Publications by authors named "Donald F Weaver"

85 Publications

COVID-19 as a Trigger of Brain Autoimmunity.

ACS Chem Neurosci 2021 07 2;12(14):2558-2561. Epub 2021 Jul 2.

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

Entry of SARS-CoV-2 into the central nervous system (CNS) activates microglia, triggering chronic neuroinflammation and possibly neurodegeneration. The complex transcriptome of SARS-CoV-2 shares molecular similarities with diverse human CNS protein epitopes, leading to a cytokine storm and various autoantibodies, potentially culminating in an autoimmune state. A COVID-19 initiated CNS autoimmune cascade may occur via multiple pathways including molecular mimicry, bystander activation, epitope spreading, production of autoantibodies, and immortalization of effector B-cells.
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http://dx.doi.org/10.1021/acschemneuro.1c00403DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8265531PMC
July 2021

Drug-Receptor Interactions: It is a Numbers Game.

Can J Neurol Sci 2021 Jun 29:1-2. Epub 2021 Jun 29.

Krembil Research Institute, University Health Network, Toronto, Ontario, Canada.

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http://dx.doi.org/10.1017/cjn.2021.152DOI Listing
June 2021

Ferulic acid amide derivatives with varying inhibition of amyloid-β oligomerization and fibrillization.

Bioorg Med Chem 2021 Jun 6;43:116247. Epub 2021 Jun 6.

Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, ON M5S 3H6, Canada; Krembil Research Institute, University Health Network, Krembil Discovery Tower, 60 Leonard Avenue, 4KD477, Toronto, ON M5T 0S7, Canada; Department of Pharmaceutical Chemistry, University of Toronto, 144 College Street, Toronto, ON M5S 3M2, Canada. Electronic address:

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized, in part, by the misfolding, oligomerization and fibrillization of amyloid-β (Aβ). Evidence suggests that the mechanisms underpinning Aβ oligomerization and subsequent fibrillization are distinct, and may therefore require equally distinct therapeutic approaches. Prior studies have suggested that amide derivatives of ferulic acid, a natural polyphenol, may combat multiple AD pathologies, though its impact on Aβ aggregation is controversial. We designed and synthesized a systematic library of amide derivatives of ferulic acid and evaluated their anti-oligomeric and anti-fibrillary capacities independently. Azetidine tethered, triphenyl derivatives were the most potent anti-oligomeric agents (compound 2i: IC = 1.8 µM ± 0.73 µM); notably these were only modest anti-fibrillary agents (20.57% inhibition of fibrillization), and exemplify the poor correlation between anti-oligomeric/fibrillary activities. These data were subsequently codified in an in silico QSAR model, which yielded a strong predictive model of anti-Aβ oligomeric activity (κ = 0.919 for test set; κ = 0.737 for validation set).
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http://dx.doi.org/10.1016/j.bmc.2021.116247DOI Listing
June 2021

Design, synthesis, and biological evaluation of furosemide analogs as therapeutics for the proteopathy and immunopathy of Alzheimer's disease.

Eur J Med Chem 2021 Jun 2;222:113565. Epub 2021 Jun 2.

Krembil Research Institute, University Health Network, Toronto, Canada; Faculty of Pharmacy, University of Toronto, Ontario, Canada; Faculty of Medicine, University of Toronto, Ontario, Canada; Department of Chemistry, University of Toronto, Ontario, Canada. Electronic address:

β-Amyloid (Aβ) triggered proteopathic and immunopathic processes are a postulated cause of Alzheimer's disease (AD). Monomeric Aβ is derived from amyloid precursor protein, whereupon it aggregates into various assemblies, including oligomers and fibrils, which disrupt neuronal membrane integrity and induce cellular damage. Aβ is directly neurotoxic/synaptotoxic, but may also induce neuroinflammation through the concomitant activation of microglia. Previously, we have shown that furosemide is a known anthranilate-based drug with the capacity to downregulate the proinflammatory microglial M1 phenotype and upregulate the anti-inflammatory M2 phenotype. To further explore the pharmacologic effects of furosemide, this study reports a series of furosemide analogs that target both Aβ aggregation and neuroinflammation, thereby addressing the combined proteopathic-immunopathic pathogenesis of AD. Forty compounds were synthesized and evaluated. Compounds 3c, 3g, and 20 inhibited Aβ oligomerization; 33 and 34 inhibited Aβ fibrillization. 3g and 34 inhibited the production of TNF-α, IL-6, and nitric oxide, downregulated the expression of COX-2 and iNOS, and promoted microglial phagocytotic activity, suggesting dual activity against Aβ aggregation and neuroinflammation. Our data demonstrate the potential therapeutic utility of the furosemide-like anthranilate platform in the development of drug-like molecules targeting both the proteopathy and immunopathy of AD.
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http://dx.doi.org/10.1016/j.ejmech.2021.113565DOI Listing
June 2021

A Series of 2-((1-Phenyl-1H-imidazol-5-yl)methyl)-1H-indoles as Indoleamine 2,3-Dioxygenase 1 (IDO1) Inhibitors.

ChemMedChem 2021 Jul 26;16(14):2195-2205. Epub 2021 May 26.

Krembil Research Institute, University Health Network, 60 Leonard Avenue, Toronto, ON M5T 2S8, Canada.

Indoleamine 2,3-dioxygenase 1 (IDO1) is a promising therapeutic target in cancer immunotherapy and neurological disease. Thus, searching for highly active inhibitors for use in human cancers is now a focus of widespread research and development efforts. In this study, we report the structure-based design of 2-(5-imidazolyl)indole derivatives, a series of novel IDO1 inhibitors which have been designed and synthesized based on our previous study using N1-substituted 5-indoleimidazoles. Among these, we have identified one with a strong IDO1 inhibitory activity (IC =0.16 μM, EC =0.3 μM). Structural-activity relationship (SAR) and computational docking simulations suggest that a hydroxyl group favorably interacts with a proximal Ser167 residue in Pocket A, improving IDO1 inhibitory potency. The brain penetrance of potent compounds was estimated by calculation of the Blood Brain Barrier (BBB) Score and Brain Exposure Efficiency (BEE) Score. Many compounds had favorable scores and the two most promising compounds were advanced to a pharmacokinetic study which demonstrated that both compounds were brain penetrant. We have thus discovered a flexible scaffold for brain penetrant IDO1 inhibitors, exemplified by several potent, brain penetrant, agents. With this promising scaffold, we provide herein a basis for further development of brain penetrant IDO1 inhibitors.
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http://dx.doi.org/10.1002/cmdc.202100107DOI Listing
July 2021

Inter-individual variability in disease expression: the Tudor-Churchill spectrum.

Authors:
Donald F Weaver

Neurol Sci 2021 Mar 3. Epub 2021 Mar 3.

Krembil Brain Institute, University Health Network, Toronto, Ontario, M5T 0S8, Canada.

Henry VIII and Winston Churchill are clinically instructive when appreciating inter-individual variability in disease expression. Both were illustrious English leaders who as young men sustained multiple traumatic brain injuries, which may (or may not) have profoundly influenced their successes and failures of later years. Both men were admired and castigated; both struggled at various times with their bodies and their minds. Ultimately, one was initially a great man who descended as a flawed leader; the other was initially a flawed man who ascended as a great leader. Their similar yet contrasting case histories define the full spectrum ("Tudor-Churchill Spectrum") of inter-individual variability in response to brain disease or injury. The Tudor-Churchill spectrum is the immense variability between individual patients and reminds us that every person is unique, deserving of individualized thought, personalized diagnosis and tailored treatment.
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http://dx.doi.org/10.1007/s10072-021-05129-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7927761PMC
March 2021

Furazans in Medicinal Chemistry.

J Med Chem 2021 02 11;64(4):1786-1815. Epub 2021 Feb 11.

Treventis Corporation, Toronto, Ontario M5T 0S8, Canada.

Incorporation of heterocycles into drug molecules can enhance physical properties and biological activity. A variety of heterocyclic groups is available to medicinal chemists, many of which have been reviewed in detail elsewhere. Oxadiazoles are a class of heterocycle containing one oxygen and two nitrogen atoms, available in three isomeric forms. While the 1,2,4- and 1,3,4-oxadiazoles have seen widespread application in medicinal chemistry, 1,2,5-oxadiazoles (furazans) are less common. This Review provides a summary of the application of furazan-containing molecules in medicinal chemistry and drug development programs from analysis of both patent and academic literature. Emphasis is placed on programs that reached clinical or preclinical stages of development. The examples provided herein describe the pharmacology and biological activity of furazan derivatives with comparative data provided where possible for other heterocyclic groups and pharmacophores commonly used in medicinal chemistry.
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http://dx.doi.org/10.1021/acs.jmedchem.0c01901DOI Listing
February 2021

A Day That Changed Lives.

Authors:
Donald F Weaver

Neurology 2021 03 27;96(12):583-585. Epub 2021 Jan 27.

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http://dx.doi.org/10.1212/WNL.0000000000011547DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8032366PMC
March 2021

Furosemide as a Probe Molecule for the Treatment of Neuroinflammation in Alzheimer's Disease.

ACS Chem Neurosci 2020 12 23;11(24):4152-4168. Epub 2020 Nov 23.

Krembil Research Institute, University Health Network, Toronto, Canada.

The accumulation and deposition of β-amyloid (Aβ) is one postulated cause of Alzheimer's disease (AD). In addition to its direct toxicity on neurons, Aβ may induce neuroinflammation through the concomitant activation of microglia. Emerging evidence suggests that microglia-mediated neuroinflammation plays an important role in the pathogenesis of AD. As brain macrophages, microglia engulf misfolded-Aβ by phagocytosis. However, the accumulated toxic Aβ may paradoxically "hyper-activate" microglia into a neurotoxic proinflammatory and less phagocytotic phenotype, contributing to neuronal death. This study reports that the known drug furosemide is a potential probe molecule for reducing AD-neuroinflammation. Our data demonstrate that furosemide inhibits the secretion of proinflammatory TNF-α, IL-6, and nitric oxide; downregulates the mRNA level of and the protein expression of COX-2, iNOS; promotes phagocytic activity; and enhances the expression of anti-inflammatory IL-1RA and arginase. Our mechanism of action studies further demonstrate that furosemide reduces LPS-induced upregulation of endoplasmic reticulum (ER) stress marker genes, including , , , , and . These data support the observation that furosemide is a known drug with the capacity to downregulate the proinflammatory microglial M1 phenotype and upregulate the anti-inflammatory M2 phenotype, a potentially powerful and beneficial pharmacologic effect for inflammatory diseases such as AD.
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http://dx.doi.org/10.1021/acschemneuro.0c00445DOI Listing
December 2020

Amyloid beta is an early responder cytokine and immunopeptide of the innate immune system.

Authors:
Donald F Weaver

Alzheimers Dement (N Y) 2020 2;6(1):e12100. Epub 2020 Nov 2.

Department of Neurobiology Krembil Research Institute University Health Network University of Toronto Toronto Ontario Canada.

A molecular level conceptualization of the pathogenesis of Alzheimer's disease (AD) remains elusive with many competing hypotheses, particularly via proteopathic and immunopathic mechanisms. However, these need not be competitive. If amyloid beta (Aβ) is regarded as an "early responder cytokine," then proteopathic considerations become encompassed within an overarching hybrid proteopathic-immunopathic mechanism. As argued in this commentary, Aβ is in fact a molecular constituent of the innate immune system. Aβ is an antimicrobial peptide (AMP) functioning not only as a killer peptide, but also as a modulatory immunopeptide. Aβ satisfies the definition of a cytokine, exhibiting interdependency with other cytokines. Aβ also satisfies the functional definition of a chemokine, existing within the AMP-chemokine spectrum. Aβ, like conventional cytokines, both binds to and is released by microglial cells. Finally, Aβ interacts with the complement and Toll-like receptor systems analogously to established cytokines. Aβ may thus be regarded as an effector molecule of innate immunity.
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http://dx.doi.org/10.1002/trc2.12100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7606184PMC
November 2020

Small molecule therapeutics for COVID-19: repurposing of inhaled furosemide.

PeerJ 2020 7;8:e9533. Epub 2020 Jul 7.

Krembil Research Institute, University Health Network, Toronto, ON, Canada.

The novel coronavirus SARS-CoV-2 has become a global health concern. The morbidity and mortality of the potentially lethal infection caused by this virus arise from the initial viral infection and the subsequent host inflammatory response. The latter may lead to excessive release of pro-inflammatory cytokines, IL-6 and IL-8, as well as TNF-α ultimately culminating in hypercytokinemia ("cytokine storm"). To address this immuno-inflammatory pathogenesis, multiple clinical trials have been proposed to evaluate anti-inflammatory biologic therapies targeting specific cytokines. However, despite the obvious clinical utility of such biologics, their specific applicability to COVID-19 has multiple drawbacks, including they target only one of the multiple cytokines involved in COVID-19's immunopathy. Therefore, we set out to identify a small molecule with broad-spectrum anti-inflammatory mechanism of action targeting multiple cytokines of innate immunity. In this study, a library of small molecules endogenous to the human body was assembled, subjected to in silico molecular docking simulations and a focused in vitro screen to identify anti-pro-inflammatory activity via interleukin inhibition. This has enabled us to identify the loop diuretic furosemide as a candidate molecule. To pre-clinically evaluate furosemide as a putative COVID-19 therapeutic, we studied its anti-inflammatory activity on RAW264.7, THP-1 and SIM-A9 cell lines stimulated by lipopolysaccharide (LPS). Upon treatment with furosemide, LPS-induced production of pro-inflammatory cytokines was reduced, indicating that furosemide suppresses the M1 polarization, including IL-6 and TNF-α release. In addition, we found that furosemide promotes the production of anti-inflammatory cytokine products (IL-1RA, arginase), indicating M2 polarization. Accordingly, we conclude that furosemide is a reasonably potent inhibitor of IL-6 and TNF-α that is also safe, inexpensive and well-studied. Our pre-clinical data suggest that it may be a candidate for repurposing as an inhaled therapy against COVID-19.
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http://dx.doi.org/10.7717/peerj.9533DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7350920PMC
July 2020

Rotator drift: A sign of upper motor neuron leg weakness.

Authors:
Donald F Weaver

Clin Neurol Neurosurg 2020 10 13;197:106084. Epub 2020 Jul 13.

Krembil Research Institute, University Health Network, University of Toronto, 60 Leonard Avenue, Krembil Discovery Tower, 4th Floor, Toronto Western Hospital, Toronto, Ontario, M5T 2S8, Canada. Electronic address:

Objective: There are techniques for eliciting subtle arm weakness (pronator drift), but the accompanying abnormal reflex response (Hoffmann's sign) is of limited value; conversely, in the leg there are no techniques for eliciting subtle weakness equivalent to pronator drift, but there is a robust abnormal reflex response (Babinski's sign). Thus, there is a need to devise a simple and rapid technique for detecting leg weakness capable of being used in either cooperative or comatose patients.

Patients And Methods: Using three patient groups (discovery set, training set, test set) a technique for detecting upper motor neuron (UMN) lesion leg weakness was devised.

Results: With the patient supine, the examiner grasps both big toes, pointing them towards the ceiling with the long axis of the foot perpendicular to the bed; the patient is asked to maintain this position for 30 s. People with pyramidal tract weakness show external rotator drift on their weak side: on the normal side the foot is deviated 20-25⁰ from the perpendicular, on the paretic side the foot is deviated more than 30°.

Conclusion: This rotator drift sign is a simple method for detecting subtle UMN leg weakness. When combined with the pronator drift sign, these two signs constitute "pyramidal drift" signs for the bedside detection of UMN hemiparetic weakness.
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http://dx.doi.org/10.1016/j.clineuro.2020.106084DOI Listing
October 2020

Is Inhaled Furosemide a Potential Therapeutic for COVID-19?

Am J Med Sci 2020 09 1;360(3):216-221. Epub 2020 Jun 1.

Krembil Research Institute, University Health Network, Toronto, Ontario, Canada; Faculty of Medicine, University of Toronto, Medical Sciences Building, Toronto, Ontario, Canada. Electronic address:

The potentially lethal infection caused by the novel Severe Acute Respiratory Disease Coronavirus-2 (SARS-CoV-2) has evolved into a global crisis. Following the initial viral infection is the host inflammatory response that frequently results in excessive secretion of inflammatory cytokines (e.g., IL-6 and TNFα), developing into a self-targeting, toxic "cytokine storm" causing critical pulmonary tissue damage. The need for a therapeutic that is available immediately is growing daily but the de novo development of a vaccine may take years. Therefore, repurposing of approved drugs offers a promising approach to address this urgent need. Inhaled furosemide, a small molecule capable of inhibiting IL-6 and TNFα, may be an agent capable of treating the Coronavirus Disease 2019 cytokine storm in both resource-rich and developing countries. Furosemide is a "repurpose-able" small molecule therapeutics, that is safe, easily synthesized, handled, and stored, and is available in reasonable quantities worldwide.
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http://dx.doi.org/10.1016/j.amjms.2020.05.044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7833957PMC
September 2020

Anticonvulsant effects of sertraline: a case report.

Seizure 2020 08 22;80:1-2. Epub 2020 May 22.

Krembil Brain Institute, University Health Network, University of Toronto, 60 Leonard Avenue, Krembil Discovery Tower, Room 4KD477, Toronto, Ontario, Canada. Electronic address:

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http://dx.doi.org/10.1016/j.seizure.2020.05.016DOI Listing
August 2020

Effect of Cholesterol on the Structure of Networked Water at the Surface of a Model Lipid Membrane.

J Phys Chem B 2020 05 24;124(18):3686-3694. Epub 2020 Apr 24.

Krembil Research Institute, University Health Network, Toronto, Ontario M5T 0S8, Canada.

Using all-atom molecular dynamics simulations and network analysis, we investigated the effect of membrane cholesterol level on the structure of organized water at the interface between bulk water and a model lipid membrane. Irrespective of membrane cholesterol content, interfacial water structure is largely perturbed by the presence of the membrane surface due to water-phospholipid interactions, which deplete the chance of hydrogen bonding among water molecules. In contrast, the addition of cholesterol suppresses the disturbing effect of the membrane on water-water hydrogen bonding as cholesterol provides a more bulklike environment for the interfacial water molecules, as evidenced by enhancement of local water density, a reduction in their orientational bias, and increases in both the number of hydrogen bonds and the topological complexity of the hydrogen bond network.
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http://dx.doi.org/10.1021/acs.jpcb.0c01889DOI Listing
May 2020

Misfolded proteins as a therapeutic target in Alzheimer's disease.

Adv Protein Chem Struct Biol 2019 21;118:371-411. Epub 2019 Sep 21.

Krembil Research Institute, University Health Network, Toronto, ON, Canada; Departments of Medicine (Neurology), Chemistry and Pharmaceutical Sciences, University of Toronto, Toronto, ON, Canada.

For decades, Alzheimer's Disease (AD) was defined as a disorder of protein misfolding and aggregation. In particular, the extracellular peptide fragment: amyloid-β (Aβ), and the intracellular microtubule-associated protein: tau, were thought to initiate a neurodegenerative cascade which culminated in AD's progressive loss of memory and executive function. As such, both proteins became the focus of intense scrutiny, and served as the principal pathogenic target for hundreds of clinical trials. However, with varying efficacy, none of these investigations produced a disease-modifying therapy - offering patients with AD little recourse aside from transient, symptomatic medications. The near universal failure of clinical trials is unprecedented for a major research discipline. In part, this has motivated an increasing skepticism of the relevance of protein misfolding to AD's etiology. Several recent observations, principally the presence of significant protein pathologies in non-demented seniors, have lent credence to an apparent cursory role for Aβ and tau. Herein, we review both Aβ and tau, examining the processes from their biosynthesis to their pathogenesis and evaluate their vulnerability to medicinal intervention. We further attempt to reconcile the apparent failure of trials with the potential these targets hold. Ultimately, we seek to answer if protein misfolding is a viable platform in the pursuit of a disease-arresting strategy for AD.
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http://dx.doi.org/10.1016/bs.apcsb.2019.08.003DOI Listing
April 2020

The Brain Exposure Efficiency (BEE) Score.

ACS Chem Neurosci 2020 01 27;11(2):205-224. Epub 2019 Dec 27.

Krembil Research Institute , University Health Network , 60 Leonard Avenue , Toronto , Ontario M5T 2S8 , Canada.

The blood-brain barrier (BBB), composed of microvascular tight junctions and glial cell sheathing, selectively controls drug permeation into the central nervous system (CNS) by either passive diffusion or active transport. Computational techniques capable of predicting molecular brain penetration are important to neurological drug design. A novel prediction algorithm, termed the Brain Exposure Efficiency Score (BEE), is presented. BEE addresses the need to incorporate the role of trans-BBB influx and efflux active transporters by considering key brain penetrance parameters, namely, steady state unbound brain to plasma ratio of drug () and dose normalized unbound concentration of drug in brain (). BEE was devised using quantitative structure-activity relationships (QSARs) and molecular modeling studies on known transporter proteins and their ligands. The developed algorithms are provided as a user-friendly open source calculator to assist in optimizing a brain penetrance strategy during the early phases of small molecule molecular therapeutic design.
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http://dx.doi.org/10.1021/acschemneuro.9b00650DOI Listing
January 2020

Understanding the effect of nanoconfinement on the structure of water hydrogen bond networks.

Phys Chem Chem Phys 2019 Dec 26;21(47):26237-26250. Epub 2019 Nov 26.

Departments of Medicine, Chemistry, and Pharmaceutical Sciences, University of Toronto, Toronto, Ontario M5G 2C4, Canada.

Using an integrated approach of network theory and atomistic molecular dynamics simulations, we performed a detailed topological analysis on hydrogen bond networks of water confined between either two graphene sheets or two lipid bilayers to explore the structural perturbation of these networks under nanoscale confinement. The hydrogen bond network structure can be perturbed to a considerable extent when water is confined by such surfaces, yet no small-world behaviour is observed. The presence of ions also reduces the network complexity but its effect may be small depending on the type of confining surfaces. We developed an information flow model to evaluate the fluctuating nature of hydrogen bond networks and to characterise the dynamic, long-distance hydrogen-bonded chains in water. We found that the length and directionality of the hydrogen bond "trails" are highly susceptible to the type of confining surfaces and the degree of confinement. In particular, the endpoints of the hydrogen bond trails are not completely random in confined water, in which inherent distributions are determined by the density of water and the density of hydrogen bonds. This work forms the basis for the study of the pure effect of hydrogen bond network topology on various transport processes, such as proton transfer, that occur along a sequence of hydrogen bonds in a biochemical system. Our results suggest that a combined effect of the structure and lifetime of the hydrogen bond network of interfacial water may contribute to high lateral proton diffusivity at the surface of a lipid membrane.
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http://dx.doi.org/10.1039/c9cp05014kDOI Listing
December 2019

Impaired Spatial Learning and Memory in Middle-Aged Mice with Kindling-Induced Spontaneous Recurrent Seizures.

Front Pharmacol 2019 24;10:1077. Epub 2019 Sep 24.

Krembil Research Institute, University Health Network, Toronto, ON, Canada.

Temporal lobe epilepsy is the most common and often drug-resistant type of epilepsy in the adult and aging populations and has great diversity in etiology, electro-clinical manifestations, and comorbidities. Kindling through repeated brief stimulation of limbic structures is a commonly used model of temporal lobe epilepsy. Particularly, extended kindling can induce spontaneous recurrent seizures in several animal species. However, kindling studies in middle-aged, aging, or aged animals remain scarce, and currently, little is known about kindling-induced behavioral changes in middle-aged/aging animals. We therefore attempted to provide more information in this area using a mouse model of extended hippocampal kindling. We conducted experiments in middle-aged mice (C57BL/6, male, 12-14 months of age) to model new-onset epilepsy in adult/aging populations. Mice experienced twice daily hippocampal stimulations or handling manipulations for 60-70 days and then underwent continuous electroencephalogram (EEG)-video monitoring to detect spontaneous recurrent seizures. Extended kindled mice consistently exhibited spontaneous recurrent seizures with mean incidences of 6-7 events per day, and these seizures featured EEG discharges and corresponding convulsions. The handling control mice showed neither seizure nor aberrant EEG activity. The two groups of mice underwent the Morris water maze test of spatial learning and memory 1-2 weeks after termination of the kindling stimulation or handling manipulation. During visible platform trials, the kindled mice took a longer distance and required more time than the control mice to find the platform. During hidden platform trials, the kindled mice showed no improvement over 5-day trials in finding the platform whereas the control mice improved significantly. During probe tests in which the hidden platform was removed, the kindled mice spent less time than the controls searching in the correct platform location. There were no significant differences between the kindled and control mice with respect to swim speed or total locomotor activity in an open-field test. Together, these observations indicate that the extended kindled mice with spontaneous recurrent seizures are impaired in spatial learning and memory as assessed by the Morris water maze test. We postulate that the extended hippocampal kindling in middle-aged mice may help explore epileptogenic mechanisms and comorbidities potentially relevant to new-onset temporal lobe epilepsy in adult and aging patients. Limitations and confounds of our present experiments are discussed to improve future examinations of epileptic comorbidities in extended kindled mice.
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http://dx.doi.org/10.3389/fphar.2019.01077DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6768971PMC
September 2019

Effects of the Novel IDO Inhibitor DWG-1036 on the Behavior of Male and Female 3xTg-AD Mice.

Front Pharmacol 2019 24;10:1044. Epub 2019 Sep 24.

Department of Psychology and Neuroscience, Dalhousie University, Halifax, NS, Canada.

The kynurenine pathway metabolizes tryptophan into nicotinamide adenine dinucleotide, producing a number of intermediary metabolites, including 3-hydroxy kynurenine and quinolinic acid, which are involved in the neurodegenerative mechanisms that underlie Alzheimer's disease (AD). Indolamine 2,3-dioxygenase (IDO), the first and rate-limiting enzyme of this pathway, is increased in AD, and it has been hypothesized that blocking this enzyme may slow the progression of AD. In this study, we treated male and female 3xTg-AD and wild-type mice with the novel IDO inhibitor DWG-1036 (80 mg/kg) or vehicle (distilled water) from 2 to 6 months of age and then tested them in a battery of behavioral tests that measured spatial learning and memory (Barnes maze), working memory (trace fear conditioning), motor coordination and learning (rotarod), anxiety (elevated plus maze), and depression (tail suspension test). The 3xTg-AD mice treated with DWG-1036 showed better memory in the trace fear conditioning task and significant improvements in learning but poorer spatial memory in the Barnes maze. DWG-1036 treatment also ameliorated the behaviors associated with increased anxiety in the elevated plus maze and depression-like behaviors in the tail suspension test in 3xTg-AD mice. However, the effects of DWG-1036 treatment on the behavioral tasks were variable, and sex differences were apparent. In addition, high doses of DWG-1036 resulted in reduced body weight, particularly in females. Taken together, our results suggest that the kynurenine pathway is a promising target for treating AD, but more work is needed to determine the effective compounds, examine sex differences, and understand the side effects of the compounds.
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http://dx.doi.org/10.3389/fphar.2019.01044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6773979PMC
September 2019

The Blood-Brain Barrier (BBB) Score.

J Med Chem 2019 11 25;62(21):9824-9836. Epub 2019 Oct 25.

Krembil Research Institute , University Health Network , 60 Leonard Avenue , Toronto M5T 2S8 , Canada.

The blood-brain barrier (BBB) protects the brain from the toxic side effects of drugs and exogenous molecules. However, it is crucial that medications developed for neurological disorders cross into the brain in therapeutic concentrations. Understanding the BBB interaction with drug molecules based on physicochemical property space can guide effective and efficient drug design. An algorithm, designated "BBB Score", composed of stepwise and polynomial piecewise functions, is herein proposed for predicting BBB penetration based on five physicochemical descriptors: number of aromatic rings, heavy atoms, MWHBN (a descriptor comprising molecular weight, hydrogen bond donor, and hydrogen bond acceptors), topological polar surface area, and pKa. On the basis of statistical analyses of our results, the BBB Score outperformed (AUC = 0.86) currently employed MPO approaches (MPO, AUC = 0.61; MPO_V2, AUC = 0.67). Initial evaluation of physicochemical property space using the BBB Score is a valuable addition to currently available drug design algorithms.
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http://dx.doi.org/10.1021/acs.jmedchem.9b01220DOI Listing
November 2019

Inhibition of Pantothenate Synthetase by Analogs of β-Alanine Precursor Ineffective as an Antibacterial Strategy.

Chemotherapy 2019 5;64(1):22-27. Epub 2019 Jun 5.

Krembil Research Institute, University Health Network, Toronto, Ontario, Canada,

Background: Pantothenate, the fundamental precursor to coenzyme A, is required for optimal growth and virulence of microbial pathogens. It is synthesized by the enzyme-catalyzed condensation of β-alanine and pantoate, which has shown susceptibility to inhibition by analogs of its molecular constituents. Accordingly, analogs of β-alanine are gaining inquiry as potential antimicrobial chemotherapeutics.

Methods: We synthesized and evaluated 35 derivatives of β-alanine, substituted at the α, β, amine, and carboxyl sites, derived from in silico, dynamic molecular modeling to be potential competitive inhibitors of pantothenate synthetase. Employing the Clinical Laboratory Standards M7-A6 broth microdilution method, we tested these for inhibition of growth in Escherichia coli, Staphylococcus aureus, and Pseudomonas aeruginosa.

Results: All compounds proved entirely ineffective in all species tested, with no inhibition of growth being observed up to 200 µM/mL.

Conclusions: Upon revision of the literature, we conclude that high enzyme selectivity or external salvage mechanisms may render this strategy futile against most bacteria.
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http://dx.doi.org/10.1159/000499899DOI Listing
July 2019

Understanding Water Structure in an Ion-Pair Solvation Shell in the Vicinity of a Water/Membrane Interface.

J Phys Chem B 2019 05 1;123(18):3945-3954. Epub 2019 May 1.

Krembil Research Institute , University Health Network , Toronto , Ontario M5T 0S8 , Canada.

The anomalous properties of interfacial water at the surface of a lipid membrane and their implications on nearby chemical processes are well recognized. However, we have found that ion pairing thermodynamics may not be significantly affected by interfacial water in a classical, nonpolarizable force field. To trace the root cause of such a counterintuitive finding, we performed atomistic molecular dynamics simulations to explore the impact of polarizable interactions and characterize the hydration structure of a sodium chloride (NaCl) ion pair at the surface of a model lipid membrane and in a bulk phase. Our study reveals that the effect of the aqueous interface on the first solvation shell of the ion pair and thus on the ion pairing thermodynamics becomes more pronounced in the polarizable model, and that the free energy profile along the interionic distance cannot capture the difference in the degree of solvent participation in ion pairing at the water/membrane interface. This study also forms the basis for the future design of a reaction coordinate that takes the behavior of the interfacial water into account.
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http://dx.doi.org/10.1021/acs.jpcb.9b01331DOI Listing
May 2019

In the Alzheimer waiting room.

Authors:
Donald F Weaver

CMAJ 2018 08;190(33):E989-E990

Krembil Research Institute, University Health Network, University of Toronto, Toronto, Ont.

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http://dx.doi.org/10.1503/cmaj.180320DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6102110PMC
August 2018

Nutrients in Alzheimer's Disease: The Interaction of Diet, Drugs and Disease.

Can J Neurol Sci 2019 01;46(1):23-34

Krembil Research Institute, University Health Network, Toronto, ON, Canada.

In recent decades, clinical trials in Alzheimer's disease (AD) have failed at an unprecedented rate. The etiology of AD has since come under renewed scrutiny, both to elucidate the underlying pathologies and to identify novel therapeutic strategies. Here, diet has emerged as a potential causative/protective agent. A variety of nutrients, including lipids, minerals, vitamins, antioxidants and sugars as well as broader dietary patterns and microbiotal interactions have demonstrated associations with AD. Although clinical trials have yet to definitively implicate any singular dietary element as therapeutic or causative, it is apparent that dietary preferences, likely in complex synergies, may influence the risk, onset and course of AD. This review catalogs the impact of major dietary elements on AD. It further examines an unexplored reciprocal association where AD may modulate diet, as well as how potential therapeutics may complicate these interactions. In doing so, we observe diet may have profound effects on the outcome of a clinical trial, either as a confounder of a drug/disease interaction or as a generally disruptive covariate. We therefore conclude that future clinical trials in AD should endeavor to control for diet, either in study design or subsequent analyses.
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http://dx.doi.org/10.1017/cjn.2018.353DOI Listing
January 2019

The hidden variables problem in Alzheimer's disease clinical trial design.

Alzheimers Dement (N Y) 2018 13;4:628-635. Epub 2018 Nov 13.

Krembil Research Institute, University Health Network, Toronto, ON, Canada.

As the leading cause of dementia worldwide, Alzheimer's disease has garnered intense academic and clinical interest. Yet, trials in search of a disease-modifying therapy have failed overwhelmingly. We suggest that, in part, this may be attributable to the influence of disruptive variables inherent to the framework of a clinical trial. Specifically, we observe that everyday factors such as diet, education, mental exertion, leisure participation, multilingualism, sleep, trauma, and physical activity, as well as clinical/study parameters including environment, family coaching, concurrent medications, and illnesses may serve as potent confounders, disruptors, or sources of bias to an otherwise significant drug-disease interaction. This perspective briefly summarizes the potential influence of these hidden variables on the outcomes of clinical trials and suggests strategies to abate their impact.
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http://dx.doi.org/10.1016/j.trci.2018.09.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6260222PMC
November 2018

Point-of-care brain injury evaluation of conscious awareness: wide scale deployment of portable HCS EEG evaluation.

Neurosci Conscious 2018 23;2018(1):niy011. Epub 2018 Nov 23.

Faculty of Applied Sciences (Engineering Science and Computing Science), Simon Fraser University, Canada.

Survivors of severe brain injury may remain in a decreased state of conscious awareness for an extended period of time. Clinical scales are used to describe levels of consciousness but rely on behavioural responses, precipitating misdiagnosis. We have previously utilized event-related potentials (ERPs) to circumvent reliance on behavioural responses. However, practical implementation barriers limit the clinical utility of ERP assessment at point-of-care (POC). To address this challenge, we developed the Halifax Consciousness Scanner (HCS)-a rapid, semi-automated electroencephalography system. The current study evaluated: (i) HCS feasibility in sub-acute, POC settings nationwide; (ii) ERP P300 responses in patients with acquired brain injury versus healthy controls; and (iii) correlations within and between clinical measures and P300 latencies. We assessed 28 patients with severe, chronic impairments from brain injuries and contrasted the results with healthy control data ( = 100). Correlational analyses examined relationships between P300 latencies and the commonly used clinical scales. P300 latencies were significantly delayed in patients compared to healthy controls ( < 0.05). Clinical assessment scores were significantly inter-correlated and correlated significantly with P300 latencies ( < 0.05). In sub-acute and chronic care settings, the HCS provided a physiological measure of neurocognitive processing at POC for patients with severe acquired brain injury, including those with disorders of consciousness.
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http://dx.doi.org/10.1093/nc/niy011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6251986PMC
November 2018

Concussion, Cagney, Captains of the Clouds.

Authors:
Donald F Weaver

Can J Neurol Sci 2018 11;45(6):682-685

Krembil Research Institute,University Health Network,Toronto,Ontario,Canada.

The case of James Cagney adds interesting details to the history of concussion. It is underappreciated that a movie-star of Cagney's stature incurred multiple concussions over many years. Moreover, the fact that he sustained one of these concussions in Canada while filming Captains of the Clouds, a major Hollywood film, is essentially unknown, and was seldom discussed by Cagney despite his willingness to discuss his many other concussions. The scene showing this concussion was left in the final released version of the movie, making it one of the earliest filmed concussions and the first concussion ever filmed in Technicolor.
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http://dx.doi.org/10.1017/cjn.2018.332DOI Listing
November 2018

Phenylindanes in Brewed Coffee Inhibit Amyloid-Beta and Tau Aggregation.

Front Neurosci 2018 12;12:735. Epub 2018 Oct 12.

Department of Fundamental Neurobiology, Krembil Research Institute, University Health Network, Toronto, ON, Canada.

Coffee consumption has been correlated with a decreased risk of developing Alzheimer's disease (AD) and Parkinson's disease (PD), but the mechanism by which coffee may provide neuroprotection in humans is not fully understood. We hypothesized that compounds found in brewed coffee may elicit neuroprotective effects by inhibiting the aggregation of amyloid-beta (Aβ) and tau (AD) or α-synuclein (PD). Three instant coffee extracts (light roast, dark roast, decaffeinated dark roast) and six coffee components [caffeine (), chlorogenic acid (), quinic acid (), caffeic acid (), quercetin (), and phenylindane ()] were investigated for their ability to inhibit the fibrillization of Aβ and tau proteins using thioflavin T (ThT) and thioflavin S (ThS) fluorescence assays, respectively. Inhibition of Aβ and α-synuclein oligomerization was assessed using ELISA assays. All instant coffee extracts inhibit fibrillization of Aβ and tau, and promote α-synuclein oligomerization at concentrations above 100 μg/mL. Dark roast coffee extracts are more potent inhibitors of Aβ oligomerization (IC ca. 10 μg/mL) than light roast coffee extract (IC = 40.3 μg/mL), and pure caffeine () has no effect on Aβ, tau or α-synuclein aggregation. Coffee components , and inhibit the fibrillization of Aβ at 100 μM concentration, yet only inhibits Aβ oligomerization (IC = 10.3 μM). - have no effect on tau fibrillization. Coffee component , however, is a potent inhibitor of both Aβ and tau fibrillization, and also inhibits Aβ oligomerization (IC = 42.1 μM). Coffee components and promote the aggregation of α-synuclein at concentrations above 100 μM; no other coffee components affect α-synuclein oligomerization. While the neuroprotective effect of coffee consumption is likely due to a combination of factors, our data suggest that inhibition Aβ and tau aggregation by phenylindane (formed during the roasting of coffee beans, higher quantities found in dark roast coffees) is a plausible mechanism by which coffee may provide neuroprotection. The identification of as a dual-inhibitor of both Aβ and tau aggregation is noteworthy, and to our knowledge this is the first report of the aggregation inhibition activity of .
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http://dx.doi.org/10.3389/fnins.2018.00735DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6194148PMC
October 2018

Topically applied linoleic/linolenic acid for chronic migraine.

J Clin Neurosci 2018 Dec 11;58:200-201. Epub 2018 Oct 11.

Krembil Research Institute, University Health Network, University of Toronto, Toronto, Ontario, Canada. Electronic address:

The topical application of linoleic and linolenic acids is a potential prophylactic approach to migraine via an anti-inflammatory mechanism. We present a 45-year-old woman with chronic migraine without aura. Previous use of abortive or prophylactic therapies including sumatriptan, amitriptyline and topiramate had failed due to lack of efficacy or side-effects, especially vomiting. In search of a topical agent she performed an n-of-1 trial comparing application of linoleic acid (safflower oil) versus oleic acid (olive oil) for migraine relief. She found safflower oil to be effective. Topically applied safflower oil rich in linoleic and linolenic acids may offer a safe, easily applied, well-tolerated, effective anti-inflammatory approach for the prophylactic treatment of chronic migraine.
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http://dx.doi.org/10.1016/j.jocn.2018.10.013DOI Listing
December 2018