Identifying New AMP-Activated Protein Kinase Inhibitors That Protect against Ischemic Brain Injury.


:We recently reported that AMP-activated protein kinase (AMPK) contributes to zinc-induced neuronal death by inducing Bim, a pro-apoptotic Bcl-2 homology domain 3-only protein, in a liver kinase B1 (LKB1)-dependent manner. Current data suggest AMPK plays key roles in excitotoxicity and ischemic brain injury, with zinc neurotoxicity representing at least one mechanism of ischemic neuronal death. Inhibition of AMPK could be a viable therapeutic strategy to prevent ischemic brain injury following stroke. This prompted our search for novel inhibitors of AMPK activity and zinc-induced neuronal death using cultured mouse cortex and a rat model of brain injury after middle cerebral artery occlusion (MCAO). In structure-based virtual screening, 118 compounds were predicted to bind the active site of AMPK α2, and 40 showed in vitro AMPK α2 inhibitory activity comparable to compound C (a well-known, potent AMPK inhibitor). In mouse cortical neuronal cultures, 7 of 40 compound reduced zinc-induced neuronal death at levels comparable to compound C. Ultimately, only agents 2G11 and 1H10 significantly attenuated various types of neuronal death, including oxidative stress, excitotoxicity, and apoptosis. When administered as intracerebroventricular injections prior to permanent MCAO in rats, 2G11 and 1H10 reduced brain infarct volumes, whereas compound C did not. Therefore, these novel AMPK inhibitors could be drug development candidates to treat stroke.


ACS Chem Neurosci


Eom JW,Kim TY,Seo BR,Park H,Koh JY,Kim YH




Has Abstract


2019-05-15 00:00:00










  • Food-Induced Increase of Acetylcholine in Mouse Hypothalamus.

    abstract::Using microdialysis in C57Bl6 mice, we monitored cholinergic activity in the hypothalamus. Food intake after an overnight fast caused a 3-fold increase of extracellular acetylcholine (ACh) concentrations in the hypothalamus. The effect lasted for about 30 min. Food containing no calories (kaolin pellets), or food that...

    journal_title:ACS chemical neuroscience

    pub_type: 杂志文章


    authors: Thinnes A,Klein J

    更新日期:2019-04-17 00:00:00

  • The implications of angiotensin-converting enzymes and their modulators in neurodegenerative disorders: current and future perspectives.

    abstract::Angiotensin converting enzyme (ACE) is a dipeptidyl peptidase transmembrane bound enzyme. Generally, ACE inhibitors are used for the cardiovascular disorders. ACE inhibitors are primary agents for the management of hypertension, so these cannot be avoided for further use. The present Review focuses on the implications...

    journal_title:ACS chemical neuroscience

    pub_type: 杂志文章,评审


    authors: Kaur P,Muthuraman A,Kaur M

    更新日期:2015-04-15 00:00:00

  • Alzheimer's Disease, the "One-Molecule, One-Target" Paradigm, and the Multitarget Directed Ligand Approach.

    abstract::No selective drugs exist, and we have been designing, synthesizing, and evaluating multitarget-directed ligands since the beginning of modern medicinal chemistry, without knowing it, most possibly. The challenge to discover the efficient Multi-Target Small Molecules (MTSMs) for Alzheimer's disease (AD) therapy implies...

    journal_title:ACS chemical neuroscience

    pub_type: 杂志文章,评审


    authors: Oset-Gasque MJ,Marco-Contelles J

    更新日期:2018-03-21 00:00:00

  • Novel Tadalafil Derivatives Ameliorates Scopolamine-Induced Cognitive Impairment in Mice via Inhibition of Acetylcholinesterase (AChE) and Phosphodiesterase 5 (PDE5).

    abstract::On the basis of the drug-repositioning and redeveloping strategy, first-generation dual-target inhibitors of acetylcholinesterase (AChE) and phosphodiesterase 5 (PDE5) have been recently reported as a potentially novel therapeutic method for the treatment of Alzheimer's disease (AD), and the lead compound 2 has proven...

    journal_title:ACS chemical neuroscience

    pub_type: 杂志文章


    authors: Ni W,Wang H,Li X,Zheng X,Wang M,Zhang J,Gong Q,Ling D,Mao F,Zhang H,Li J

    更新日期:2018-07-18 00:00:00

  • Tau-derived-hexapeptide 306VQIVYK311 aggregation inhibitors: nitrocatechol moiety as a pharmacophore in drug design.

    abstract::The nitrocatechol derivatives tolcapone (1) and entacapone (2), used as adjunctive therapy in the treatment of Parkinson's disease, were investigated for their potential to inhibit the tau-derived-hexapeptide 306VQIVYK311. They were compared to small molecules that contain similar pharmacophores including the catechol...

    journal_title:ACS chemical neuroscience

    pub_type: 杂志文章


    authors: Mohamed T,Hoang T,Jelokhani-Niaraki M,Rao PP

    更新日期:2013-12-18 00:00:00

  • Conformational Propensities of Peptides Mimicking Transmembrane Helix 5 and Motif C in Wild-type and Mutant Vesicular Acetylcholine Transporters.

    abstract::Vesicular acetylcholine transporter (VAChT) is a member of the major facilitator superfamily (MFS). It contains conserved sequence motifs originally defined in the bacterial multidrug resistance transporter family of the MFS. Motif C (GSLV(227) A(228)PPFGGIL) is located at the C-terminal end of transmembrane helix 5 (...

    journal_title:ACS chemical neuroscience

    pub_type: 杂志文章


    authors: Luo J,Parsons SM

    更新日期:2010-05-19 00:00:00

  • Improved Calibration of Voltammetric Sensors for Studying Pharmacological Effects on Dopamine Transporter Kinetics in Vivo.

    abstract::The distribution and density of neurons within the brain poses many challenges when making quantitative measurements of neurotransmission in the extracellular space. A volume neurotransmitter is released into the synapse during chemical communication and must diffuse through the extracellular space to an implanted sen...

    journal_title:ACS chemical neuroscience

    pub_type: 杂志文章


    authors: Atcherley CW,Laude ND,Monroe EB,Wood KM,Hashemi P,Heien ML

    更新日期:2015-09-16 00:00:00

  • Neuromicrobiology: How Microbes Influence the Brain.

    abstract::We review here recent discoveries in the exciting new field of neuromicrobiology. This field encompasses the interactions between the microbiome and the central nervous system. The microbiome has a tremendous impact on human health. In particular, the gut microbiota may play a key role in many essential processes in h...

    journal_title:ACS chemical neuroscience

    pub_type: 杂志文章,评审


    authors: de la Fuente-Nunez C,Meneguetti BT,Franco OL,Lu TK

    更新日期:2018-02-21 00:00:00

  • Synthesis and characterization of a dual kappa-delta opioid receptor agonist analgesic blocking cocaine reward behavior.

    abstract::3-Iodobenzoyl naltrexamine (IBNtxA) is a potent analgesic belonging to the pharmacologically diverse 6β-amidoepoxymorphinan group of opioids. We present the synthesis and pharmacological evaluation of five analogs of IBNtxA. The scaffold of IBNtxA was modified by removing the 14-hydroxy group, incorporating a 7,8 doub...

    journal_title:ACS chemical neuroscience

    pub_type: 杂志文章


    authors: Váradi A,Marrone GF,Eans SO,Ganno ML,Subrath JJ,Le Rouzic V,Hunkele A,Pasternak GW,McLaughlin JP,Majumdar S

    更新日期:2015-11-18 00:00:00

  • Could Artesunate Have a Positive Effect on the Neurological Complications Related to Infection When It Is Used in the Treatment of COVID-19?

    abstract::Artesunate is a safe noncytotoxic drug with low side effects which is used in the treatment of chloroquine-resistant malaria. In addition to being an antimalarial drug, artesunate also has immunomodulatory, anticarcinogenic, and antiviral activity. There are in vivo and in vitro studies reporting that artesunate may h...

    journal_title:ACS chemical neuroscience

    pub_type: 杂志文章


    authors: Uzun T,Toptaş O,Aydın Türkoğlu Ş

    更新日期:2020-12-16 00:00:00

  • Preference for Glucose over Inositol Headgroup during Lysolipid Activation of G Protein-Coupled Receptor 55.

    abstract::G protein-coupled receptor 55 (GPR55) is highly expressed in brain and peripheral nervous system. Originally deorphanized as a cannabinoid receptor, recently GPR55 has been described as a lysophospholipid-responsive receptor, specifically toward lysophosphatidylinositol and lysophosphatidyl-β-d-glucoside (LysoPtdGlc)....

    journal_title:ACS chemical neuroscience

    pub_type: 杂志文章


    authors: Guy AT,Kano K,Ohyama J,Kamiguchi H,Hirabayashi Y,Ito Y,Matsuo I,Greimel P

    更新日期:2019-01-16 00:00:00

  • Diverse Effects of Gut-Derived Serotonin in Intestinal Inflammation.

    abstract::The gut is the largest producer of serotonin or 5-hydroxytryptamine (5-HT) in the human body, and 5-HT has been recognized as an important signaling molecule in the gut for decades. There are two distinct sources of enteric 5-HT. Mucosal 5-HT is predominantly produced by enterochromaffin (EC) cells of the gastrointest...

    journal_title:ACS chemical neuroscience

    pub_type: 杂志文章,评审


    authors: Shajib MS,Baranov A,Khan WI

    更新日期:2017-05-17 00:00:00

  • Interrogating the Molecular Basis for Substrate Recognition in Serotonin and Dopamine Transporters with High-Affinity Substrate-Based Bivalent Ligands.

    abstract::The transporters for the neurotransmitters serotonin and dopamine (SERT and DAT, respectively) are targets for drugs used in the treatment of mental disorders and widely used drugs of abuse. Studies of prokaryotic homologues have advanced our structural understanding of SERT and DAT, but it still remains enigmatic whe...

    journal_title:ACS chemical neuroscience

    pub_type: 杂志文章


    authors: Andersen J,Ladefoged LK,Kristensen TN,Munro L,Grouleff J,Stuhr-Hansen N,Kristensen AS,Schiøtt B,Strømgaard K

    更新日期:2016-10-19 00:00:00

  • Unraveling the Role of Receptor for Advanced Glycation End Products (RAGE) and Its Ligands in Myasthenia Gravis.

    abstract::Myasthenia gravis (MG) is an autoimmune T cell-dependent B cell-mediated disorder of the neuromuscular junction (NMJ) characterized by fluctuating skeletal muscle weakness, most commonly attributed to pathogenic autoantibodies against postsynaptic nicotinic acetylcholine receptors (AChRs). Although MG pathogenesis is ...

    journal_title:ACS chemical neuroscience

    pub_type: 杂志文章


    authors: Angelopoulou E,Paudel YN,Piperi C

    更新日期:2020-03-04 00:00:00

  • D-512 and D-440 as novel multifunctional dopamine agonists: characterization of neuroprotection properties and evaluation of in vivo efficacy in a Parkinson's disease animal model.

    abstract::In this article, we have demonstrated the in vivo efficacy of D-512 and D-440 in a 6-OHDA-induced unilaterally lesioned rat model experiment, a Parkinson's disease animal model. D-512 is a novel highly potent D2/D3 agonist, and D-440 is a novel highly selective D3 agonist. We evaluated the neuroprotective properties o...

    journal_title:ACS chemical neuroscience

    pub_type: 杂志文章


    authors: Santra S,Xu L,Shah M,Johnson M,Dutta A

    更新日期:2013-10-16 00:00:00

  • Development of a new photochromic ion channel blocker via azologization of fomocaine.

    abstract::Photochromic blockers of voltage gated ion channels are powerful tools for the control of neuronal systems with high spatial and temporal precision. We now introduce fotocaine, a new type of photochromic channel blocker based on the long-lasting anesthetic fomocaine. Fotocaine is readily taken up by neurons in brain s...

    journal_title:ACS chemical neuroscience

    pub_type: 杂志文章


    authors: Schoenberger M,Damijonaitis A,Zhang Z,Nagel D,Trauner D

    更新日期:2014-07-16 00:00:00

  • Fluorescent filter-trap assay for amyloid fibril formation kinetics in complex solutions.

    abstract::Amyloid fibrils are the most distinct components of the plaques associated with various neurodegenerative diseases. Kinetic studies of amyloid fibril formation shed light on the microscopic mechanisms that underlie this process as well as the contributions of internal and external factors to the interplay between diff...

    journal_title:ACS chemical neuroscience

    pub_type: 杂志文章


    authors: Nasir I,Linse S,Cabaleiro-Lago C

    更新日期:2015-08-19 00:00:00

  • Immunity-Boosting Spices and the Novel Coronavirus.

    abstract::Although there is no reported genetic predisposition in contracting coronavirus disease 2019 (COVID-19), the mortality rate varies among different ethnic groups. Here we determined potential correlation between COVID-19 and spice consumption. The data from 163 countries including total cases, total deaths, and total r...

    journal_title:ACS chemical neuroscience

    pub_type: 杂志文章


    authors: Elsayed Y,Khan NA

    更新日期:2020-06-17 00:00:00

  • Pharmacology of Valinate and tert-Leucinate Synthetic Cannabinoids 5F-AMBICA, 5F-AMB, 5F-ADB, AMB-FUBINACA, MDMB-FUBINACA, MDMB-CHMICA, and Their Analogues.

    abstract::Indole and indazole synthetic cannabinoids (SCs) featuring l-valinate or l-tert-leucinate pendant group have recently emerged as prevalent recreational drugs, and their use has been associated with serious adverse health effects. Due to the limited pharmacological data available for these compounds, 5F-AMBICA, 5F-AMB,...

    journal_title:ACS chemical neuroscience

    pub_type: 杂志文章


    authors: Banister SD,Longworth M,Kevin R,Sachdev S,Santiago M,Stuart J,Mack JB,Glass M,McGregor IS,Connor M,Kassiou M

    更新日期:2016-09-21 00:00:00

  • Activation of Dopamine D3 Receptor Subtypes Inhibits the Neurogenic Systemic Vasodilation Induced by Stimulation of the Perivascular CGRPergic Discharge.

    abstract::The sensory nervous system controls cardiovascular homeostasis via capsaicin-sensitive neurons that release calcitonin gene-related peptide (CGRP), which subsequently activates CGRP receptors. How this perivascular CGRPergic discharge is modulated, nevertheless, remains unclear. In pithed rats, systemic vasodilation i...

    journal_title:ACS chemical neuroscience

    pub_type: 杂志文章


    authors: Manrique-Maldonado G,Altamirano-Espinoza AH,Rivera-Mancilla E,Hernández-Abreu O,Villalón CM

    更新日期:2019-08-21 00:00:00

  • Pair of Residue Substitutions at the Outer Mouth of the Channel Pore Act as Inputs for a Boolean Logic "OR" Gate Based on the Glycine Receptor.

    abstract::The glycine receptor (GlyR) is a ligand-activated chloride channel, whose mutations are the major cause of hereditary hyperekplexia. The hyperekplexia-causing R271Q mutation, which is located at the extracellular outer mouth of the channel pore, dramatically impairs the GlyR function manifesting a reduced sensitivity ...

    journal_title:ACS chemical neuroscience

    pub_type: 杂志文章


    authors: Han L,Shan Q

    更新日期:2020-10-21 00:00:00

  • Phosphorylation of α-Synuclein at Y125 and S129 alters its metal binding properties: implications for understanding the role of α-Synuclein in the pathogenesis of Parkinson's Disease and related disorders.

    abstract::α-Synuclein (α-syn) is a 140-amino acid protein that plays a central role in the pathogenesis of Parkinson's disease (PD) and other synucleinopathies. However, the molecular determinants that are responsible for triggering and/or propagating α-syn aggregation and toxicity remain poorly understood. Several studies have...

    journal_title:ACS chemical neuroscience

    pub_type: 杂志文章


    authors: Lu Y,Prudent M,Fauvet B,Lashuel HA,Girault HH

    更新日期:2011-11-16 00:00:00

  • In Utero Exposure to Citalopram Mitigates Maternal Stress Effects on Fetal Brain Development.

    abstract::Human epidemiological and animal-model studies suggest that separate exposure to stress or serotonin-selective reuptake inhibitor (SSRI) antidepressants during pregnancy increases risks for neurodevelopmental disorders in offspring. Yet, little is known about the combined effects of maternal stress and SSRIs with rega...

    journal_title:ACS chemical neuroscience

    pub_type: 杂志文章


    authors: Velasquez JC,Zhao Q,Chan Y,Galindo LCM,Simasotchi C,Wu D,Hou Z,Herod SM,Oberlander TF,Gil S,Fournier T,Burd I,Andrews AM,Bonnin A

    更新日期:2019-07-17 00:00:00

  • CuATSM Protects Against the In Vitro Cytotoxicity of Wild-Type-Like Copper-Zinc Superoxide Dismutase Mutants but not Mutants That Disrupt Metal Binding.

    abstract::Mutations in the SOD1 gene are associated with some forms of familial amyotrophic lateral sclerosis (fALS). There are more than 150 different mutations in the SOD1 gene that have various effects on the copper-zinc superoxide dismutase (SOD1) enzyme structure, including the loss of metal binding and a decrease in dimer...

    journal_title:ACS chemical neuroscience

    pub_type: 杂志文章


    authors: Farrawell NE,Yerbury MR,Plotkin SS,McAlary L,Yerbury JJ

    更新日期:2019-03-20 00:00:00

  • Positive Allosteric Modulation of the 5-HT1A Receptor by Indole-Based Synthetic Cannabinoids Abused by Humans.

    abstract::The nonmedical (i.e., recreational) misuse of synthetic cannabinoids (SCs) is a worldwide public health problem. When compared to cannabis, the misuse of SCs is associated with a higher incidence of serious adverse effects, suggesting the possible involvement of noncannabinoid sites of action. Here, we find that, unli...

    journal_title:ACS chemical neuroscience

    pub_type: 杂志文章


    authors: Yano H,Adhikari P,Naing S,Hoffman AF,Baumann MH,Lupica CR,Shi L

    更新日期:2020-05-20 00:00:00

  • Deciphering the Mechanism of the Anti-Hypertensive Effect of Isorhynchophylline by Targeting Neurotransmitters Metabolism of Hypothalamus in Spontaneously Hypertensive Rats.

    abstract::Essential hypertension is a major risk factor for cardiovascular disease that can lead eventually to structural and functional alterations in the brain. Accumulating evidence has suggested that the increased activities in renin-angiotensin system and sympathetic nerve participated in the pathogenesis of hypertension t...

    journal_title:ACS chemical neuroscience

    pub_type: 杂志文章


    authors: Li Y,Yu R,Zhang D,Yang W,Hou Q,Li Y,Jiang H

    更新日期:2020-06-03 00:00:00

  • Rethinking Glioblastoma Therapy: MDA-9/Syntenin Targeted Small Molecule.

    abstract::Effective therapies for glioblastoma multiforme (GBM) are not currently available. A small molecule has been identified using fragment-based drug-discovery guided by NMR that targets important protein-protein interactions controlling GBM invasion and pathogenicity. This first generation drug displays excellent pharmac...

    journal_title:ACS chemical neuroscience

    pub_type: 杂志文章,评审


    authors: Das SK,Sarkar D,Cavenee WK,Emdad L,Fisher PB

    更新日期:2019-03-20 00:00:00

  • An early folding contact between Phe19 and Leu34 is critical for amyloid-β oligomer toxicity.

    abstract::Small hydrophobic oligomers of aggregation-prone proteins are thought to be generically toxic. Here we examine this view by perturbing an early folding contact between Phe19 and Leu34 formed during the aggregation of Alzheimer's amyloid-β (Aβ40) peptide. We find that even conservative single mutations altering this in...

    journal_title:ACS chemical neuroscience

    pub_type: 杂志文章


    authors: Das AK,Rawat A,Bhowmik D,Pandit R,Huster D,Maiti S

    更新日期:2015-08-19 00:00:00

  • Cationic amino acid based lipids as effective nonviral gene delivery vectors for primary cultured neurons.

    abstract::The delivery of specific genes into neurons offers a potent approach for treatment of diseases as well as for the study of neuronal cell biology. Here we investigated the capabilities of cationic amino acid based lipid assemblies to act as nonviral gene delivery vectors in primary cultured neurons. An arginine-based l...

    journal_title:ACS chemical neuroscience

    pub_type: 杂志文章


    authors: Aoshima Y,Hokama R,Sou K,Sarker SR,Iida K,Nakamura H,Inoue T,Takeoka S

    更新日期:2013-12-18 00:00:00

  • Involvement of protein kinase C in morphine tolerance at spinal levels of rats.

    abstract::The present study was performed to investigate the possible role of protein kinase C (PKC) in morphine tolerance at spinal levels of rats. Intrathecal injection of 10 μg of morphine induced increases in the hindpaw withdrawal latency (HWL) to noxious thermal and mechanical stimulation in rats. After intrathecal inject...

    journal_title:ACS chemical neuroscience

    pub_type: 杂志文章


    authors: Jin WY,Yu LC

    更新日期:2010-02-17 00:00:00