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Preclinical evaluation of MK-8189: A novel phosphodiesterase 10A inhibitor for the treatment of schizophrenia.

MK-8189 is a novel phosphodiesterase 10A (PDE10A) inhibitor being evaluated in clinical studies for the treatment of schizophrenia. PDE10A is a cyclic nucleotide phosphodiesterase enzyme highly expressed in medium spiny neurons of the striatum. MK-8189 exhibits subnanomolar potency on the PDE10A enzyme and has excellent pharmaceutical properties. Oral administration of MK-8189 significantly increased cyclic guanosine monophosphate and phospho glutamate receptor 1 in rat striatal tissues. Activation of the dopamine D1 direct and D2 indirect pathways was demonstrated by detecting significant ele…

Modulation of striatal glutamatergic, dopaminergic and cholinergic neurotransmission pathways concomitant with motor disturbance in rats with kaolin-induced hydrocephalus.

BACKGROUND: Hydrocephalus is characterized by abnormal accumulation of cerebrospinal fluid in the cerebral ventricles and causes motor impai … stance P immunohistochemistry were used to distinguish between direct and indirect pathway striatal medium spiny neurons (d and i-MSNs) for the analysis of their dendritic spine density changes. RESULTS: Hydrocephalic rats showed compromised open-field gait behavior. However, male but not female rats displayed stereotypic movements and compromised rotarod performance …

Molecular Components of Store-Operated Calcium Channels in the Regulation of Neural Stem Cell Physiology, Neurogenesis, and the Pathology of Huntington's Disease.

One of the major Ca2+ signaling pathways is store-operated Ca2+ entry (SOCE), which is responsible for Ca2+ flow into cells in response to t … sion in the huntingtin (HTT) protein, characterized by the loss of γ-aminobutyric acid (GABA)-ergic medium spiny neurons (MSNs) in the striatum. However, recent research has shown that HD is also a neurodevelopmental disorder and Ca2+ signaling is dysregulated in HD. The relationship between HD pathology and elevations of SOCE was demonstrated in different cellular an …

Increased Dopamine Type 2 Gene Expression in the Dorsal Striatum in Individuals With Autism Spectrum Disorder Suggests Alterations in Indirect Pathway Signaling and Circuitry.

Autism spectrum disorder (ASD) is behaviorally defined and diagnosed by delayed and/or impeded language, stereotyped repetitive behaviors, a … r BG structures. Excitatory dopamine (DA) type 1 receptors are predominantly expressed on GABAergic medium spiny neurons (MSNs) in the dorsal striatum as part of the "direct pathway" to GPi and SNpr whereas inhibitory DA type 2 receptors are predominantly expressed on MSNs that primarily project to GPe. This study aimed to better understand how this circuitry may be a …

Neuropeptide Y (NPY) in cerebrospinal fluid from patients with Huntington's Disease: increased NPY levels and differential degradation of the NPY1-30 fragment.

Huntington's disease (HD) is an inherited and fatal polyglutamine neurodegenerative disorder caused by an expansion of the CAG triplet repeat coding region within the HD gene. Progressive dysfunction and loss of striatal GABAergic medium spiny neurons (MSNs) may account for some of the characteristic symptoms in HD patients. Interestingly, in HD, MSNs expressing neuropeptide Y (NPY) are spared and their numbers is even up-regulated in HD patients. Consistent with this, we report here on increased immuno-linked NPY (IL-NPY) levels in human cerebrospinal fluid (hCSF) from HD patients (Control n …

Impairment of bidirectional synaptic plasticity in the striatum of a mouse model of DYT1 dystonia: role of endogenous acetylcholine.

DYT1 dystonia is a severe form of inherited dystonia, characterized by involuntary twisting movements and abnormal postures. It is linked to … her the normal human torsinA or its mutant form, in comparison to non-transgenic (NT) control mice. Medium spiny neurons recorded from both NT and normal human torsinA mice exhibited normal long-term depression (LTD), whereas in mutant human torsinA littermates LTD could not be elicited. In addition, although long-term potentiation (LTP) could be induced in all the mi …

In Humans, fMRI Reveals That Striosome-like and Matrix-like Striatal Voxels are Engaged in Different Phases of Movement.

INTRODUCTION: The striatum is organized into two neurochemically and anatomically distinct compartments, the striosome and matrix, that play … ocircuitry in motivated behavior and the planning and execution of movements. KEY POINTS: Striatal medium spiny neurons develop in two interdigitated tissue compartments, the striosome and matrix, that are embryologically, pharmacologically, and anatomically distinct. Inter-compartmental differences in function have been identified in animals, but never in humans.We …

Prior Cocaine Use Alters the Normal Evolution of Information Coding in Striatal Ensembles during Value-Guided Decision-Making.

Substance use disorders (SUDs) are characterized by maladaptive behavior. The ability to properly adjust behavior according to changes in en … coding of state and state-related information is affected by prior drug exposure. We found that DMS medium spiny neurons (MSNs) and fast-spiking interneurons (FSIs) encoded such information and that prior cocaine experience disrupted the evolution of representations both within trials and across recording sessions. Specifically, DMS MSNs and FSIs from cocaine-experien …

Histone deacetylase (HDAC) inhibitors targeting HDAC3 and HDAC1 ameliorate polyglutamine-elicited phenotypes in model systems of Huntington's disease.

We have previously demonstrated amelioration of Huntington's disease (HD)-related phenotypes in R6/2 transgenic mice in response to treatment with the novel histone deacetylase (HDAC) inhibitor 4b. Here we have measured the selectivity profiles of 4b and related compounds against class I and class II HDACs and have tested their ability to restore altered expression of genes related to HD pathology in mice and to rescue disease effects in cell culture and Drosophila models of HD. R6/2 transgenic and wild-type (wt) mice received daily injections of HDAC inhibitors for 3 days followed by real-tim

The phosphodiesterase 10 positron emission tomography tracer, [18F]MNI-659, as a novel biomarker for early Huntington disease.

IMPORTANCE: In Huntington disease (HD) striatal neuron loss precedes and predicts motor signs or symptoms. Current imaging biomarkers lack a … sessing the extent of disease in early mHD. Furthermore, [18F]MNI-659 may identify early changes in medium spiny neurons and serve as a marker to predict conversion to mHD. Additional studies with larger, stratified cohorts of patients with HD and prospective studies of individuals with pre-HD are warranted.

AMPA and NMDA Receptor Trafficking at Cocaine-Generated Synapses.

Cocaine experience generates AMPA receptor (AMPAR)-silent synapses in the nucleus accumbens (NAc), which are thought to be new synaptic cont … he dynamic roles played by AMPARs and NMDARs in generation and maturation of silent synapses on NAc medium spiny neurons after cocaine self-administration and withdrawal. We report that cocaine-induced generation of silent synapses not only required synaptic insertion of GluN2B-containing NMDARs, but also, counterintuitively, involved insertion of AMPARs, which subseq …

A Conditioned Place Preference for Heroin Is Signaled by Increased Dopamine and Direct Pathway Activity and Decreased Indirect Pathway Activity in the Nucleus Accumbens.

Repeated pairing of a drug with a neutral stimulus, such as a cue or context, leads to the attribution of the drug's reinforcing properties to that stimulus, and exposure to that stimulus in the absence of the drug can elicit drug-seeking. A principal role for the NAc in the response to drug-associated stimuli has been well documented. Direct and indirect pathway medium spiny neurons (dMSNs and iMSNs) have been shown to bidirectionally regulate cue-induced heroin-seeking in rats expressing addiction-like phenotypes, and a shift in NAc activity toward the direct pathway has been shown in mice f…

NOX1/NADPH Oxidase Promotes Synaptic Facilitation Induced by Repeated D2 Receptor Stimulation: Involvement in Behavioral Repetition.

Repetitive behavior is a widely observed neuropsychiatric symptom. Abnormal dopaminergic signaling in the striatum is one of the factors ass … aled that repeated D2 receptor stimulation facilitated excitatory inputs in the CS indirect pathway medium spiny neurons (iMSNs), and this effect was suppressed by the genetic deletion or pharmacological inhibition of NOX1. Nox1 deficiency potentiated protein tyrosine phosphatase activity and attenuated the accumulation of activated Src kinase, which is required for t …

Inducible CRISPR Epigenome Systems Mimic Cocaine Induced Bidirectional Regulation of Nab2 and Egr3.

Substance use disorder is a chronic disease and a leading cause of disability around the world. The NAc is a major brain hub mediating reward behavior. Studies demonstrate exposure to cocaine is associated with molecular and functional imbalance in NAc medium spiny neuron subtypes (MSNs), dopamine receptor 1 and 2 enriched D1-MSNs and D2-MSNs. We previously reported repeated cocaine exposure induced transcription factor early growth response 3 (Egr3) mRNA in NAc D1-MSNs, and reduced it in D2-MSNs. Here, we report our findings of repeated cocaine exposure in male mice inducing MSN subtype-speci

IL-34 в неврологическом гомеостазисе и его многогранная роль в заболеваниях центральной нервной системы.

Interleukin-34 (IL-34), лиганд для рецептора макрофажных колоний (CSF1R), играет незаменимую роль в развитии и поддержании гомеостазиса центральной нервной системы (CNS). В настоящем обзоре систематически излагаются основные механизмы, с помощью которых ось сигнала IL-34/CSF1R регулирует развитие, колонизацию и функциональную дифференциацию иммунных клеток-резидентов, включая микроглию и макрофаги, связанные с границами (BAM). Она подчеркивает свою роль в критических физиологических процессах, таких, как синаптическое обрезка, созревание нервной цепи и поддержание целостности мозгового барьера

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… •HD (striatum, brain slice): IL-34/CSF1R signaling accelerates mHTT-induced medium spiny neurons (MSNs) degeneration. … Furthermore, in brain slice models with intact neuron-glia networks, IL-34 acts on microglia by binding its receptor CSF1R, exacerbating mHTTx1-induced degeneration of medium spiny neurons (MSNs) in the striatum ( 43 ). …

Роль микроглии в синаптогенезе, синаптической и синаптической пластичности в физиологических условиях и в нарушениях центральной нервной системы.

Микроглии являются постоянными иммунными клетками мозга, которые были широко изучены для их иммунного наблюдения и фагоцитоза. В последние годы постепенно признается важная роль микроглии в синапсовом образовании, ликвидации и пластичности. Синапсы являются основным режимом связи между нейронами. Они постоянно меняются в количестве и пластичности на протяжении всего жизненного цикла, который является основой обучения и памяти. Микроглии являются сильно мотилированными, ветковыми формами, которые осуществляют мониторинг микроокружающей среды центральной нервной системы (КНС) и поощряют синапсов

Preclinical Evaluation of a Lentiviral Vector for Huntingtin Silencing.

Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder resulting from a polyglutamine expansion in the huntingtin (HTT) protein. There is currently no cure for this disease, but recent studies suggest that RNAi to downregulate the expression of both normal and mutant HTT is a promising therapeutic approach. We previously developed a small hairpin RNA (shRNA), vectorized in an HIV-1-derived lentiviral vector (LV), that reduced pathology in an HD rodent model. Here, we modified this vector for preclinical development by using a tat-independent third-generation LV (pCCL) ba

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… At DIV22, 90.2% ± 3.8% of cells were CTIP2 + , an early marker of medium spiny neurons 62 (MSNs), whereas less than 0.3% ± 0.1% of cells expressed NKX2.1, a transcription factor necessary for MGE development that specifies the fate of non-striatal interneurons 62 , 63 , 64 ( Figures 3 A and 3B). … Ctip2 controls the differentiation of medium spiny neurons and the establishment of the cellular architecture of the striatum J. Neurosci. 28 2008 622 632 18199763 10.1523/JNEUROSCI.2986-07.2008 PMC6670353 63 Sussel L. Marin O. Kimura S. Rubenstein J.L. …

Нанозимы: инновационная терапия в борьбе с нейродегенеративными заболеваниями.

Нейродегенеративные заболевания, включая болезнь Альцгеймера (AD), болезнь Паркинсона (PD), множественный склероз (MS), амиотропический боковой склероз (ALS) и болезнь Хантингтона (HD), представляют собой серьезную проблему для здоровья населения мира из-за их прогрессивного характера и отсутствия лечения. Эти расстройства характеризуются окислительным стрессом, завязыванием белка и нейроинфламмацией, которые в совокупности приводят к нервным повреждениям и смерти. Последние достижения в нанотехнологии позволили внедрить нанозменные наноматериалы, которые имитируют деятельность, похожую на фер

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… It is characterized by the degeneration of striatal medium spiny neurons (spiny projection neurons), a special type of inhibitory GABAergic neuron, representing approximately 90% of neurons within the human striatum, a basal ganglia structure. …

Пересадка глиальных клеток человека в муринные мозги: систематический обзор эффективности и безопасности в нейродегенеративных расстройствах.

Справочная информация: Нейродегенеративные заболевания затрагивают миллионы людей во всем мире. С годами исследования мозга были сосредоточены главным образом на нейронах, но сейчас внимание перемещается на глиальные клетки, вспомогательные клетки мозга, которые играют жизненно важную роль в нейродегенеративных расстройствах. Таким образом, трансплантация глиальных клеток представляет собой новаторский подход к лечению различных нейродегенеративных расстройств, способных восстановить нейронную функцию. Мы провели оценку терапевтической эффективности трансплантации человеческих глиальных клеток

GLP-1 Рецептор агонисты в неврологических расстройствах: от механизмов к клиническому переводу.

Глукагон-подобный peptide-1 агонисты рецепторов или GLP-1RAs, были использованы годами для обработки типа 2 диабет и ожирение. Совсем недавно стало ясно, что эти рецепторы широко распространяются по всей центральной нервной системе (СНС), что расширило возможность повторного использования этих лекарств для лечения неврологических расстройств. В этом обзоре мы анализируем улики по целому ряду неврологических условий, обсуждаем основные механизмы, которые, как предполагается, объясняют их нейрозащитные эффекты, и указываем на препятствия, которые еще предстоит устранить, прежде чем их можно буде

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… This mutation leads to progressive loss of medium spiny neurons in the striatum, as well as cortical atrophy in later stages. …