk factors.ConclusionOur findings indicate that careful titration of citalopram, escitalopram and mirtazapine dose may have to be considered due to drug safety issues.

Calcium Channel Blockade Mediates the Vasorelaxant Activity of Dichloromethane Extract from Roots of Oncidium cebolleta on Isolated Rat Aorta

Oncidium cebolleta belongs to the Orchidaceae family, and it is used in preparations in Mexican traditional medicine to treat several diseases. This research aimed to study the vasorelaxant activity of dichloromethane extract from the roots of Oncidium cebolleta (DEROc) on endothelium-intact and -removed rat aorta segments to determine its mode of vasorelaxant action. Several extracts (hexane, dichloromethane, and methanol) obtained from leaves and roots were evaluated on isolated rat aorta rings with and without endothelium to determine their vasorelaxant effect. Except for methanolic extract from leaves, all extracts induced a concentration-dependent vasorelaxant effect on endothelium-intact rat aorta rings pre-contracted with noradrenaline (NA, 0.1 µM). Dichloromethane extract from roots (DEROc) was the most potent and efficient, and the effect was endothelium-independent. Also, DEROc could relax KCl-induced contraction (80 mM) and inhibit the contraction induced by CaCl2-cumulative concentration on endothelium-denuded rings. However, DEROc was less potent than control nifedipine (L-type calcium channel blocker), but its effectiveness was similar. Contractions induced by NA and 5-HT [0.001 µM to 0.1 µM] were significantly reduced by DEROc. However, DEROc vasorelaxation was not reduced by TEA (potassium channel blocker, 10 mM) nor by ODQ (soluble guanylyl cyclase inhibitor, 0.1 µM) in endothelium-denuded aortic rings. Our functional results suggest that DEROc induces its relaxant effect by an endothelium-independent mechanism due to a Ca2+ channels blockade in rat aortic rings.

Vasorelaxing properties of the perivascular tissue of the human radial artery.

Perivascular adipose tissue (PVAT) surrounding the human internal thoracic artery exhibits anticontractile and vasorelaxing properties associated with the adipocyte-derived relaxing factor (ADRF). The goal of our study was to assess if perivascular tissue of the human radial artery (RA) also exhibits such anticontractile/vasorelaxant properties. It could be especially relevant in preventing RA spasms. The study was performed on isolated segments of human pedicled RA. Its skeletonized fragments were suspended on stainless steel wire hooks and gradually contracted with serotonin to establish the concentration-effect relationship in the presence/absence of PVAT. Skeletonized arterial segments were precontracted with a single dose of 10-6 M serotonin (EC80). The 5-ml PVAT aliquots (from PVAT incubated in Krebs-Henseleit solution) were transferred to the RA tissue bath resulting in its relaxation. Subsequently, we investigated if ADRF is dependent on endothelial vasorelaxants (nitric oxide and prostacyclin). We attempted to find the potassium channel responsible for mediating the activity of ADRF using different potassium channel blockers. RA without PVAT contracted more strongly in response to serotonin compared to RA with PVAT [Emax: 108.3 (20.2) vs 76.1 (13.5) mN]. The PVAT aliquot relaxed precontracted RA rings at 43% (2.4%) [72.2 (15.6) to 41.0 (5.6) mN]. ADRF is independent of endothelial vasorelaxants; hence, the addition of NG-monomethyl-l-arginine and indomethacin did not change the vasorelaxant response. Neither of the potassium channel blockers participated in the activity of ADRF. PVAT of human RA exhibits anticontractile/vasorelaxant properties that are inherently associated with ADRF secretion. We confirmed the endothelial-independent mechanism of the activity of ADRF. However, we failed to find the potassium channel responsible for the action of ADRF.

Overview of the Role of Pharmacological Management of Obstructive Sleep Apnea.

Obstructive sleep apnea (OSA) remains a prominent disease state characterized by the recurrent collapse of the upper airway while sleeping. To date, current treatment may include continuous positive airway pressure (CPAP), lifestyle changes, behavioral modification, mandibular advancement devices, and surgical treatment. However, due to the desire for a more convenient mode of management, pharmacological treatment has been thoroughly investigated as a means for a potential alternative in OSA treatment. OSA can be distinguished into various endotypic or phenotypic classes, allowing pharmacological treatment to better target the root cause or symptoms of OSA. Some medications available for use include antidepressants, CNS stimulants, nasal decongestants, carbonic anhydrase inhibitors, and potassium channel blockers. This review will cover the findings of currently available and future study medications that could potentially play a role in OSA therapy.

The antipsychotic aripiprazole induces peripheral antinociceptive effects through PI3Kγ/NO/cGMP/KATP pathway activation.

Aripiprazole is an antipsychotic drug used to treat schizophrenia and bipolar disorder. Recently, its peripheral analgesic component was evaluated, however, the mechanism involved in this effect is not fully established. Therefore, the aim of the study was to obtain pharmacological evidence for the involvement of the nitric oxide system in the peripheral antinociceptive effect induced by aripiprazole. The hyperalgesia was induced via intraplantar injection of prostaglandin E2 in mice and the nociceptive thresholds were evaluated using the paw pressure test. All drugs were injected locally into the right hind paw. The PI3K inhibitor (AS605240), but not rapamycin (mTOR kinase inhibitor), reversed the peripheral antinociceptive effect induced by Aripiprazole. Antinociception was antagonized by the non-selective inhibitor of the nitric oxide synthase (L-NOarg). The same response was observed using the selective iNOS, but not with the selective nNOS inhibitors. The selective guanylyl cyclase enzyme inhibitor (ODQ) and the non-selective potassium channel blocker tetraethylammonium were able to reverse the antinociceptive effect of aripiprazole. The same was seen using glibenclamide, an ATP-dependent K+ channel blocker. However, calcium-activated potassium channel blockers of small and high conductance, dequalinium chloride and paxilline, respectively, did not reverse this effect. The injection of cGMP-specific phosphodiesterase type 5 inhibitor zaprinast, potentiated the antinociceptive effect induced by a low dose of aripiprazole. The results provide evidence that aripiprazole induces peripheral antinociceptive effects via PI3K/NO/cGMP/KATP pathway activation.

Depolarization or hyperpolarization: Emerging role of altered bioelectricity in breast cancer metastasis.

Depolarization or hyperpolarization: Emerging role of altered bioelectricity in breast cancer metastasis.

Neuromodulation of neurological disorders in a demyelination model: effect of a potassium channel inhibitor from Androctonus scorpion venom

Scorpion’s toxins have attracted attention as a treatment for diverse neurological diseases related to myelin loss. This study aimed to investigate the effect of kaliotoxin2 (KTX2), a potassium-channel blocker from Androctonus australis hector venom on cuprizone model of demyelination. Results showed that KTX2 modulates the behavioral functions, the demyelination, and reduces the recruitment of microglia, astrocytes, and granulocyte in the brain. KTX2 modulates the inflammatory response by increasing the IL-10 release, attenuating NFκB activation, and decreasing the oxidative stress markers and IL-6 levels. Results highlight the modulating effects of KTX2 on cuprizone model and confirm its therapeutic potential in demyelination diseases. Highlights Kaliotoxin2 (KTX2) prevents the excessive reduction in body weight gain and modulate motor coordination disorder induced by cuprizone. KTX2 from Aah venom protect myelin from the destructive effects of cuprizone. KTX2 inoculation to the CNS reduce microglia, astrocytes and granulocyte infiltration in the brain. KTX2 increases the production of the anti-inflammatory cytokine IL-10 and attenuates the activation of NFκB. KTX2 counterbalances cuprizone-induced brain unbalance of neurochemical redox parameters.

Blood pressure-lowering and cardiovascular effects of plumbagin in rats: An insight into the underlying mechanisms

BackgroundPlumbagin, a natural phenolic compound is investigated for response against blood pressure and vascular reactivity. MethodologyBlood pressure lowering effects were observed by in-vivo invasive evaluation in normotensive rats, and in-vitro experimentation to measure changes of tension in isolated rat aorta and contractility in atria. ResultsThe percentage decrease in mean arterial pressure (MAP) observed with plumbagin intravenously at doses of 0.1, 0.5, 1, 5, 10 ​μg/kg in normotensive rats was 7.16 ​± ​2.35, 15.5 ​± ​5.62, 19.5 ​± ​5.27, 26 ​± ​6.67, 34.33 ​± ​8.80, respectively. Plumbagin exerted vasorelaxant effects in rat aorta, unaffected by the removal of vascular endothelium, and L-NAME and methylene blue pretreatment. Plumbagin completely inhibited phenylephrine (1 ​μM) and High K+ (80 ​mM) induced contractions. Similar to a Ca+2 channel antagonist, plumbagin caused a rightward shift in the Ca+2 concentration-response-curves (CRCs), resembling nifedipine. Pre-incubation with plumbagin, significantly suppressed contractions induced by phenylephrine in Ca+2-free medium via disrupting Ca+2 release from intracellular stores. No change in vasorelaxant response was observed with the addition of potassium channel blockers, TEA and BaCl2. In rat atrial strips, plumbagin exerted significant negative inotropic and chronotropic effects. No significant change was observed with atropine and atenolol pretreatment, so the effect appeared independent of muscarinic and beta-adrenergic receptors. ConclusionThis study suggests the blood pressure lowering effects of plumbagin. That could be contributed by a decrease in vascular resistance via calcium antagonism, interferences in calcium efflux, and depressive effects on the rate and force of cardiac contraction. Further studies would be necessary to probe deeper into the underlying mechanisms.

Advances in Reversal Strategies of Opioid-induced Respiratory Toxicity.

Opioids may produce life-threatening respiratory depression and death from their actions at the opioid receptors within the brainstem respiratory neuronal network. Since there is an increasing number of conditions where the administration of the opioid receptor antagonist naloxone is inadequate or undesired, there is an increased interest in the development of novel reversal and prevention strategies aimed at providing efficacy close to that of the opioid receptor antagonist naloxone but with fewer of its drawbacks such as its short duration of action and lesser ability to reverse high-affinity opioids, such as carfentanil, or drug combinations. To give an overview of this highly relevant topic, the authors systematically discuss predominantly experimental pharmacotherapies, published in the last 5 yr, aimed at reversal of opioid-induced respiratory depression as alternatives to naloxone. The respiratory stimulants are discussed based on their characteristics and mechanism of action: nonopioid controlled substances (e.g., amphetamine, cannabinoids, ketamine), hormones (thyrotropin releasing hormone, oxytocin), nicotinic acetylcholine receptor agonists, ampakines, serotonin receptor agonists, antioxidants, miscellaneous peptides, potassium channel blockers acting at the carotid bodies (doxapram, ENA001), sequestration techniques (scrubber molecules, immunopharmacotherapy), and opioids (partial agonists/antagonists). The authors argue that none of these often still experimental therapies are sufficiently tested with respect to efficacy and safety, and many of the agents presented have a lesser efficacy at deeper levels of respiratory depression, i.e., inability to overcome apnea, or have ample side effects. The authors suggest development of reversal strategies that combine respiratory stimulants with naloxone. Furthermore, they encourage collaborations between research groups to expedite development of viable reversal strategies of potent synthetic opioid-induced respiratory depression.

Cardiovascular characterization of the novel organic mononitrate NDIBP in rats

Organic nitrates are widely used to restore endogenous nitric oxide (NO) levels reduced by endothelial nitric oxide synthase dysfunction. However, these drugs are associated with undesirable side effects, including tolerance. This study aims to investigate the cardiovascular effects of the new organic nitrate 1,3-diisobutoxypropan-2-yl nitrate (NDIBP). Specifically, we assessed its effects on blood pressure, vascular reactivity, acute toxicity, and the ability to induce tolerance. In vitro and ex vivo techniques showed that NDIBP released NO both in a cell-free system and in isolated mesenteric arteries preparations through a process catalyzed by xanthine oxidoreductase. NDIBP also evoked endothelium-independent vasorelaxation, which was significantly attenuated by 2-phenyl-4,4,5,5,-tetramethylimidazoline-1-oxyl 3-oxide (PTIO, 300 μM), a nitric oxide scavenger; 1-H-[1,2,4] oxadiazolo–[4,3-a]quinoxalin-1-one (ODQ, 10 μM), a soluble guanylyl cyclase inhibitor; tetraethylammonium (TEA, 3 mM), a potassium channel blocker; febuxostat (500 nM), a xanthine oxidase inhibitor; and proadifen (10 μM), an inhibitor of cytochrome P450 enzyme. Furthermore, this organic nitrate did not induce tolerance in isolated vessels and presented low toxicity following acute oral administration. In vivo changes on cardiovascular parameters were assessed using normotensive and renovascular hypertensive rats. NDIBP evoked a reduction of blood pressure that was significantly higher in hypertensive animals. Our results suggest that NDIBP acts as a NO donor, inducing blood pressure reduction without having the undesirable effects of tolerance. Those effects seem to be mediated by activation of NO-sGC-cGMP pathway and positive modulation of K+ channels in vascular smooth muscle.

Pharmacological Management of Atrial Fibrillation: A Century of Expert Opinions in Cecil Textbook of Medicine.

Advances in drug therapy for atrial fibrillation (AF) have had a significant impact on the quality of life of a substantial majority of affected persons, which has contributed to a remarkable decrease in the frequency and severity of thromboembolic complications, hospitalizations, and mortality. What are the milestones of the changes in the expert approach to the pharmacological management of AF in the past century? To determine the changes in the experts' approach to the management of AF, as presented in a widely used textbook in the United States. The chapters presenting the management of AF in the 26 editions of Cecil Textbook of Medicine published from 1927 through 2020. AF was consistently described in Cecil Textbook of Medicine as the most common sustained arrhythmia in adults. The authors emphasized its thromboembolic complications and potential for hemodynamic deterioration. Rate control with digitalis and rhythm control with quinidine were the standard in 1927. The pharmacological advances have focused on atrioventricular nodal blocking for rate control, conversion to and maintenance of sinus rhythm, and preventive anticoagulation. The first new class of drugs for rate control was beta-adrenergic receptor blockers, starting with propranolol which was introduced in 1979, followed by the calcium channel blocker verapamil in 1988. Rhythm control with amiodarone, a potassium channel blocker, has been recommended since 2004, and the sodium channel blockers propafenone and flecainide became part of standard therapy in 2008. Anticoagulation with warfarin was recommended starting in 2000, followed by the introduction of direct thrombin inhibitor in 2012 and factor Xa inhibitors in 2016. The pharmacological management of AF was unchanged for more than 50 years (1927-1979), a period during which the devastating effects of thromboembolic complications were not addressed. The major therapeutic advance is represented by preventive anticoagulation with the newer, safer, and more user-friendly direct thrombin and factor Xa inhibitors.

Two engineered AAV capsid variants for efficient transduction of human cortical neurons directly converted from iPSC

BackgroundRecombinant adeno-associated virus (AAV) is the most widely used vector for gene therapy in clinical trials. To increase transduction efficiency and specificity, novel engineered AAV variants with modified capsid sequences are evaluated in human cell cultures and non-human primates. MethodsWe tested two novel AAV capsid variants, AAV2-NNPTPSR and AAV9-NVVRSSS, in human cortical neurons, which were directly converted from human induced pluripotent stem cells and cocultured with rat primary astrocytes. ResultsAAV2-NNPTPSR variant efficiently transduced both induced human cortical glutamatergic neurons and induced human cortical GABAergic interneurons. By contrast, AAV9-NVVRSSS variant transduced both induced human cortical neurons and cocultured rat primary astrocytes. High viral titers (1E+5 viral genomes per cell) caused a significant decrease in viability of induced human cortical neurons. Low viral titers (1E+4 viral genomes per cell) led to a significant increase in the neuronal activity marker c-Fos in transduced human neurons following treatment with a potassium channel blocker. ConclusionsWe identified two engineered AAV capsid variants that efficiently transduce induced human cortical neurons. The threefold higher percentage of c-Fos positive, transduced human neurons may indicate functional alterations induced by viral transduction and/or transgene expression.

Potassium channel-driven bioelectric signalling regulates metastasis in triple-negative breast cancer.

SummaryBackgroundThere is a critical need to better understand the mechanisms that drive local cell invasion and metastasis to develop new therapeutics targeting metastatic disease. Bioelectricity is an important mediator of cellular processes and changes in the resting membrane potential (RMP) are associated with increased cancer cell invasion. However, whether the RMP can be used to target invading cancer cells is unknown.MethodsWe employed both genetic and pharmacological manipulation of potassium channel activity and characterized the effects on breast cancer cell migration and invasion in vitro, and metastasis in an animal model of breast cancer.FindingsOur data demonstrate that altering the RMP of triple-negative breast cancer (TNBC) cells by manipulating potassium channel expression increases in vitro invasion, in vivo tumour growth and metastasis, and is accompanied by changes in gene expression associated with cell adhesion.InterpretationWe describe a novel mechanism for RMP-mediated cell migration involving cadherin-11 and the MAPK pathway. Importantly, we identify a new strategy to target metastatic TNBC in vivo by repurposing an FDA-approved potassium channel blocker. Our results demonstrate that bioelectricity regulates cancer cell invasion and metastasis which could lead to a new class of therapeutics for patients with metastatic disease.FundingThis work was supported by the National Institutes of Health (R00-CA207866 to M.J.O.), Tufts University (Start-up funds from the School of Engineering to M.J.O., Tufts Collaborates Award to M.J.O. and M.L.), Allen Discovery centre program (Paul G. Allen Frontiers Group (12,171) to M.L.), and Breast Cancer Alliance Young Investigator Grant to M.J.O, Laidlaw Scholar funding to D.S. M.L. also gratefully acknowledges support of the Barton Family Foundation.

Azobenzene/Tetraethyl Ammonium Photochromic Potassium Channel Blockers: Scope and Limitations for Design of Para-Substituted Derivatives with Specific Absorption Band Maxima and Thermal Isomerization Rate

Azobenzene/tetraethyl ammonium photochromic ligands (ATPLs) are photoactive compounds with a large variety of photopharmacological applications such as nociception control or vision restoration. Absorption band maximum and lifetime of the less stable isomer are important characteristics that determine the applicability of ATPLs. Substituents allow to adjust these characteristics in a range limited by the azobenzene/tetraethyl ammonium scaffold. The aim of the current study is to find the scope and limitations for the design of ATPLs with specific spectral and kinetic properties by introducing para substituents with different electronic effects. To perform this task we synthesized ATPLs with various electron acceptor and electron donor functional groups and studied their spectral and kinetic properties using flash photolysis and conventional spectroscopy techniques as well as quantum chemical modeling. As a result, we obtained diagrams that describe correlations between spectral and kinetic properties of ATPLs (absorption maxima of E and Z isomers of ATPLs, the thermal lifetime of their Z form) and both the electronic effect of substituents described by Hammett constants and structural parameters obtained from quantum chemical calculations. The provided results can be used for the design of ATPLs with properties that are optimal for photopharmacological applications.

Citral inhibits the nociception in the rat formalin test: effect of metformin and blockers of opioid receptor and the NO-cGMP-K+ channel pathway.

The objective of the present study was to scrutinize the effect of nitric oxide (NO), cyclic GMP (cGMP), potassium channel blockers, and metformin on the citral-produced peripheral antinociception. The rat paw 1% formalin test was used to assess nociception and antinociception. Rats were treated with local peripheral administration of citral (10-100µg/paw). The antinociception of citral (100µg/paw) was evaluated with and without the local pretreatment of naloxone, NG-L-nitro-arginine methyl ester (L-NAME, a NO synthesis inhibitor), 1H-(1,2,4)-oxadiazolo(4,2-a)quinoxalin-1-one (ODQ, a soluble guanylyl cyclase inhibitor), metformin, opioid receptors antagonists, and K+ channel blockers. Injection of citral in the rat paw significantly decreased the nociceptive effect of formalin administration during the two phases of the test. Local pretreatment of the paws with L-NAME and ODQ did not reduced the citral-induced antinociception. Glipizide or glibenclamide (Kir6.1-2; ATP-sensitive K+ channel blockers), tetraethylammonium or 4-aminopyridine (KV; voltage-gated K+ channel blockers), charybdotoxin (KCa1.1; big conductance calcium-activated K+ channel blocker), apamin (KCa2.1-3; small conductance Ca2+-activated K+ channel antagonist), or metformin, but not the opioid antagonists, reduced the antinociception of citral. Citral produced peripheral antinociception during both phases of the formalin test. These effects were due to the activation of K+ channels and a biguanide-dependent mechanism.

Acetylcholine Boosts Dendritic NMDA Spikes in a CA3 Pyramidal Neuron Model

Acetylcholine has been proposed to facilitate the formation of memory ensembles within the hippocampal CA3 network, by enhancing plasticity at CA3-CA3 recurrent synapses. Regenerative NMDA receptor (NMDAR) activation in CA3 neuron dendrites (NMDA spikes) increase synaptic Ca2+ influx and can trigger this synaptic plasticity. Acetylcholine inhibits potassium channels which enhances dendritic excitability and therefore could facilitate NMDA spike generation. Here, we investigate NMDAR-mediated nonlinear synaptic integration in stratum radiatum (SR) and stratum lacunosum moleculare (SLM) dendrites in a reconstructed CA3 neuron computational model and study the effect of cholinergic inhibition of potassium conductances on this nonlinearity. We found that distal SLM dendrites, with a higher input resistance, had a lower threshold for NMDA spike generation compared to SR dendrites. Simulating acetylcholine by blocking potassium channels (M-type, A-type, Ca2+-activated, and inwardly-rectifying) increased dendritic excitability and reduced the number of synapses required to generate NMDA spikes, particularly in the SR dendrites. The magnitude of this effect was heterogeneous across different dendritic branches within the same neuron. These results predict that acetylcholine facilitates dendritic integration and NMDA spike generation in selected CA3 dendrites which could strengthen connections between specific CA3 neurons to form memory ensembles.

Pellino-2 in nonimmune cells: novel interaction partners and intracellular localization.

Pellino-2 is an E3 ubiquitin ligase that mediates intracellular signaling in innate immune pathways. Most studies of endogenous Pellino-2 have been performed in macrophages, but none in nonimmune cells. Using yeast two-hybrid screening and co-immunoprecipitation, we identified six novel interaction partners of Pellino-2, with various localizations: insulin receptor substrate 1, NIMA-related kinase 9, tumor necrosis factor receptor-associated factor 7, cyclin-F, roundabout homolog 1, and disheveled homolog 2. Pellino-2 showed cytoplasmic localization in a wide range of nonimmune cells under physiological potassium concentrations. Treatment with the potassium ionophore nigericin resulted in nuclear localization of Pellino-2, which was reversed by the potassium channel blocker tetraethylammonium. Live-cell imaging revealed intracellular migration of GFP-tagged Pellino-2. In summary, Pellino-2 interacts with proteins at different cellular locations, taking part in dynamic processes that change its intracellular localization influenced by potassium efflux.

TSSF-hERG: A machine-learning-based hERG potassium channel-specific scoring function for chemical cardiotoxicity prediction

The human ether-à-go-go-related gene (hERG) encodes the Kv11.1 voltage-gated potassium ion (K+) channel that conducts the rapidly activating delayed rectifier current (IKr) in cardiomyocytes to regulate the repolarization process. Some drugs, as blockers of hERG potassium channels, cannot be marketed due to prolonged QT intervals, as well known as cardiotoxicity. Predetermining the binding affinity values between drugs and hERG through in silico methods can greatly reduce the time and cost required for experimental verification. In this study, we collected 9,215 compounds with AutoDock Vina’s docking structures as training set, and collected compounds from four references as test sets. A series of models for predicting the binding affinities of hERG blockers were built based on five machine learning algorithms and combinations of interaction features and ligand features. The model built by support vector regression (SVR) using the combination of all features achieved the best performance on both tenfold cross-validation and external verification, which was selected and named as TSSF-hERG (target-specific scoring function for hERG). TSSF-hERG is more accurate than the classic scoring function of AutoDock Vina and the machine-learning-based generic scoring function RF-Score, with a Pearson’s correlation coefficient (Rp) of 0.765, a Spearman’s rank correlation coefficient (Rs) of 0.757, a root-mean-square error (RMSE) of 0.585 in a tenfold cross-validation study. All results demonstrated that TSSF-hERG would be useful for improving the power of binding affinity prediction between hERG and compounds, which can be further used for prediction or virtual screening of the hERG-related cardiotoxicity of drug candidates.