New generation VMAT2 inhibitors induced parkinsonism.
Ontology highlight
ABSTRACT:
SUBMITTER: Vasireddy RP
PROVIDER: S-EPMC8298827 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:PURPOSE OF REVIEW:Atypical parkinsonian disorders (APDs) comprise a heterogenous group of disorders including multiple system atrophy (MSA), dementia with Lewy bodies (DLB), progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). Based on literature published in 2010, we here review recent advances in the APD field. RECENT FINDINGS:Genome-wide association studies have provided robust evidence of increased disease risk conferred by synuclein and tau gene variants in MSA and PSP. Furthermore, advanced imaging tools have been established in the differential diagnosis and as surrogate markers of disease activity in patients with APDs. Finally, although therapeutic options are still disappointing, translational research into disease-modifying strategies has accelerated with the increasing availability of transgenic animal models, particularly for MSA. SUMMARY:Remarkable progress has been achieved in the field of APDs, and advances in the genetics, molecular biology and neuroimaging of these disorders will continue to facilitate intensified clinical trial activity.
| S-EPMC6200126 | biostudies-literature
Project description:Most neurodegenerative diseases are known to affect several aspects of brain function, including neurotransmitter systems, metabolic and functional connectivity. Diseases are generally characterized by common clinical characteristics across subjects, but there are also significant inter-subject variations. It is thus reasonable to expect that in terms of brain function, such clinical behaviors will be related to a general overall multi-system pattern of disease-induced alterations and additional brain system-specific abnormalities; these additional abnormalities would be indicative of a possible unique system response to disease or subject-specific propensity to a specific clinical progression. Based on the above considerations we introduce and validate the use of a joint pattern analysis approach, canonical correlation analysis and orthogonal signal correction, to analyze multi-tracer PET data to identify common (reflecting functional similarities) and unique (reflecting functional differences) information provided by each tracer/target. We apply the method to [11C]-DTBZ (VMAT2 marker) and [11C]-MP (DAT marker) data from 15 early Parkinson's disease (PD) subjects; the behavior of these two tracers/targets is well characterized providing robust reference information for the method's outcome. Highly significant common subject profiles were identified that decomposed the characteristic dopaminergic changes into three distinct orthogonal spatial patterns: 1) disease-induced asymmetry between the less and more affected dorsal striatum; 2) disease-induced gradient with caudate and ventral striatum being relatively spared compared to putamen; 3) progressive loss in the less affected striatum, which correlated significantly with disease duration (p?<?0.01 for DTBZ, p?<?0.05 for MP). These common spatial patterns reproduce all known aspects of these two targets/tracers. In addition, orthogonality of the patterns may indicate different mechanisms underlying disease initiation or progression. Information unique to each tracer revealed a residual striatal asymmetry when targeting VMAT2, consistent with the notion that VMAT2 density is highly related to terminal degeneration; and a residual DAT disease-induced gradient in the striatum with relative DAT preservation in the substantia nigra. This finding may be indicative either of a possible DAT specific early disease compensation and/or related to disease origin. These results demonstrate the applicability and relevance of the joint pattern analysis approach to datasets obtained with two PET tracers; this data driven method, while recapitulating known aspects of the PD-induced tracer/target behaviour, was found to be statistically more robust and provided additional information on (i) correlated behaviors of the two systems, identified as orthogonal patterns, possibly reflecting different disease-induced alterations and (ii) system specific effects of disease. It is thus expected that this approach will be very well suited to the analysis of multi-tracer and/or multi-modality data and to relating the outcomes to different aspects of disease.
| S-EPMC6517523 | biostudies-literature
Project description:Tetrabenazine (TBZ) ((±)-1) and dihydrotetrabenazines (DHTBZ) are potent inhibitors of VMAT2. Herein, a practical chemical resolution of (±)-1 and stereoselective synthesis of all eight DHTBZ stereoisomers are described. The result of VMAT2 binding assay revealed that (+)-1 (Ki=4.47 nM) was 8000-fold more potent than (-)-1 (Ki=36,400 nM). Among all eight DHTBZ stereoisomers, (2R,3R,11bR)-DHTBZ ((+)-2: Ki=3.96 nM) showed the greatest affinity for VMAT2. The (3R,11bR)-configuration appeared to play a key role for VMAT2 binding. In summary, (+)-1, (+)-2, and their derivatives warrant further studies in order to develop more potent and safer drugs for the treatment of chorea associated with Huntington's disease and other hyperkinetic disorders.
| S-EPMC6191844 | biostudies-literature
Project description:Importance: Trimetazidine (TMZ) is a medication given to patients with stable coronary artery disease. While it is reportedly well-tolerated, there are increasing numbers of reports of adverse events such as parkinsonism. Objectives: The purpose of this study was to systematically review the currently available literature on TMZ-induced parkinsonism. Evidence Review: A search of Scopus, MEDLINE, EMBASE, the Cochrane Library, the Health Technology Assessment Database, PubMed, Science Direct, and Google Scholar was conducted on or before November 7, 2019. The literature search included cohort studies, prospective and/or retrospective studies, meta-analysis, and other systematic reviews published as an original article, including abstracts and full texts. We included patients taking TMZ who developed one or more of the parkinsonian symptoms of bradykinesia, tremors, rigidity, and postural instability, where these symptoms improved after withdrawal of the said medication. Findings: There are currently five studies on TMZ use and associated parkinsonism. The literature included two case reports, one case series, and one retrospective and one prospective study. We found no results from randomized clinical trials. Overall, 88 patients developed TMZ-induced parkinsonism. Regression of parkinsonism was reported in all of the participants after withdrawal of TMZ. A total of 49 patients (55.7%) had complete regression of symptoms, while 39 patients (44.3%) had significant reduction of symptoms. The duration between TMZ (dose, 60-80 mg/day) intake and onset of symptoms ranged from 4 months to 20 years. The most commonly reported extrapyramidal symptoms were akinesia, rigidity, postural disturbances, and gait disorders, which were usually mild and symmetric. Conclusions and Relevance: The current literature suggests that TMZ can induce parkinsonism that is reversible with drug withdrawal. It is warranted to examine patients, especially the elderly, on TMZ for parkinsonian symptoms and those with pre-existing neurodegenerative diseases. Further studies are needed to assess the risk-benefit ratio of this drug, especially in the elderly age group.
| S-EPMC7052178 | biostudies-literature
Project description:Neurotransporters located in synaptic vesicles are essential for communication between nerve cells in a process mediated by neurotransmitters. Vesicular monoamine transporter (VMAT), a member of the largest superfamily of transporters, mediates transport of monoamines to synaptic vesicles and storage organelles in a process that involves exchange of two H+ per substrate. VMAT transport is inhibited by the competitive inhibitor reserpine, a second-line agent to treat hypertension, and by the noncompetitive inhibitor tetrabenazine, presently in use for symptomatic treatment of hyperkinetic disorders. During the transport cycle, VMAT is expected to occupy at least three different conformations: cytoplasm-facing, occluded, and lumen-facing. The lumen- to cytoplasm-facing transition, facilitated by protonation of at least one of the essential membrane-embedded carboxyls, generates a binding site for reserpine. Here we have identified residues in the cytoplasmic gate and show that mutations that disrupt the interactions in this gate also shift the equilibrium toward the cytoplasm-facing conformation, emulating the effect of protonation. These experiments provide significant insight into the role of proton translocation in the conformational dynamics of a mammalian H+-coupled antiporter, and also identify key aspects of the mode of action and binding of two potent inhibitors of VMAT2: reserpine binds the cytoplasm-facing conformation, and tetrabenazine binds the lumen-facing conformation.
| S-EPMC5127352 | biostudies-literature
Project description:Compstatin family peptides are potent inhibitors of the complement system and promising drug candidates against diseases involving under-regulated complement activation. Compstatin is a 13-residue cyclized peptide that inhibits cleavage of complement protein C3, preventing downstream complement activation. We present three new compstatin variants, characterized by tryptophan replacement at positions 1 and/or 13. Peptide design was based on physicochemical reasoning and was inspired by earlier work, which identified tryptophan substitutions at positions 1 and 13 in peptides with predicted C3c binding abilities [Bellows M.L., Fung H.K., Taylor M.S., Floudas C.A., López de Victoria A., Morikis D. (2010) Biophys J; 98: 2337-2346]. The new variants preserve distinct polar and nonpolar surfaces of compstatin, but have altered local interaction capabilities with C3. All three peptides exhibited potent C3 binding by surface plasmon resonance and potent complement inhibition by enzyme-linked immunosorbent assay. We also present enzyme-linked immunosorbent assay data and detailed surface plasmon resonance kinetic data of three peptides from previous computational design.
| S-EPMC3095715 | biostudies-literature
Project description:The current therapy for depression is less than ideal with remission rates of only 25-35% and a slow onset of action with other associated side effects. The persistence of anhedonia originating from depressed dopaminergic activity is one of the most treatment-resistant symptoms of depression. Therefore, it has been hypothesized that triple reuptake inhibitors (TRIs) with potency to block dopamine reuptake in addition to serotonin and norepinephrine transporters should produce higher efficacy. The current review comprehensively describes the development of TRIs and discusses the importance of evaluation of in vivo transporter occupancy of TRIs, which should correlate with efficacy in humans.
| S-EPMC4976848 | biostudies-literature
Project description:This article reviews was to review genes where putative or confirmed pathogenic mutations causing Parkinson's disease or Parkinsonism have been identified since 2012, and summarizes the clinical and pathological picture of the associated disease subtypes.Newly reported genes for dominant Parkinson's disease are DNAJC13, CHCHD2, and TMEM230. However, the evidence for a disease-causing role is not conclusive, and further genetic and functional studies are warranted. RIC3 mutations have been reported from one family but not yet encountered in other patients. New genes for autosomal recessive disease include SYNJ1, DNAJC6, VPS13C, and PTRHD1. Deletions of a region on chromosome 22 (22q11.2del) are also associated with early-onset PD, but the mode of inheritance and the underlying causative gene remain unclear. PODXL mutations were reported in autosomal recessive PD, but their roles remain to be confirmed. Mutations in RAB39B cause an X-linked Parkinsonian disorder. Mutations in the new dominant PD genes have generally been found in medium- to late-onset Parkinson's disease. Many mutations in the new recessive and X-chromosomal genes cause severe atypical juvenile Parkinsonism, but less devastating mutations in these genes may cause PD.
| S-EPMC5522513 | biostudies-other
Project description:Treatment with rotenone, both in vitro and in vivo, is widely used to model dopamine neuron death in Parkinson's disease upon exposure to environmental neurotoxicants and pesticides. Mechanisms underlying rotenone neurotoxicity are still being defined. Our recent studies suggest that rotenone-induced dopamine neuron death involves microtubule destabilization, which leads to accumulation of cytosolic dopamine and consequently reactive oxygen species (ROS). Furthermore, the c-Jun N-terminal protein kinase (JNK) is required for rotenone-induced dopamine neuron death. Here we report that the neural specific JNK3 isoform of the JNKs, but not JNK1 or JNK2, is responsible for this neuron death in primary cultured dopamine neurons. Treatment with taxol, a microtubule stabilizing agent, attenuates rotenone-induced phosphorylation and presumably activation of JNK. This suggests that JNK is activated by microtubule destabilization upon rotenone exposure. Moreover, rotenone inhibits VMAT2 activity but not VMAT2 protein levels. Significantly, treatment with SP600125, a pharmacological inhibitor of JNKs, attenuates rotenone inhibition of VMAT2. Furthermore, decreased VMAT2 activity following in vitro incubation of recombinant JNK3 protein with purified mesencephalic synaptic vesicles suggests that JNK3 can inhibit VMAT2 activity. Together with our previous findings, these results suggest that rotenone induces dopamine neuron death through a series of sequential events including microtubule destabilization, JNK3 activation, VMAT2 inhibition, accumulation of cytosolic dopamine, and generation of ROS. Our data identify JNK3 as a novel regulator of VMAT2 activity.
| S-EPMC4308505 | biostudies-literature
Project description:Vesicular monoamine transporter 2 (VMAT2) is an essential component of the monoaminergic neurotransmission system in the brain as it transports monoamine neurotransmitters from the neuronal cytosol into the synaptic vesicles and thus contributes to modulation of neurotransmitter release. Considering the continuing interest in VMAT2 as a drug target, as well as a target for the design of imaging probes, we have developed a fluorescent substrate well suited for the study of VMAT2 in cell culture. Herein, we report the synthesis and characterization of a new fluorescent probe, FFN206, as an excellent VMAT2 substrate capable of detecting VMAT2 activity in intact cells using fluorescence microscopy, with subcellular localization to VMAT2-expressing acidic compartments without apparent labeling of other organelles. VMAT2 activity can also be measured via microplate reader. The apparent Km of FFN206 at VMAT2 was found to be 1.16 ± 0.10 μM, similar to that of dopamine. We further report the development and validation of a cell-based fluorescence assay amenable to high-throughput screening (HTS) using VMAT2-transfected HEK cells (Z'-factor of 0.7-0.8), enabling rapid identification of VMAT2 inhibitors and measurement of their inhibition constants over a broad range of affinities. FFN206 thus represents a new tool for optical examination of VMAT2 function in cell culture.
| S-EPMC4557792 | biostudies-literature