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ACS Chem Neurosci 2022 May 24. Epub 2022 May 24.

Department of Chemistry, Molecular Sciences Research Hub, Imperial College London, London W12 0BZ, United Kingdom.

Neurodegenerative diseases are a class of disorders linked to the formation in the nervous system of fibrillar protein aggregates called amyloids. This aggregation process is affected by a variety of post-translational modifications, whose specific mechanisms are not fully understood yet. Emerging chemical mutagenesis technology is currently striving to address the challenge of introducing protein post-translational modifications, while maintaining the stability and solubility of the proteins during the modification reaction. Read More

ACS Chem Neurosci 2022 May 23. Epub 2022 May 23.

School of Pharmacy, Ningxia Medical University, 1160 Shengli Street, Yinchuan 750004, China.

Alzheimer's disease (AD) is an irreversible and progressive neurodegenerative disorder featured by memory loss and cognitive default. However, there has been no effective therapeutic approach to prevent the development of AD and the available therapies are only to alleviate some symptoms with limited efficacy and severe side effects. Necroptosis is a new kind of cell death, being regarded as a genetically programmed and regulated pattern of necrosis. Read More

ACS Chem Neurosci 2022 May 23. Epub 2022 May 23.

Department of Radiology, Stanford University, Stanford, California 94305, United States.

Positron emission tomography (PET) is a highly sensitive and versatile molecular imaging modality that leverages radiolabeled molecules, known as radiotracers, to interrogate biochemical processes such as metabolism, enzymatic activity, and receptor expression. The ability to probe specific molecular and cellular events longitudinally in a noninvasive manner makes PET imaging a particularly powerful technique for studying the central nervous system (CNS) in both health and disease. Unfortunately, developing and translating a single CNS PET tracer for clinical use is typically an extremely resource-intensive endeavor, often requiring synthesis and evaluation of numerous candidate molecules. Read More

ACS Chem Neurosci 2022 May 23. Epub 2022 May 23.

Laboratory of Biochemistry and Molecular Neuropharmacology (LABIONEM), Postgraduate Program in Biochemistry and Bioprospecting (PPGBBio), Center of Chemical, Pharmaceutical and Food Sciences (CCQFA), Federal University of Pelotas (UFPel), P.O. Box, 354, Pelotas, 96010-900 RS, Brazil.

The monoaminergic dysfunction plays a central role in major depressive disorder (MDD), a mental disturbance associated with constant feeling of sadness and lack of interest. The available treatments do not present a desirable efficacy and some of them provoke several adverse effects. In this context, organoselenium compounds and molecules containing the indolizine nucleus have demonstrated interesting pharmacological properties, including antidepressant-like effects. Read More

ACS Chem Neurosci 2022 May 19. Epub 2022 May 19.

Department of Biochemistry, Virginia Tech, Blacksburg, Virginia 24061, United States.

Islet amyloid polypeptide (IAPP) is a 37-residue amyloidogenic hormone implicated in the progression of Type II Diabetes (T2D). T2D affects an estimated 422 million people yearly and is a comorbidity with numerous diseases. IAPP forms toxic oligomers and amyloid fibrils that reduce pancreatic β-cell mass and exacerbate the T2D disease state. Read More

ACS Chem Neurosci 2022 May 17. Epub 2022 May 17.

Institute of Biological Information Processing-Structural Biochemistry (IBI-7), Research Centre Jülich, 52425 Jülich, Germany.

The aggregation of the amyloid-β (Aβ) peptide is a major hallmark of Alzheimer's disease. This peptide can aggregate into oligomers, proto-fibrils, and mature fibrils, which eventually assemble into amyloid plaques. The peptide monomers are the smallest assembly units and play an important role in most of the individual processes involved in amyloid fibril formation, such as primary and secondary nucleation and elongation. Read More

ACS Chem Neurosci 2022 May 15. Epub 2022 May 15.

The Center for Convergent Bioscience and Medicine (CCBM), The University of Alabama, Tuscaloosa, Alabama 35401, United States.

Neurovascular eye problems are better prevented than managed or treated. Despite growing concern of occurrence in aging populations and development secondary to diseases such as diabetes and hypertension, we currently have very few options to tackle this global problem. Creating effective and high-throughput screening strategies is as important as the intervention itself. Read More

ACS Chem Neurosci 2022 May 13. Epub 2022 May 13.

Infection Bioengineering Group, Department of Biosciences and Biomedical Engineering, Indian Institute of Technology Indore, Simrol, Indore 453552, India.

Raman microspectroscopy is a vibrational spectroscopy technique used for investigating molecular fingerprints of a wide range of liquid or solid samples. The technique can be efficiently utilized to understand the virus-mediated cellular changes and could provide valuable insights into specific biomolecular alterations. The Epstein Barr virus (EBV) has been associated with various types of cancers as well as neurodegenerative diseases. Read More

ACS Chem Neurosci 2022 May 12. Epub 2022 May 12.

Department of Neuropharmacology, School of Pharmaceutical Sciences, Shoolini University, Solan, HP 173 212, India.

The present work aimed to investigate the induction of circadian rhythm dysfunction and dementia upon chronic exposure to light-light and its reversal by melatonin in Wistar rats. Animals underwent different light-dark conditions, viz., light/dark (LD), light/light (LL), and dark/dark (DD) in respective groups for 4 months. Read More

ACS Chem Neurosci 2022 May 12. Epub 2022 May 12.

Department of Anatomy and Neurobiology, University of Maryland School of Medicine, University of Maryland, Baltimore, Maryland 21201, United States.

As neurons age, protein homeostasis becomes less efficient, resulting in misfolding and aggregation. Chaperone proteins perform vital functions in the maintenance of cellular proteostasis, and chaperone-based therapies that promote sequestration of toxic aggregates may prove useful in blocking the development of neurodegenerative disease. We previously demonstrated that proSAAS, a small secreted neuronal protein, exhibits potent chaperone activity against protein aggregation in vitro and blocks the cytotoxic effects of amyloid and synuclein oligomers in cell culture systems. Read More

ACS Chem Neurosci 2022 May 11. Epub 2022 May 11.

Toxicology Centre, University of Saskatchewan, 44 Campus Drive, Saskatoon, Saskatchewan S7N 5B3, Canada.

Mercury is ubiquitous in the environment, with rising levels due to pollution and climate change being a current global concern. Many mercury compounds are notorious for their toxicity, with the potential of organometallic mercury compounds for devastating effects on the structures and functions of the central nervous system being of particular concern. Chronic exposure of human populations to low levels of methylmercury compounds occurs through consumption of fish and other seafood, although the health consequences, if any, from this exposure remain controversial. Read More

ACS Chem Neurosci 2022 May 11. Epub 2022 May 11.

College of Life Sciences, Nanjing Agricultural University, Nanjing 210095, China.

The parathyroid hormone type 1 receptor (PTH1R), a canonical class B GPCR, is regulated by a positive allosteric modulator, extracellular Ca. Calcium ions prolong the residence time of PTH on the PTH1R, leading to increased receptor activation and duration of cAMP signaling. But the essential mechanism of the allosteric behavior of PTH1R is not fully understood. Read More

ACS Chem Neurosci 2022 May 9;13(10):1491-1504. Epub 2022 May 9.

Division of Neuroscience and Ageing Biology, CSIR-Central Drug Research Institute, Lucknow 226031, U.P., India.

Hypertension is reported to cause major brain disorders including Parkinson's disease (PD), apart from cardiovascular and chronic kidney disorders. Considering this, for the first time, we explored the effect of modulation of the ACE2/Ang (1-7)/MasR axis using diminazene aceturate (DIZE), an ACE2 activator, in 6-hydroxydopamine (6-OHDA) induced PD model. We found that DIZE treatment improved neuromuscular coordination and locomotor deficits in the 6-OHDA induced PD rat model. Read More

ACS Chem Neurosci 2022 May 6;13(10):1549-1557. Epub 2022 May 6.

Department of Medicinal Chemistry, The University of Minnesota, Minneapolis, Minnesota 55455, United States.

Synaptic and cognitive deficits mediated by a severe reduction in excitatory neurotransmission caused by a disproportionate accumulation of the neuronal protein tau in dendritic spines is a fundamental mechanism that has been found repeatedly in models of tauopathies, including Alzheimer's disease, Lewy body dementia, frontotemporal dementia, and traumatic brain injury. Synapses thus damaged may contribute to dementia, among the most feared cause of debilitation in the elderly, and currently there are no treatments to repair them. Caspase-2 (Casp2) is an essential component of this pathological cascade. Read More

ACS Chem Neurosci 2022 May 6;13(10):1505-1516. Epub 2022 May 6.

Memory and Aging Center, Department of Neurology, University of California, San Francisco, California, California 94158, United States.

Lysosomes are intracellular organelles responsible for the degradation of diverse macromolecules in a cell. A highly acidic pH is required for the optimal functioning of lysosomal enzymes. Loss of lysosomal intralumenal acidity can disrupt cellular protein homeostasis and is linked to age-related diseases such as neurodegeneration. Read More

ACS Chem Neurosci 2022 May 5;13(10):1479-1490. Epub 2022 May 5.

School of Chemistry, Faculty of Science, University of Sydney, Sydney, New South Wales 2006, Australia.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by upper and lower motor neuron loss. The pathomechanisms of ALS are still poorly understood with current hypotheses involving genetic mutations, excitotoxicity, and reactive oxygen species formation. In the absence of a disease-altering clinically approved therapeutic, there is an ever-increasing need to identify new targets to develop drugs that delay disease onset and/or progression. Read More

ACS Chem Neurosci 2022 May 4;13(10):1467-1478. Epub 2022 May 4.

Beijing Key Laboratory of Bioactive Substances and Functional Foods, Beijing Union University, , Beijing 100191, China.

Alzheimer's disease (AD) is a multifactorial disease, and it has become a serious health problem in the world. Senile plaques (SPs) and neurofibrillary tangles (NFTs) are two main pathological characters of AD. SP mainly consists of aggregated β-amyloid (Aβ), and NFT is formed by hyperphosphorylated tau protein. Read More

ACS Chem Neurosci 2022 May 2;13(10):1594-1603. Epub 2022 May 2.

School of Medicine, Fu Jen Catholic University, New Taipei City 24205, Taiwan.

Several plant compounds have been found to possess neuroactive properties. The aim of this study was to investigate the anticonvulsant effect of eupafolin, a major active component extracted from , a herb used in traditional medicine for its anti-inflammatory properties. To this end, we assessed the anticonvulsant effects of eupafolin in rats intraperitoneally (i. Read More

ACS Chem Neurosci 2022 May 2;13(10):1517-1525. Epub 2022 May 2.

Functional Proteomics Laboratory, Regional Centre for Biotechnology (RCB), NCR Biotech Science Cluster, 3rd Milestone Gurgaon-Faridabad Expressway, Faridabad 121001, India.

S-Nitrosylation is a reversible post-translational modification that regulates protein function involving the covalent attachment of the nitric oxide (NO) moiety to sulfhydryl residues of the protein. It is an important regulator in the cell signaling process under physiological conditions. However, the release of an excess amount of NO due to dysregulated NOS machinery causes aberrant S-nitrosylation of proteins, which affects protein folding, localization, and activity. Read More

ACS Chem Neurosci 2022 May 28;13(10):1534-1548. Epub 2022 Apr 28.

Department of Cellular Biology and Physiology, Brigham Young University, Provo, Utah 84602, United States.

Fast-scan cyclic voltammetry (FSCV) is an effective tool for measuring dopamine release and clearance throughout the brain, especially the striatum where dopamine terminals are abundant and signals are heavily regulated by release machinery and the dopamine transporter (DAT). Peak height measurement is perhaps the most common method for measuring dopamine release, but it is influenced by changes in clearance. Michaelis-Menten-based modeling has been a standard in measuring dopamine clearance, but it is problematic in that it requires experimenter fitted modeling subject to experimenter bias. Read More

ACS Chem Neurosci 2022 May 27;13(10):1566-1579. Epub 2022 Apr 27.

Cancer and Neurobiology Laboratory, Department of Biochemistry, Institute of Science, Banaras Hindu University, Varanasi 221005, India.

A new rhodamine-based probe 3,5-di--butylsalicylaldehyde rhodamine hydrazone () has been synthesized and well characterized using spectroscopic techniques and single-crystal X-ray crystallography. Among several metal ions, it selectively detects Cu ions as monitored by UV-Vis and emission spectral titrations. It displays "turn on" behavior owing to the opening of a spirolactum ring and the presence of 3,5-di--butyl as an electron releasing group. Read More

ACS Chem Neurosci 2022 May 27;13(10):1558-1565. Epub 2022 Apr 27.

Department of Nuclear Medicine, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China.

The current diagnoses of Alzheimer's disease (AD) mainly rely on such measures as amyloid-β (Aβ) and tau neuropathology biomarkers in vivo via cerebrospinal fluid (CSF) and positron emission tomography (PET) imaging, which had been systematically studied in Caucasian individuals, whereas diagnostic performances of these approaches in Chinese dementia population still remain unclear. This study investigated the associations between the levels of CSF core AD biomarkers, including phosphorylated tau (p-Tau181), total tau (t-Tau), Aβ42, and Aβ40 measured by the single-molecule array (Simoa) and cerebral Aβ deposition status assessed by F-Florbetapir PET (Aβ PET), and evaluated the predictive values of CSF core AD biomarkers in discriminating Aβ PET status in a clinical dementia cohort of the Chinese population, which consisted of patients with mild cognitive impairment (MCI), AD dementia, and non-Alzheimer's dementia disease (Non-ADD). Global standard uptake value ratios (SUVRs) were calculated by Aβ PET, which was divided into positive (Aβ+) and negative (Aβ-) through visual analysis. Read More

ACS Chem Neurosci 2022 May 27;13(10):1580-1587. Epub 2022 Apr 27.

Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, 2100 Copenhagen, Denmark.

The development of tool compounds for the ionotropic glutamate receptors (iGluRs) remains an important research objective, as these are essential for the study and understanding of the roles of these receptors in health and disease. Herein, we report on the pharmacological characterization of ()-2-hydroxyhistidine () and ()-2-mercaptohistidine () as mediators of glutamatergic neurotransmission. While displayed negligible binding affinity or activity at all glutamate receptors and transporters investigated, displayed selectivity for homomeric GluK3 with binding affinities in the low micromolar range ( = 6. Read More

ACS Chem Neurosci 2022 May 26;13(10):1588-1593. Epub 2022 Apr 26.

Department of Chemical Sciences, University of Catania, Viale Andrea Doria 6, Catania 95125, Italy.

l-Carnosine is an endogenous dipeptide that has high potential for therapeutic purposes, being an antioxidant with metal chelating, anti-aggregating, anti-inflammatory, and neuroprotective properties. Despite its potential therapeutic values, the biomolecular mechanisms involved in neuroprotection are not fully understood. Here, we demonstrate, at chemical and biochemical levels, that insulin-degrading enzyme plays a pivotal role in carnosine neuroprotection. Read More

ACS Chem Neurosci 2022 05 25;13(9):1456-1466. Epub 2022 Apr 25.

CSIR-Centre for Cellular and Molecular Biology, Uppal Road, Hyderabad 500 007, India.

Cellular hypoxia causes numerous pathophysiological conditions associated with the disruption of oxygen homeostasis. Under oxygen-deficient conditions, cells adapt by controlling the cellular functions to facilitate the judicious use of available oxygen, such as cessation of cell growth and proliferation. In higher eukaryotes, the process of cholesterol biosynthesis is intimately coupled to the availability of oxygen, where the synthesis of one molecule of cholesterol requires 11 molecules of O. Read More

ACS Chem Neurosci 2022 05 22;13(9):1358-1369. Epub 2022 Apr 22.

National Institute of Pharmaceutical Education and Research, Ahmedabad, Opposite Air Force Station, Palaj, Gandhinagar, Gujarat 382355, India.

Disturbance in the neuronal network leads to instability in the microtubule (MT) railroad of axons, causing hindrance in the intra-axonal transport and making it difficult to re-establish the broken network. Peripheral nervous system (PNS) neurons can stabilize their MTs, leading to the formation of regeneration-promoting structures called "growth cones". However, central nervous system (CNS) neurons lack this intrinsic reparative capability and, instead, form growth-incompetent structures called "retraction bulbs", which have a disarrayed MT network. Read More

ACS Chem Neurosci 2022 05 20;13(9):1370-1381. Epub 2022 Apr 20.

Department of Health Toxicology, MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan 430030, P. R. China.

Acrylamide (ACR), a well-documented neurotoxicant to humans, is extensively found in starchy foods. More than 30% of the typical daily calorie intake comes from ACR-containing foods. Epidemiological and toxicological studies have found that ACR exposure is associated with mild cognitive change in men and experimental animals. Read More

ACS Chem Neurosci 2022 05 20;13(9):1395-1409. Epub 2022 Apr 20.

The Lambert Initiative for Cannabinoid Therapeutics, Brain and Mind Centre, The University of Sydney, NSW 2050, Australia.

Synthetic cannabinoid receptor agonists (SCRAs) are a large and growing class of new psychoactive substances (NPSs). Two recently identified compounds, MEPIRAPIM and 5F-BEPIRAPIM (NNL-2), have not been confirmed as agonists of either cannabinoid receptor subtype but share structural similarities with both SCRAs and a class of T-type calcium channel (Ca3) inhibitors under development as new treatments for epilepsy and pain. In this study, MEPIRAPIM and 5F-BEPIRAPIM and 10 systematic analogues were synthesized, analytically characterized, and pharmacologically evaluated using cannabinoid receptor and Ca3 assays. Read More

ACS Chem Neurosci 2022 May 19;13(10):1526-1533. Epub 2022 Apr 19.

Institute of Theoretical Chemistry, College of Chemistry, Jilin University, Changchun 130023, China.

CYP46A1 is an important potential target for the treatment of Alzheimer's disease (AD), which is the most common neurodegenerative disease among older individuals. However, the binding mechanism between CYP46A1 and substrate cholesterol (CH) has not been clarified and will not be conducive to the research of relevant drug molecules. In this study, we integrated molecular docking, molecular dynamics (MD) simulations, and adaptive steered MD simulations to explore the recognition and binding mechanism of CYP46A1 with CH. Read More

ACS Chem Neurosci 2022 05 15;13(9):1355-1357. Epub 2022 Apr 15.

Krembil Research Institute, University Health Network, 60 Leonard Avenue, Toronto M5T 0S8, Canada.

Alzheimer's disease (AD) and related dementias constitute a worldwide health crisis for which the design and development of global solutions is a neuropharmacologic priority. The much-publicized failures of multiple investigational agents for AD over the past 20 years drive the need to rethink our approach to therapeutics development. Herein we present the ABCDE paradigm as a conceptual tool to facilitate the development of safe, effective therapies for AD cure: (A) accessible; (B) blood-brain barrier permeant; (C) cognitive enhancing; (D) disease-modifying; (E) environmentally nontoxic. Read More