Vesicular Transporter Inhibitor Research Articles

Tardive Dyskinesia: A Complicated Iatrogenic Movement Condition-An Updated Overview of Diagnosis, Management, and Pharmacological Treatment

Background: Tardive dyskinesia (TD) is a complex iatrogenic movement disorder resulting from prolonged dopamine receptor antagonism. It presents as involuntary abnormal movements such as akathisia, dystonia, and buccolingual stereotypy, predominantly affecting individuals on long-term antipsychotics. Despite the cessation of the causative medication, symptoms often persist, complicating management. Aim: This review provides an updated overview of the diagnosis, management, and pharmacological treatment options for TD, emphasizing its multifaceted nature and the challenges it presents. Methods: The article synthesizes current evidence on TD's etiology, pathophysiology, clinical presentation, and treatment strategies. Key diagnostic tools, including the Abnormal Involuntary Movement Scale (AIMS), and therapeutic approaches such as vesicular monoamine transporter (VMAT2) inhibitors, are discussed. Results: The etiology of TD is linked to first- and second-generation antipsychotics, with the former posing a greater risk. Pathophysiological insights highlight dopamine receptor hypersensitivity, oxidative stress, and neurotransmitter interactions as pivotal contributors. Diagnosis is reliant on symptom persistence post-medication exposure. While treatment options remain limited, valbenazine and deutetrabenazine show efficacy. Preventative measures, including cautious prescribing and regular monitoring, are crucial. Conclusion: TD remains a challenging condition with significant implications for affected individuals. Comprehensive evaluation and targeted therapies are essential for effective management. Advances in VMAT2 inhibitors offer promise, but prevention through judicious medication use is paramount.

Favorable inhibitory effect of clodronate on hepatic steatosis in short bowel syndrome model rats

PurposeThis study investigated the anti-inflammatory effect of clodronate, a vesicular nucleotide transporter (VNUT) inhibitor, on intestinal-failure-associated liver disease (IFALD) in a rat model of short bowel syndrome (SBS).MethodsThe rats underwent jugular vein catheterization for continuous total parenteral nutrition (TPN) and 90% small bowel resection. The animals were divided into the following groups: TPN/SBS (Control group), TPN/SBS/intravenous administration of low-dose clodronate (20 mg/kg twice per week; Low group), or TPN/SBS/intravenous administration of high-dose clodronate (60 mg/kg twice per week; High group). On day 7, the rats were euthanized. Hepatic steatosis and hepatocellular injury were also assessed.ResultsHepatic steatosis and lobular inflammation in the liver were observed in all groups. The High group showed histologically reduced hepatic steatosis compared with the Control group. IL-6 and Nlrp3 expression in the High group was significantly suppressed compared to that in the Control group. The expression of other inflammatory cytokines tended to be lower in the High dose group than in the control group. The lipid metabolism gene expression in the liver specimens showed no significant differences among the groups.ConclusionThe high-dose administration of clodronate may, therefore, inhibit hepatic steatosis and inflammation associated with IFALD in patients with SBS.

Regulation of neurotransmission in regenerating neuromuscular junctions involving endocannabinoids

The work was dedicated to investigation of the influence of two endocannabinoids – arachidonoylethanolamide (AEA), also known as anandamide, and 2-arachidonoylglycerol (2-AG) on the parameters of miniature endplate potentials (MEPP) and evoked endplate potentials (EPP) of motor synapses at the early stage of regeneration during muscle reinnervation. 2-AG increased the amplitude of MEPP by 35%, and also increased the amplitude of EPP by 37%, without affecting quantal content of EPP or any other parameters of neurotransmitter secretion. This effect was prevented by vesicular acetylcholine transporter inhibitor vesamicol and by inverse agonist of CB1-type cannabinoid receptors AM251. AEA did not change the amplitude or any other parameters of MEPP, but reduced the quantal content of EPP by 27%. The inhibitory effect of AEA was prevented by AM251 and by the L-type Ca2+ channel blocker nitrendipine. Thus, it was established for the first time that in newly formed motor synapses AEA and 2-AG activate the same type of presynaptic cannabinoid receptors, but have different final targets, influence different parameters of quantal ACh secretion and have multidirectional effects on synaptic transmission. The presence of both facilitatory and inhibitory effects of endocannabinoids in regenerating synapses may serve to fine-tune and regulate synaptic transmission during their maturation.

Albiflorin Decreases Glutamate Release from Rat Cerebral Cortex Nerve Terminals (Synaptosomes) through Depressing P/Q-Type Calcium Channels and Protein Kinase A Activity.

The purpose of this study was to investigate whether and how albiflorin, a natural monoterpene glycoside, affects the release of glutamate, one of the most important neurotransmitters involved in neurotoxicity, from cerebrocortical nerve terminals (synaptosomes) in rats. The results showed that albiflorin reduced 4-aminopyridine (4-AP)-elicited glutamate release from synaptosomes, which was abrogated in the absence of extracellular Ca2+ or in the presence of the vesicular glutamate transporter inhibitor or a P/Q-type Ca2+ channel inhibitor, indicating a mechanism of action involving Ca2+-dependent depression of vesicular exocytotic glutamate release. Albiflorin failed to alter the increase in the fluorescence intensity of 3,3-diethylthiacarbocyanine iodide (DiSC3(5)), a membrane-potential-sensitive dye. In addition, the suppression of protein kinase A (PKA) abolished the effect of albiflorin on glutamate release. Albiflorin also reduced the phosphorylation of PKA and synaptosomal-associated protein of 25 kDa (SNAP-25) and synapsin I at PKA-specific residues, which correlated with decreased available synaptic vesicles. The results of transmission electron microscopy (TEM) also observed that albiflorin reduces the release competence of synaptic vesicles evoked by 4-AP in synaptosomes. In conclusion, by studying synaptosomally released glutamate, we suggested that albiflorin reduces vesicular exocytotic glutamate release by decreasing extracellular Ca2+ entry via P/Q-type Ca2+ channels and reducing PKA-mediated synapsin I and SNAP-25 phosphorylation.

A Model-Informed Drug Development Approach Supporting the Approval of an Unstudied Valbenazine Dose for Patients With Tardive Dyskinesia.

Valbenazine is a highly potent and selective inhibitor of synaptic vesicular monoamine transporter 2. The current therapeutic doses of valbenazine for tardive dyskinesia (TD) are 40, 60, or 80 mg capsules, given orally, once daily (QD). While 40 and 80 mg were investigated in phase 3 KINECT® 3 trial and initially approved, the approval of valbenazine 60mg was based on the analysis utilizing the Model-informed drug development (MIDD) approach, facilitated through the US Food and Drug Administration's MIDD Pilot Program. This study aimed to demonstrate the efficacy of 60 mg QD dose through model simulations using an established exposure-response (E-R) relationship between valbenazine active metabolite [+]-α-dihydrotetrabenazine exposure and the change from baseline in Abnormal Involuntary Movement Scale total score (AIMS-CFB). A longitudinal E-R model was constructed based on the 40 and 80 mg data from the KINECT 3 trial. The final Emax model adequately predicted dose-dependent improvement in the primary endpoint and was used to interpolate AIMS-CFB for 60 mg at week 6. The efficacy of the unstudied 60 mg dose regimen is expected to be within the range of doses studied clinically with predicted mean AIMS-CFB (95% confidence interval) of -2.69 (-3.30, -2.13) between observed mean AIMS-CFB for 40 mg of -1.92 and 80 mg of -3.39. Results from this analysis provided the key evidence to establish efficacy of 60 mg QD without the need for an additional clinical trial. The availability of valbenazine 60mg dose fills an existing medical need for patients with TD who could benefit from this third effective dose.

Hepatic extracellular ATP/adenosine dynamics in zebrafish models of alcoholic and metabolic steatotic liver disease

Steatotic liver disease (SLD) is a burgeoning health problem predominantly associated with excessive alcohol consumption, which causes alcohol-related liver disease (ALD), and high caloric intake, which results in metabolic dysfunction-associated SLD (MASLD). The pathogenesis of ALD and MASLD, which can progress from steatohepatitis to more severe conditions such as liver fibrosis, cirrhosis, and hepatocellular carcinoma, is complicated by several factors. Recently, extracellular ATP and adenosine (Ado), as damage-associated molecular patterns, were reported to promote inflammation and liver fibrosis, contributing to SLD pathogenesis. Here, we explored the in vivo dynamics of hepatic extracellular ATP and Ado during the progression of steatohepatitis using a genetically encoded GPCR-activation-based sensor (GRAB) in zebrafish models. We established hepatocyte-specific GRABATP and GRABAdo in zebrafish and investigated the changes in in vivo hepatic extracellular ATP and Ado levels under ALD or MASLD conditions. Disease-specific changes in hepatocyte extracellular ATP and Ado levels were observed, clearly indicating a correlation between hepatocyte extracellular ATP/Ado dynamics and disease progression. Furthermore, clodronate, a vesicular nucleotide transporter inhibitor, alleviated the MASLD phenotype by reducing the hepatic extracellular ATP and Ado content. These findings provide deep insights into extracellular ATP/Ado dynamics in disease progression, suggesting therapeutic potential for ALD and MASLD.

A novel class of insecticidal alkylsulfones are potent inhibitors of vesicular acetylcholine transport

Pyridine alkylsulfone derivatives typified by oxazosulfyl (Sumitomo Chemical Company Ltd.) and compound A2 (Syngenta) represent a new class of insecticides, with potent activity against several insect orders. Whilst the MOA of this class has been attributed to interaction with the voltage-gated sodium channel (VGSC), here we present strong evidence that their toxicity to insects is mediated primarily through inhibition of the vesicular acetylcholine transporter (VAChT). Alkylsulfone intoxication in insects is characterised by (i) a reduction in cholinergic synaptic transmission efficiency demonstrated by a depression of cercal afferent activity in giant-interneurone preparations of American cockroach (Periplaneta americana), (ii) selective block of cholinergic-transmission dependent post-synaptic potentials in the Drosophila giant-fibre pathway and (iii) abolition of miniature excitatory post-synaptic currents (mEPSCs) in an identified synapse in Drosophila larvae.Ligand-binding studies using a tritiated example compound ([3H]-A1) revealed a single saturable binding-site, with low nanomolar Kd value, in membrane fractions of green bottle fly (Lucilia sericata). Binding is inhibited by vesamicol and by several examples of a previously identified class of insecticidal compounds known to target VAChT, the spiroindolines. Displacement of this binding by analogues of the radioligand reveals a strong correlation with insecticidal potency. No specific binding was detected in untransformed PC12 cells but a PC12 line stably expressing Drosophila VAChT showed similar affinity for [3H]-A1 as that seen in fly head membrane preparations. Previously identified VAChT point mutations confer resistance to the spiroindoline class of insecticides in Drosophila by Gal-4/UAS directed expression in cholinergic neurones and by CRISPR gene-editing of VAChT, but none of these flies show detectable cross-resistance to this new chemical class.Oxazosulfyl was previously shown to stabilise voltage-gated sodium channels in their slow-inactivated conformation with an IC50 value of 12.3μM but inhibits binding of [3H]-A1 with approximately 5000 times greater potency. We believe this chemistry class represents a novel mode-of-action with high potential for invertebrate selectivity.

Lipopolysaccharide-mediated ATP signaling regulates interleukin-6 mRNA expression via the P2-purinoceptor in human dental pulp cells.

Dental pulp cells play a crucial role in maintaining the balance of the pulp tissue. They actively respond to bacterial inflammation by producing proinflammatory cytokines, particularly interleukin-6 (IL-6). While many cell types release adenosine triphosphate (ATP) in response to various stimuli, the mechanisms and significance of ATP release in dental pulp cells under inflammatory conditions are not well understood. This study aimed to investigate ATP release and its relationship with IL-6 during the inflammatory response in immortalized human dental pulp stem cells (hDPSC-K4DT) following lipopolysaccharide (LPS) stimulation. We found that hDPSC-K4DT cells released ATP extracellularly when exposed to LPS concentrations above 10 μg/mL. ATP release was exclusively attenuated by N-ethylmaleimide, whereas other inhibitors, including clodronic acid (a vesicular nucleotide transporter inhibitor), probenecid (a selective pannexin-1 channel inhibitor), meclofenamic acid (a selective connexin 43 inhibitor), suramin (a nonspecific P2 receptor inhibitor), and KN-62 (a specific P2X7 antagonist), did not exhibit any effect. Additionally, LPS increased IL-6 mRNA expression, which was mitigated by the ATPase apyrase enzyme, N-ethylmaleimide, and suramin, but not by KN-62. Moreover, exogenous ATP induced IL-6 mRNA expression, whereas ATPase apyrase, N-ethylmaleimide, and suramin, but not KN-62, diminished ATP-induced IL-6 mRNA expression. Overall, our findings suggest that LPS-induced ATP release stimulates the IL-6 pathway through P2-purinoceptor, indicating that ATP may function as an anti-inflammatory signal, contributing to the maintenance of dental pulp homeostasis.

Azetidines with All-Carbon Quaternary Centers: Merging Relay Catalysis with Strain Release Functionalization.

Given the importance and beneficial characteristics of decorated azetidines in medicinal chemistry, efficient strategies for their synthesis are highly sought after. Herein, we report a facile synthesis of the elusive all-carbon quaternary-center-bearing azetidines. By adopting a well-orchestrated polar-radical relay strategy, ring strain release of bench-stable benzoylated 1-azabicyclo[1.1.0]butane (ABB) can be harnessed for nickel-catalyzed Suzuki Csp2-Csp3 cross-coupling with commercially available boronic acids in broad scope (>50 examples), excellent functional group tolerance, and gram-scale utility. Preliminary mechanistic studies provided insights into the underlying mechanism, wherein the ring opening of ABB with a catalytic quantity of bromide accounts for the conversion of ABB into a redox-active azetidine, which subsequently engages in the cross-coupling reaction through a radical pathway. The synergistic bromide and nickel catalysis could intriguingly be derived from a single nickel source (NiBr2). Application of the method to modify natural products, biologically relevant molecules, and pharmaceuticals has been successfully achieved as well as the synthesis of melanocortin-1 receptor (MC-1R) agonist and vesicular acetylcholine transporter (VAChT) inhibitor analogues through bioisosteric replacements of piperidine with azetidine moieties, highlighting the potential of the method in drug optimization studies. Aside from the synthesis of azetidines, we demonstrate the ancillary utility of our nickel catalytic system toward the restricted Suzuki cross-coupling of tertiary alkyl bromides with aryl boronic acids to construct all-carbon quaternary centers.

Reserpine and PCPA reduce heat tolerance in Drosophila melanogaster

Drosophila melanogaster is a model organism to study molecular mechanisms and the role of the genes and proteins involved in thermal nociception. Monoamines (i.e. dopamine) have been involved in temperature preference behavior in D. melanogaster. Therefore, we investigated whether the monoamines, particularly dopamine and serotonin, participate in the response to thermal nociceptive stimuli in D. melanogaster. Flies were treated with reserpine (an inhibitor of vesicular monoamines transporter, 3–300 μM), 3-Iodo-L-tyrosine (3-I-T, an inhibitor of tyrosine hydroxylase, 16.28–65.13 mM), and para-Chloro-DL-phenylalanine (PCPA, an inhibitor of tryptophan hydroxylase, 20–80 mM); then, the flies were subjected to tests of thermal tolerance and avoidance of noxious heat. Climbing behavior was used as a test to evaluate locomotor activity. Reserpine reduces the thermal tolerance profile of the D. melanogaster, as well as the avoidance of noxious heat and locomotor activity depending on the concentration. PCPA, but not 3-I-T, decreased heat tolerance and avoidance of noxious heat. These data suggest that monoamines, particularly serotonin, are associated with the impaired avoidance of noxious heat which could be related to the reduction of heat tolerance in D. melanogaster.

β-N-methylamino-l-alanine is a non-competitive inhibitor of vesicular monoamine transporter 2

The neurotoxic, non-proteinogenic amino acid β-N-methylamino-l-alanine (BMAA) has been implicated in the development of neurodegenerative diseases; however, the mechanism(s) and mode(s) of toxicity remain unclear. Similarities in the neuropathology and behavioural deficits of neonatal rats exposed to either BMAA or reserpine, a known vesicular monoamine transporter 2 (VMAT2) inhibitor, suggest a similar mode of action. The aims of this study were therefore to determine if BMAA could prevent the uptake of serotonin into dense granules via inhibition of VMAT2, and, if so, the type of inhibition caused by BMAA. Exposing platelet dense granules to BMAA resulted in a concentration-dependent reduction in serotonin uptake. The inhibition of VMAT2 was non-competitive. The findings from this study support previous reports that BMAA-associated neuropathologies in a neonatal rat model may be due to VMAT2 inhibition during critical periods of neurogenesis.

A new era in the diagnosis and treatment of tardive dyskinesia.

Tardive dyskinesia (TD) is a heterogeneous, hyperkinetic movement disorder induced by dopamine-receptor blocking agents that presents a unique challenge in the treatment of psychosis. Although acceptance of TD as a serious consequence of antipsychotic treatment was resisted initially, subsequent research by many investigators in psychopharmacology contributed to a rich store of knowledge on many aspects of the disorder. While basic neuroscience investigations continue to deepen our understanding of underlying motor circuitry, past trials of potential treatments of TD focusing on a range of theoretical targets were often inconclusive. Development of newer antipsychotics promised to reduce the risk of TD compared to older drugs, but their improved tolerability unexpectedly enabled an expanding market that paradoxically both increased the absolute number of patients at risk and diminished attention to TD which was relegated to legacy status. Fortunately, development and approval of novel vesicular monoamine transporter inhibitors offered evidence-based symptomatic treatment of TD for the first time and rekindled interest in the disorder. Despite recent progress, many questions remain for future research including the mechanisms underlying TD, genetic predisposition, phenomenological diversity, whether new cases are reversible, how to implement best practices to prevent and treat TD, and whether the development of novel antipsychotics free of the risk of TD is attainable. We owe our patients the aspirational goal of striving for zero prevalence of persistent symptoms of TD in anyone treated for psychosis.

Deutetrabenazine for the treatment of chorea associated with Huntington's disease.

This is a comprehensive review of the literature regarding the use of Deutetrabenazine in treating chorea associated with Huntington's disease. Unfortunately, treatment has been limited for many aspects of this neurodegenerative disease. The present investigation presents the background, evidence, and indications for the use Deutetrabenazine in the setting of Huntington's disease. Huntington's disease is characterized by a variety of motor, psychiatric, and cognitive symptoms with chorea being one of the more notable ones. Chorea is a movement disorder present in multiple neurologic diseases that causes involuntary and irregular muscle movements theorized to be stemming from high dopamine levels. Deutetrabenazine is thought to function as an inhibitor of the VMAT2 vesicular monoamine transporter resulting in decreased monoamine release, including dopamine, in the synaptic cleft which has a therapeutic effect in management of chorea. This drug was approved by the FDA in 2017 with a specific indication for tardive dyskinesia and choreiform movement in Huntington's disease. Currently, there is no definitive treatment for Huntington's disease. Thus, management is primarily focused on symptom management with the use of a variety of pharmaceutical agents. Chorea is one of the many manifestations that significantly alter the quality of life of many patients. Deutetrabenazine is a promising new option for the treatment of chorea in the setting of Huntington's disease. Although studies so far have displayed mixed results, further research, including head-to-head studies, is necessary to elucidate the true potential of this drug.

Lappaconitine inhibits glutamate release from rat cerebrocortical nerve terminals by suppressing Ca2+ influx and protein kinase A cascade

The inhibition of the excessive release of glutamate in the brain has emerged as a promising new option for developing therapeutic strategies for neurodegenerative disorders. This study investigated the effect and mechanism of lappaconitine, a diterpenoid alkaloid found in species of Aconitum, on glutamate release in rat cerebral cortex nerve terminals (synaptosomes). Here, we report that in the rat cortical synaptosomal preparation, lappaconitine reduced the K+ channel blocker 4-aminopyridine (4-AP)-evoked Ca2+-dependent release of glutamate. The inhibitory effect of lappaconitine on the evoked glutamate release was blocked by the vesicular transporter inhibitor bafilomycin A1 and calcium-chelating agent ethylene glycol tetraacetic acid (EGTA), but was unaffected by exposure to the glutamate transporter inhibitor dl-threo-beta-benzyloxyaspartate (dl-TBOA). The depolarization-induced elevation of cytosolic calcium concentration ([Ca2+]c) was inhibited by lappaconitine, while the 4-AP-mediated depolarization of the synaptosomal membrane potential was not affected. The inhibition of glutamate release by lappaconitine was markedly decreased in synaptosomes pretreated with the Cav2.3 (R-type) channel blocker SNX-482 or the protein kinase A inhibitor H89. Nevertheless, the lappaconitine-mediated inhibition of glutamate release was not abolished by the intracellular Ca2+-release inhibitors dantrolene and CGP37157. Lappaconitine also significantly decreased the 4-AP-induced phosphorylation of PKA and SNAP-25, a presynaptic substrate for PKA. Our data suggest that lappaconitine reduces Ca2+ influx through R-type Ca2+ channels, subsequently reducing the protein kinase A cascade to inhibit the evoked glutamate release from rat cerebral cortex nerve terminals.

Using complex behavior to understand brain mechanisms in health and disease.

Using complex behavior to understand brain mechanisms in health and disease.

Inhibition of Glutamate Release from Rat Cortical Nerve Terminals by Dehydrocorydaline, an Alkaloid from Corydalis yanhusuo.

Excessive release of glutamate induces excitotoxicity and causes neuronal damage in several neurodegenerative diseases. Natural products have emerged as potential neuroprotective agents for preventing and treating neurological disorders. Dehydrocorydaline (DHC), an active alkaloid compound isolated from Corydalis yanhusuo, possesses neuroprotective capacity. The present study investigated the effect of DHC on glutamate release using a rat brain cortical synaptosome model. Our results indicate that DHC inhibited 4-aminopyridine (4-AP)-evoked glutamate release and elevated intrasynaptosomal calcium levels. The inhibitory effect of DHC on 4-AP-evoked glutamate release was prevented in the presence of the vesicular transporter inhibitor bafilomycin A1 and the N- and P/Q-type Ca2+ channel blocker ω-conotoxin MVIIC but not the intracellular inhibitor of Ca2+ release dantrolene or the mitochondrial Na+/Ca2+ exchanger inhibitor CGP37157. Moreover, the inhibitory effect of DHC on evoked glutamate release was prevented by the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) inhibitor PD98059. Western blotting data in synaptosomes also showed that DHC significantly decreased the level of ERK1/2 phosphorylation and synaptic vesicle-associated protein synapsin I, the main presynaptic target of ERK. Together, these results suggest that DHC inhibits presynaptic glutamate release from cerebrocortical synaptosomes by suppressing presynaptic voltage-dependent Ca2+ entry and the MAPK/ERK/synapsin I signaling pathway.

Evaluation of radiolabeled acetylcholine synthesis and release in rat striatum.

Cholinergic transmission underlies higher brain functions such as cognition and movement. To elucidate the process whereby acetylcholine (ACh) release is maintained and regulated in the central nervous system, uptake of [3 H]choline and subsequent synthesis and release of [3 H]ACh were investigated in rat striatal segments. Incubation with [3 H]choline elicited efficient uptake via high-affinity choline transporter-1, resulting in accumulation of [3 H]choline and [3 H]ACh. However, following inhibition of ACh esterase (AChE), incubation with [3 H]choline led predominantly to the accumulation of [3 H]ACh. Electrical stimulation and KCl depolarization selectively released [3 H]ACh but not [3 H]choline. [3 H]ACh release gradually declined upon repetitive stimulation, whereas the release was reproducible under inhibition of AChE. [3 H]ACh release was abolished after treatment with vesamicol, an inhibitor of vesicular ACh transporter. These results suggest that releasable ACh is continually replenished from the cytosol to releasable pools of cholinergic vesicles to maintain cholinergic transmission. [3 H]ACh release evoked by electrical stimulation was abolished by tetrodotoxin, but that induced by KCl was largely resistant. ACh release was Ca2+ dependent and exhibited slightly different sensitivities to N- and P-type Ca2+ channel toxins (ω-conotoxin GVIA and ω-agatoxin IVA, respectively) between both stimuli. [3 H]ACh release was negatively regulated by M2 muscarinic and D2 dopaminergic receptors. The present results suggest that inhibition of AChE within cholinergic neurons and of presynaptic negative regulation of ACh release contributes to maintenance and facilitation of cholinergic transmission, providing a potentially useful clue for the development of therapies for cholinergic dysfunction-associated disorders, in addition to inhibition of synaptic cleft AChE.

Carrier-mediated serotonin efflux induced by pharmacological anoxia in the rat heart in vivo.

Serotonin (5-HT) accumulates in the heart during myocardial ischaemia and induces deleterious effects on the cardiomyocytes. We aimed to investigate whether carrier-mediated 5-HT efflux contributed to the increase in interstitial 5-HT level during ischaemia. Using microdialysis technique applied to the heart of anaesthetised Wistar rats, myocardial interstitial concentration of 5-HT was measured by electro-chemical detection coupled with high-performance liquid chromatography (HPLC-ECD) while simultaneously various pharmacological agents, which create a similar condition to ischaemia, were locally administered by reverse-microdialysis. Sodium cyanide-induced chemical anoxia increased dialysate 5-HT concentration. A similar increase in dialysate 5-HT concentration was induced by ouabain, an inhibitor of sodium-potassium ATPase and reserpine, an inhibitor of vesicular monoamine transporter. Fluoxetine, a selective serotonin reuptake inhibitor raised the baseline level of 5-HT, and neither sodium cyanide nor the combination of ouabain and reserpine induced further increase in 5-HT in the presence of fluoxetine. The results indicate that reverse transport of 5-HT via SERT, which is caused by an impaired ion gradient, contributes to the rise in interstitial level of 5-HT during ischaemia suggesting carrier-mediated 5-HT efflux occurs in the heart in vivo.

Valbenazine for the Treatment of Adults with Tardive Dyskinesia.

This a comprehensive review of the literature regarding the use of Valbenazine in treating tardive dyskinesia. A primarily oral movement disorder induced by chronic exposure to certain classes of medications, tardive dyskinesia is often resistant to many therapeutic approaches. This review presents the background, evidence, and indications for the use of Valbenazine as a treatment option for this condition. Tardive dyskinesia is a disorder arising from long-term exposure to medications that blocked dopamine receptors, primarily antipsychotics. It is characterized by abnormal movements of the oral-buccal-lingual structures as well as associated pain and hypertrophy. Simply stopping the use of the dopamine blocking agents effectively alleviates the symptoms but is not always reliable hence the need for another therapeutic approach.Valbenazine is thought to function as a highly selective inhibitor of the VMAT2 vesicular monoamine transporter resulting in decreased availability of dopamine in the presynaptic cleft. This leads to decreased dopaminergic activation of the striatal motor pathway. The FDA approved Valbenazine in 2017 to treat tardive dyskinesia in adults and needs to be evaluated with existing therapeutic approaches. The chronic use of dopamine receptor blocking agents, most commonly antipsychotics, can lead to a movement disorder called tardive dyskinesia. Once symptom onset has occurred, these movement abnormalities can persist for years to permanently, depending on the speed and effectiveness of treatment. Valbenazine is a relatively newer option for the treatment of tardive dyskinesia in adults. Compared to other pharmaceutical agents, it is more selective and has limited toxicities making it an effective treatment regimen. However, further research, including additional direct comparison studies, should be conducted to fully evaluate this drug's usefulness.

Typhaneoside Suppresses Glutamate Release Through Inhibition of Voltage-Dependent Calcium Entry in Rat Cerebrocortical Nerve Terminals.

Glutamate is the major excitatory neurotransmitter in the brain and is involved in many brain functions. In this study, we investigated whether typhaneoside, a flavonoid from Typhae angustifolia pollen, affects endogenous glutamate release from rat cortical synaptosomes. Using a one-line enzyme-coupled fluorometric assay, glutamate release stimulated by the K+ channel blocker 4-aminopyridine was monitored to explore the possible underlying mechanisms. The vesicular transporter inhibitor bafilomycin A1 and chelation of extracellular Ca2+ ions with EGTA suppressed the effect of typhaneoside on the induced glutamate release. Nevertheless, the typhaneoside activity has not been affected by the glutamate transporter inhibitor dl-threo-beta-benzyloxyaspartate. The synaptosomal plasma membrane potential was assayed using a membrane potential-sensitive dye DiSC3(5), and cytosolic Ca2+ concentrations ([Ca2+]C) was monitored by a Ca2+ indicator Fura-2. Results showed that typhaneoside did not alter the synaptosomal membrane potential but lowered 4-aminopyridine-induced increases in [Ca2+]C. Furthermore, the Cav2.2 (N-type) channel blocker ω-conotoxin GVIA blocked Ca2+ entry and inhibited the effect of typhaneoside on 4-aminopyridine-induced glutamate release. However, the inhibitor of intracellular Ca2+ release dantrolene and the mitochondrial Na+/Ca2+ exchanger blocker 7-chloro-5-(2-chloropheny)-1,5-dihydro-4,1-benzothiazepin-2(3H)-one have no effect on the suppression of glutamate release mediated by typhaneoside. Moreover, inhibition of mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) prevented the inhibitory effect of typhaneoside on induced glutamate release. Typhaneoside reduced 4-aminopyridine-induced phosphorylation of ERK1/2 and the major presynaptic ERK target synapsin I, which is a synaptic vesicle-associated protein. In conclusion, these findings suggest a role for typhaneoside in modulating glutamate release by suppressing voltage-dependent Ca2+ channel mediated presynaptic Ca2+ influx and the MAPK/ERK/synapsin I signaling cascade.