“D-cell hypothesis of schizophrenia”: Background theory of Novel non-D2 receptor medicinal chemistry

2021 ◽  
Vol 3 (1) ◽  
pp. 033-040
Author(s):  
Keiko Ikemoto
Keyword(s):  
Medicinal Chemistry ◽  
Partial Agonist ◽  
D2 Receptor ◽  
Immunohistochemical Method ◽  
Post Mortem ◽  
Background Theory ◽  
Related Substances ◽  
Post Mortem Brain ◽  
Receptor Profile ◽  
D Cell

The latest psychopharmacological study showed effectiveness of a novel non-D2-receptor-binding drug, SEP-363856, for the treatment of schizophrenia. Characteristic receptor profile of the compound is shown to be trace amine-associated receptor 1 (TAAR1) full agonist and 5-hydroxytryptamin 1A (5-HT 1A) receptor partial agonist. I found the TAAR1 ligand neuron, D-neuron, in the striatum and nucleus accumbens (Acc), an antipsychotic acting site, of human brain, though failed to find in the homologous area of monkey. To study human D-neuron functions, total of 154 post-mortem brains, and a modified immunohistochemical method using high qualified antibodies against monoamine-related substances, was applied. Number of D-neurons in the caudate nucleus, putamen, and Acc was reduced in post-mortem brains with schizophrenia. The reduction was significant (p<0.05) in Acc. “D-cell hypothesis of schizophrenia”, which I proposed based on this post-mortem brain study, that NSC dysfunction-induced D-neuron reduction as cellular and molecular basis of mesolimbic dopamine (DA) hyperactivity, showing progressive pathophysiology of schizophrenia, has been proved to be a predictive hypothesis for TAAR1 medicinal chemistry.

D-neuron, ligand neuron of trace amine-associated receptor 1 (TAAR1): Key of novel non-D2 receptor-binding antipsychotics

2021 ◽  
Vol 1 (1) ◽  
pp. 031-038
Author(s):  
Keiko Ikemoto
Keyword(s):  
Receptor Binding ◽  
Molecular Basis ◽  
Partial Agonist ◽  
D2 Receptor ◽  
Immunohistochemical Method ◽  
Post Mortem ◽  
Related Substances ◽  
Trace Amine ◽  
D Cell ◽  
Human Brains

The latest psychopharmacological study showed effectiveness of a novel non-D2-receptor-binding drug, SEP-363856, for the treatment of schizophrenia. The compound is trace amine-associated receptor 1 (TAAR1) full agonist and also 5-hydroxytryptamin 1A (5-HT 1A) receptor partial agonist. I found the TAAR1 ligand neuron, D-neuron, in the striatum and nucleus accumbens (Acc), a neuroleptic acting site, of human brains, though failed to find in the homologous area of monkey brains. To study human D-neuron functions, total of 154 post-mortem brains, and a modified immunohistochemical method using high qualified antibodies against monoamine-related substances, was applied. The number of D-neuron in the caudate nucleus, putamen, and Acc was reduced in post-mortem brains with schizophrenia. The reduction was significant (p<0.05) in Acc. I proposed “D-cell hypothesis of schizophrenia”, that NSC dysfunction-based D-neuron reduction is cellular and molecular basis of mesolimbic dopamine (DA) hyperactivity, progressive pathophysiology and prospectiveness of TAAR1 medicinal chemistry, emphasizing importance of D-neuron.

scholarly journals Revealing Adenosine A2A-Dopamine D2 Receptor Heteromers in Parkinson’s Disease Post-Mortem Brain through a New AlphaScreen-Based Assay

2019 ◽  
Vol 20 (14) ◽  
pp. 3600 ◽  
Author(s):  
Víctor Fernández-Dueñas ◽  
Maricel Gómez-Soler ◽  
Marta Valle-León ◽  
Masahiko Watanabe ◽  
Isidre Ferrer ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Dynamic Range ◽  
Dopamine D2 Receptor ◽  
D2 Receptor ◽  
Post Mortem ◽  
Dopamine D2 ◽  
Post Mortem Brain ◽  
Receptor Heteromers ◽  
Adenosine A2a

Background: Several biophysical techniques have been successfully implemented to detect G protein-coupled receptors (GPCRs) heteromerization. Although these approaches have made it possible to ascertain the presence of GPCR heteromers in animal models of disease, no success has been accomplished in pathological human post-mortem brains. The AlphaScreen technology has been consistently used to quantify small analyte accumulation or depletion, bimolecular interactions, and post-translational modifications. The high signal-to-background, dynamic range and sensitivity exhibited by this technology support that it may be suitable to detect GPCR heteromers even under non-optimal conditions. Methods: Here, we describe the development of a new AlphaScreen assay to detect GPCR oligomers in human post-mortem brain. Results: Adenosine A2A-dopamine D2 receptor (A2AR/D2R) heteromer formation was monitored in caudate from healthy and Parkinson’s disease (PD) subjects. The approach was first validated using striatal membranes from wild type and A2AR deficient mice. Secondly, we took advantage of the 6-hydroxydopamine hemiparkinsonian rat model to validate previous results. In addition, finally, A2AR/D2R heteromer formation was assessed in caudate membranes from human post-mortem brains. Importantly, our preliminary results revealed an increase in A2AR/D2R heteromer formation in PD brains. Conclusions: The new AlphaScreen assay allowed assessing GPCR heteromers in human post-mortem brains with high sensitivity.

scholarly journals The neurochemical pathology of schizophrenia: post-mortem studies from dopamine to parvalbumin

2021 ◽  
Author(s):  
Gavin P. Reynolds
Keyword(s):  
Brain Tissue ◽  
D2 Receptor ◽  
Gabaergic Neurons ◽  
Future Research ◽  
Post Mortem ◽  
Psychotic Illness ◽  
Neuroscience Research ◽  
Post Mortem Brain ◽  
Neurochemical Pathology ◽  
Generous Support

AbstractResearch in Peter Riederer’s lab in Vienna in the late 1970’s came from a strong tradition in post-mortem neurochemical studies, at that time a relatively niche approach in neuroscience research. He was also early to recognise the value of post-mortem brain tissue in elucidating pharmacological mechanisms of neuropsychiatric treatments. I was fortunate to have Peter Riederer as a mentor in my early post-doctoral career; his generous support and the opportunities to use post-mortem brain tissue provided an invaluable grounding on which much of my future research was based. In this paper, I shall provide a brief overview of one trajectory of my research into the neurobiology of schizophrenia that started in the Riederer lab in Vienna investigating dopamine and the D2 receptor. Subsequent research to understand findings of increased dopamine resulted in the identification of reduced GABAergic innervation, culminating in the finding of a deficit in the parvalbumin-containing subtype of GABAergic neurons. Most recent work has been studying how changes in DNA methylation of the parvalbumin gene may relate to these findings in psychotic illness and its animal models.

P1-155: Post-Mortem Brain Tissue Characterisation of Inflammatory and Pathological Hallmarks of Alzheimer’s Disease During Disease Progression

2016 ◽  
Vol 12 ◽  
pp. P462-P462
Author(s):  
Martina M. Hughes ◽  
Beatriz G. Perez-Nievas ◽  
Claire Troakes ◽  
Michael Perkinton ◽  
Diane P. Hanger ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Disease Progression ◽  
Brain Tissue ◽  
Post Mortem ◽  
Tissue Characterisation ◽  
Post Mortem Brain

scholarly journals The choice of embedding media affects image quality, tissue R 2 * , and susceptibility behaviors in post‐mortem brain MR microscopy at 7.0T

2018 ◽  
Vol 81 (4) ◽  
pp. 2688-2701 ◽  
Author(s):  
Petr Dusek ◽  
Vince Istvan Madai ◽  
Till Huelnhagen ◽  
Erik Bahn ◽  
Radoslav Matej ◽  
...  
Keyword(s):  
Image Quality ◽  
Post Mortem ◽  
Mr Microscopy ◽  
Post Mortem Brain

scholarly journals Natriuretic Peptides in Post-mortem Brain Tissue and Cerebrospinal Fluid of Non-demented Humans and Alzheimer’s Disease Patients

2018 ◽  
Vol 12 ◽  
Author(s):  
Simin Mahinrad ◽  
Marjolein Bulk ◽  
Isabelle van der Velpen ◽  
Ahmed Mahfouz ◽  
Willeke van Roon-Mom ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cerebrospinal Fluid ◽  
Brain Tissue ◽  
Natriuretic Peptides ◽  
Post Mortem ◽  
Post Mortem Brain

scholarly journals Emergence of distinct and heterogeneous strains of amyloid beta as Alzheimer′s disease progresses in Down syndrome

2021 ◽  
Author(s):  
Alison M Maxwell ◽  
Peng Yuan ◽  
Brianna M Rivera ◽  
Wilder Schaaf ◽  
Mihovil Mladinov ◽  
...  
Keyword(s):  
Down Syndrome ◽  
Amyloid Beta ◽  
Fluorescent Probes ◽  
Clinical Symptoms ◽  
Critical Role ◽  
Phenotypic Heterogeneity ◽  
Post Mortem ◽  
Strain Profile ◽  
Post Mortem Brain ◽  
And Control

Amyloid beta (A&#946) is thought to play a critical role in the pathogenesis of Alzheimer&#8242s disease (AD). Prion-like Aβ polymorphs, or strains, can have varying pathogenicity and may underlie the phenotypic heterogeneity of the disease. In order to develop effective AD therapies, it is critical to identify the strains of A&#946 that might arise prior to the onset of clinical symptoms and understand how they may change with progressing disease. Down syndrome (DS), as the most common genetic cause of AD, presents promising opportunities to compare such features between early and advanced AD. In this work, we evaluate the neuropathology and A&#946 strain profile in the post-mortem brain tissues of 210 DS, AD, and control individuals. We assayed the levels of various A&#946 and tau species and used conformation-sensitive fluorescent probes to detect differences in A&#946 strains among individuals and populations. We found that these cohorts have some common but also some distinct strains from one another, with the most heterogeneous populations of A&#946 emerging in subjects with high levels of AD pathology. The emergence of distinct strains in DS at these later stages of disease suggests that the confluence of aging, pathology, and other DS-linked factors may favor conditions that generate strains that are unique from sAD.

scholarly journals LINE-1 and Alu methylation Signatures in Autism Spectrum Disorder and Their Function in The Regulation of Autism-Related Genes

2021 ◽  
Author(s):  
Thanit Saeliw ◽  
Tiravut Permpoon ◽  
Nutta Iadsee ◽  
Tewin Tencomnao ◽  
Tewarit Sarachana ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Dna Methylation ◽  
Autism Spectrum ◽  
Small Sample ◽  
Spectrum Disorder ◽  
Post Mortem ◽  
Global Methylation ◽  
Post Mortem Brain ◽  
Dna Methylation Profiling ◽  
Methylation Profiling

Abstract BackgroundLong interspersed nucleotide element-1 (LINE-1) and Alu elements are retrotransposons whose abilities cause abnormal gene expression and genomic instability. Several studies have focused on DNA methylation profiling of gene regions, but the locus-specific methylation of LINE-1 and Alu elements has not been identified in autism spectrum disorder (ASD).MethodsHere, DNA methylation age was predicted using Horvath’s method. We interrogated locus- and family-specific methylation profiles of LINE-1 and Alu elements (22,352 loci) in ASD blood using publicly-available Illumina Infinium 450K methylation datasets from heterogeneous ASD (n = 52), ASD with 16p11.2 del (n = 7), and ASD with Chromodomain Helicase DNA-binding 8 (CHD8) variants (n = 15). The differentially methylated positions of LINE-1 and Alu elements corresponding to genes were combined with transcriptome data from multiple ASD studies. ROC curve was conducted to examine the specificity of target loci.ResultsEpigenetic age acceleration was significantly decelerated in ASD children over the age of 11 years. DNA methylation profiling revealed LINE-1 and Alu methylation signatures in each ASD risk loci by which global methylation were notably hypomethylated exclusively in ASD with CHD8 variants. When LINE-1 and Alu elements were clustered into subfamilies, we found methylation changes in a family-specific manner in L1P, L1H, HAL, AluJ, and AluS families in the heterogeneous ASD and ASD with CHD8 variants. Our results showed that LINE-1 and Alu methylation within target genes is inversely related to the expression level in each ASD variant. Moreover, LINE-1 and Alu methylation signatures can be used to predict ASD individuals from non-ASD.LimitationsIntegration of methylome and transcriptome datasets was performed from different ASD cohorts. The small sample size of the validation cohort used post-mortem brain tissues and necessitates future validation in a larger cohort.ConclusionsThe DNA methylation signatures of the LINE-1 and Alu elements in ASD, as well as their functional impact on ASD-related genes, have been studied. These findings are considered for further research into DNA methylation profiles and the expression of the LINE-1 and Alu elements in post-mortem brain tissue, which has been linked to ASD pathogenesis.

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