The classical D1 dopamine receptor antagonist SCH23390 is a functional sigma-1 receptor allosteric modulator.

SCH23390 is a widely used D dopamine receptor (DR) antagonist that also elicits some DR-independent effects. We previously found that the benzazepine, SKF83959, an analog of SCH23390, produces positive allosteric modulation of the Sigma-1 receptor (Sig1R). SCH23390 does not bind to the orthodoxic site of Sig1R but enhances the binding of H (+)-pentazocine to Sig1R.

Dynamic regulation of excitatory and inhibitory synaptic transmission by growth hormone in the developing mouse brain.

Normal sensory and cognitive function of the brain relies on its intricate and complex neural network. Synaptogenesis and synaptic plasticity are critical to neural circuit formation and maintenance, which are regulated by coordinated intracellular and extracellular signaling. Growth hormone (GH) is the most abundant anterior pituitary hormone.

Structural optimizations and bioevaluation of N-H aporphine analogues as G-biased and selective serotonin 5-HT receptor agonists.

The concept of subtype selectivity and functional bias has recently reshaped current GPCR drug discovery for G protein-coupled receptors. A series of new N-H aporphines with A-ring modifications have been synthesized, and their efficacy on 5-HT receptor activation was evaluated. SAR analysis led to the discovery of several more potent and selective 5-HT receptor agonists (e.

Dysregulation of iron homeostasis and methamphetamine reward behaviors in Clk1-deficient mice.

Chronic administration of methamphetamine (METH) leads to physical and psychological dependence. It is generally accepted that METH exerts rewarding effects via competitive inhibition of the dopamine transporter (DAT), but the molecular mechanism of METH addiction remains largely unknown. Accumulating evidence shows that mitochondrial function is important in regulation of drug addiction.

Discovery of novel MIF inhibitors that attenuate microglial inflammatory activation by structures-based virtual screening and in vitro bioassays.

Macrophage migration inhibitory factor (MIF) is a pluripotent pro-inflammatory cytokine and is related to acute and chronic inflammatory responses, immune disorders, tumors, and other diseases. In this study, an integrated virtual screening strategy and bioassays were used to search for potent MIF inhibitors. Twelve compounds with better bioactivity than the prototypical MIF-inhibitor ISO-1 (IC = 14.

Glycoproteins as diagnostic and prognostic biomarkers for neurodegenerative diseases: A glycoproteomic approach.

Neurodegenerative diseases (NDs) are incurable and can develop progressively debilitating disorders, including dementia and ataxias. Alzheimer's disease and Parkinson's disease are the most common NDs that mainly affect the elderly people. There is an urgent need to develop new diagnostic tools so that patients can be accurately stratified at an early stage.

Small Molecules Selectively Targeting Sigma-1 Receptor for the Treatment of Neurological Diseases.

The sigma-1 (σ) receptor, an enigmatic protein originally classified as an opioid receptor subtype, is now understood to possess unique structural and functional features of its own and play critical roles to widely impact signaling transduction by interacting with receptors, ion channels, lipids, and kinases. The σ receptor is implicated in modulating learning, memory, emotion, sensory systems, neuronal development, and cognition and accordingly is now an actively pursued drug target for various neurological and neuropsychiatric disorders. Evaluation of the five selective σ receptor drug candidates (pridopidine, ANAVEX2-73, SA4503, S1RA, and T-817MA) that have entered clinical trials has shown that reaching clinical approval remains an evasive and important goal.

Development and characterization of an inducible Dicer conditional knockout mouse model of Parkinson's disease: validation of the antiparkinsonian effects of a sigma-1 receptor agonist and dihydromyricetin.

Parkinson's disease (PD) is a common neurodegenerative disease characterized by motor impairment and progressive loss of dopamine (DA) neurons. At present, the acute application of neurotoxic drugs such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 6-hydroxydopamine (6-OHDA) are commonly used to simulate the pathology of PD; however, it is difficult to induce the progressive pathogenesis of PD with these models. In this study, we employed DAT promoter-mediated Cre transgenic mice to establish tamoxifen-inducible Dicer conditional knockout (cKO) mice in an effort to mimic the progressive loss of DA neurons and the development of PD-like behavioral phenotypes.

Absence of TRIM32 Leads to Reduced GABAergic Interneuron Generation and Autism-like Behaviors in Mice via Suppressing mTOR Signaling.

Mammalian target of rapamycin (mTOR) signaling plays essential roles in brain development. Hyperactive mTOR is an essential pathological mechanism in autism spectrum disorder (ASD). Here, we show that tripartite motif protein 32 (TRIM32), as a maintainer of mTOR activity through promoting the proteasomal degradation of G protein signaling protein 10 (RGS10), regulates the proliferation of medial/lateral ganglionic eminence (M/LGE) progenitors.

The oncometabolite 2-hydroxyglutarate inhibits microglial activation via the AMPK/mTOR/NF-κB pathway.

Microglia, the brain-resident macrophage, is known as the innate immune cell type in the central nervous system. Microglia is also the major cellular component of tumor mass of gliomas that plays a key role in glioma development. Mutations of isocitrate dehydrogenases 1 and 2 (IDH1/2) frequently occur in gliomas, which leads to accumulation of oncometabolic product 2-hydroxyglutarate (2HG).

Dysregulation of miRNA and its potential therapeutic application in schizophrenia.

Although it is generally believed that genetic and developmental factors play critical roles in pathogenesis of schizophrenia, however, the precise etiological mechanism of schizophrenia remains largely unknown. Over past decades, miRNAs have emerged as an essential post-transcriptional regulator in gene expression regulation. The importance of miRNA in brain development and neuroplasticity has been well-established.

GSK-3β Interacts with Dopamine D1 Receptor to Regulate Receptor Function: Implication for Prefrontal Cortical D1 Receptor Dysfunction in Schizophrenia.

Introduction: Impaired dopamine D1 receptor (D1R) function in prefrontal cortex (PFC) is believed to contribute to the PFC hypofunction that has been hypothesized to be associated with negative symptoms and cognitive deficits in schizophrenia. It is therefore critical to understand the mechanisms for modulation of D1R function.

Aims: To investigate the physical interaction and functional modulation between D1R and GSK-3β.

Activation of Nur77 in microglia attenuates proinflammatory mediators production and protects dopaminergic neurons from inflammation-induced cell death.

Microglia-mediated neuroinflammation plays a critical role in the pathological development of Parkinson's disease (PD). Orphan nuclear receptor Nur77 (Nur77) is abundant in neurons, while its role in microglia-mediated neuroinflammation remains unclear. The present data demonstrated that the expression of Nur77 in microglia was reduced accompanied by microglia activation in response to lipopolysaccharide (LPS) in vitro and in experimental 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-PD mouse model.

Dihydromyricetin protects neurons in an MPTP-induced model of Parkinson's disease by suppressing glycogen synthase kinase-3 beta activity.

Aim: It is general believed that mitochondrial dysfunction and oxidative stress play critical roles in the pathology of Parkinson's disease (PD). Dihydromyricetin (DHM), a natural flavonoid extracted from Ampelopsis grossedentata, has recently been found to elicit potent anti-oxidative effects. In the present study, we explored the role of DHM in protecting dopaminergic neurons.

Allosteric Modulation of Sigma-1 Receptors Elicits Rapid Antidepressant Activity.

Aims: Sigma-1 receptors are involved in the pathophysiological process of several neuropsychiatric diseases such as epilepsy, depression. Allosteric modulation represents an important mechanism for receptor functional regulation. In this study, we examined antidepressant activity of the latest identified novel and selective allosteric modulator of sigma-1 receptor 3-methyl-phenyl-2, 3, 4, 5-tetrahydro-1H-benzo[d]azepin-7-ol (SOMCL-668).

Protease Omi facilitates neurite outgrowth in mouse neuroblastoma N2a cells by cleaving transcription factor E2F1.

Aim: Omi is an ATP-independent serine protease that is necessary for neuronal function and survival. The aim of this study was to investigate the role of protease Omi in regulating differentiation of mouse neuroblastoma cells and to identify the substrate of Omi involved in this process.

Methods: Mouse neuroblastoma N2a cells and Omi protease-deficient mnd2 mice were used in this study.

Glial pathology in bipolar disorder: potential therapeutic implications.

Bipolar disorder (BD) is a chronic and severe mental disorder with recurrent episodes of mania and depression. In addition to neuronal alterations, accumulating evidences have revealed the importance of glial system in pathophysiology and phenotype of the illness. Postmortem studies have repeatedly demonstrated the alterations in glial cells and its functions in patients with BD.

Effects of SKF83959 on the excitability of hippocampal CA1 pyramidal neurons: a modeling study.

Aim: 3-Methyl-6-chloro-7,8-hydroxy-1-(3-methylphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine (SKF83959) have been shown to affect several types of voltage-dependent channels in hippocampal pyramidal neurons. The aim of this study was to determine how modulation of a individual type of the channels by SKF83959 contributes to the overall excitability of CA1 pyramidal neurons during either direct current injections or synaptic activation.

Methods: Rat hippocampal slices were prepared.

Mutation of SLC35D3 causes metabolic syndrome by impairing dopamine signaling in striatal D1 neurons.

Obesity is one of the largest health problems facing the world today. Although twin and family studies suggest about two-thirds of obesity is caused by genetic factors, only a small fraction of this variance has been unraveled. There are still large numbers of genes to be identified that cause variations in body fatness and the associated diseases encompassed in the metabolic syndrome (MetS).

Synthesis of 5α-cholestan-6-one derivatives and their inhibitory activities of NO production in activated microglia: discovery of a novel neuroinflammation inhibitor.

Glial activation-mediated neuroinflammation plays a pivotal role in the process of several neuroinflammatory diseases including stroke, Alzheimer's diseases, Parkinson's diseases, multiple sclerosis and ischemia. Inhibition of microglial activation may ameliorate neuronal degeneration under the inflammatory conditions. In the present study, a number of 5α-cholestan-6-one derivatives were prepared and the anti-inflammatory effects of these compounds were evaluated in LPS-stimulated BV-2 microglia cells.

SKF83959 is a novel triple reuptake inhibitor that elicits anti-depressant activity.

Aim: SKF83959 (3-methyl-6-chloro-7,8-hydroxy-1-(3-methylphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine) is an atypical dopamine receptor-1 (D1 receptor) agonist, which exhibits many D1 receptor-independent effects. In the present work, we examined the effects of SKF83959 on monoaminergic transporters in vitro and its anti-depressant activity in vivo.

Methods: Human serotonin transporter (SERT), norepinephrine transporters (NET) or dopamine transporters (DAT) were stably expressed in CHO cells.

Methylphenidate enhances NMDA-receptor response in medial prefrontal cortex via sigma-1 receptor: a novel mechanism for methylphenidate action.

Methylphenidate (MPH), commercially called Ritalin or Concerta, has been widely used as a drug for Attention Deficit Hyperactivity Disorder (ADHD). Noteworthily, growing numbers of young people using prescribed MPH improperly for pleasurable enhancement, take high risk of addiction. Thus, understanding the mechanism underlying high level of MPH action in the brain becomes an important goal nowadays.