Lisa M. Eubanks

Bio: Lisa M. Eubanks is an academic researcher from Scripps Research Institute. The author has contributed to research in topics: Medicine & Opioid. The author has an hindex of 15, co-authored 34 publications receiving 1025 citations.

A Molecular Link between the Active Component of Marijuana and Alzheimer's Disease Pathology

Abstract: Alzheimer's disease is the leading cause of dementia among the elderly, and with the ever-increasing size of this population, cases of Alzheimer's disease are expected to triple over the next 50 years. Consequently, the development of treatments that slow or halt the disease progression have become imperative to both improve the quality of life for patients as well as reduce the health care costs attributable to Alzheimer's disease. Here, we demonstrate that the active component of marijuana, Δ 9 -tetrahydrocannabinol (THC), competitively inhibits the enzyme acetylcholinesterase (AChE) as well as prevents AChE-induced amyloid β-peptide (Aβ) aggregation, the key pathological marker of Alzheimer's disease. Computational modeling of the THC-AChE interaction revealed that THC binds in the peripheral anionic site of AChE, the critical region involved in amyloidgenesis. Compared to currently approved drugs prescribed for the treatment of Alzheimer's disease, THC is a considerably superior inhibitor of Aβ aggregation, and this study provides a previously unrecognized molecular mechanism through which cannabinoid molecules may directly impact the progression of this debilitating disease.

Technological advancements for the detection of and protection against biological and chemical warfare agents

Abstract: There is a growing need for technological advancements to combat agents of chemical and biological warfare, particularly in the context of the deliberate use of a chemical and/or biological warfare agent by a terrorist organization. In this tutorial review, we describe methods that have been developed both for the specific detection of biological and chemical warfare agents in a field setting, as well as potential therapeutic approaches for treating exposure to these toxic species. In particular, nerve agents are described as a typical chemical warfare agent, and the two potent biothreat agents, anthrax and botulinum neurotoxin, are used as illustrative examples of potent weapons for which countermeasures are urgently needed.

An in vitro and in vivo disconnect uncovered through high-throughput identification of botulinum neurotoxin A antagonists.

Abstract: Among the agents classified as "Category A" by the U.S. Centers for Disease Control and Prevention, botulinum neurotoxin (BoNT) is the most toxic protein known, with microgram quantities of the protein causing severe morbidity and mortality by oral or i.v. routes. Given that this toxin easily could be used in a potential bioterrorist attack, countermeasures urgently are needed to counteract the pathophysiology of BoNT. At a molecular level, BoNT exerts its paralytic effects through intracellular cleavage of vesicle docking proteins and subsequent organism-wide autonomic dysfunction. In an effort to identify small molecules that would disrupt the interaction between the light-chain metalloprotease of BoNT serotype A and its cognate substrate, a multifaceted screening effort was undertaken. Through the combination of in vitro screening against an optimized variant of the light chain involving kinetic analysis, cellular protection assays, and in vivo mouse toxicity assays, molecules that prevent BoNT/A-induced intracellular substrate cleavage and extend the time to death of animals challenged with lethal toxin doses were identified. Significantly, the two most efficacious compounds in vivo showed less effective activity in cellular assays intended to mimic BoNT exposure; indeed, one of these compounds was cytotoxic at concentrations three orders of magnitude below its effective dose in animals. These two lead compounds have surprisingly simple molecular structures and are readily amenable to optimization efforts for improvements in their biological activity. The findings validate the use of high-throughput screening protocols to define previously unrecognized chemical scaffolds for the development of therapeutic agents to treat BoNT exposure.

Repositioning of an existing drug for the neglected tropical disease Onchocerciasis

Abstract: Onchocerciasis, or river blindness, is a neglected tropical disease caused by the filarial nematode Onchocerca volvulus that affects more than 37 million people, mainly in third world countries. Currently, the only approved drug available for mass treatment is ivermectin, however, drug resistance is beginning to emerge, thus, new therapeutic targets and agents are desperately needed to treat and cure this devastating disease. Chitin metabolism plays a central role in invertebrate biology due to the critical structural function of chitin for the organism. Taken together with its absence in mammals, targeting chitin is an appealing therapeutic avenue. Importantly, the chitinase OvCHT1 from O. volvulus was recently discovered, however, its exact role in the worm's metabolism remains unknown. A screening effort against OvCHT1 was conducted using the Johns Hopkins Clinical Compound Library that contains over 1,500 existing drugs. Closantel, a veterinary anthelmintic with known proton ionophore activities, was identified as a potent and specific inhibitor of filarial chitinases, an activity not previously reported for this compound. Notably, closantel was found also to completely inhibit molting of O. volvulus infective L3 stage larvae. Closantel appears to target two important biochemical processes essential to filarial parasites. To begin to unravel closantel's effects, a retro-fragment-based study was used to define structural elements critical for closantel's chitinase inhibitor function. As resources towards the development of new agents that target neglected tropical diseases are scant, the finding of an existing drug with impact against O. volvulus provides promise in the hunt for new therapies against river blindness.

Bimodal modulation of the botulinum neurotoxin protein-conducting channel

Abstract: Clostridium botulinum neurotoxin (BoNT) is the causative agent of botulism, a neuroparalytic disease. We describe here a semisynthetic strategy to identify inhibitors based on toosendanin, a traditional Chinese medicine reported to protect from BoNT intoxication. Using a single molecule assay of BoNT serotypes A and E light chain (LC) translocation through the heavy chain (HC) channel in neurons, we discovered that toosendanin and its tetrahydrofuran analog selectively arrest the LC translocation step of intoxication with subnanomolar potency, and increase the unoccluded HC channel propensity to open with micromolar efficacy. The inhibitory profile on LC translocation is accurately recapitulated in 2 different BoNT intoxication assays, namely the mouse protection and the primary rat spinal cord cell assays. Toosendanin has an unprecedented dual mode of action on the protein-conducting channel acting as a cargo-dependent inhibitor of translocation and as cargo-free channel activator. These results imply that the bimodal modulation by toosendanin depends on the dynamic interactions between channel and cargo, highlighting their tight interplay during the progression of LC transit across endosomes.

Taming THC: potential cannabis synergy and phytocannabinoid‐terpenoid entourage effects

Abstract: Tetrahydrocannabinol (THC) has been the primary focus of cannabis research since 1964, when Raphael Mechoulam isolated and synthesized it. More recently, the synergistic contributions of cannabidiol to cannabis pharmacology and analgesia have been scientifically demonstrated. Other phytocannabinoids, including tetrahydrocannabivarin, cannabigerol and cannabichromene, exert additional effects of therapeutic interest. Innovative conventional plant breeding has yielded cannabis chemotypes expressing high titres of each component for future study. This review will explore another echelon of phytotherapeutic agents, the cannabis terpenoids: limonene, myrcene, α-pinene, linalool, β-caryophyllene, caryophyllene oxide, nerolidol and phytol. Terpenoids share a precursor with phytocannabinoids, and are all flavour and fragrance components common to human diets that have been designated Generally Recognized as Safe by the US Food and Drug Administration and other regulatory agencies. Terpenoids are quite potent, and affect animal and even human behaviour when inhaled from ambient air at serum levels in the single digits ng·mL−1. They display unique therapeutic effects that may contribute meaningfully to the entourage effects of cannabis-based medicinal extracts. Particular focus will be placed on phytocannabinoid-terpenoid interactions that could produce synergy with respect to treatment of pain, inflammation, depression, anxiety, addiction, epilepsy, cancer, fungal and bacterial infections (including methicillin-resistant Staphylococcus aureus). Scientific evidence is presented for non-cannabinoid plant components as putative antidotes to intoxicating effects of THC that could increase its therapeutic index. Methods for investigating entourage effects in future experiments will be proposed. Phytocannabinoid-terpenoid synergy, if proven, increases the likelihood that an extensive pipeline of new therapeutic products is possible from this venerable plant. LINKED ARTICLES This article is part of a themed issue on Cannabinoids in Biology and Medicine. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2011.163.issue-7

Destruction and Detection of Chemical Warfare Agents

Abstract: 1. Scope of Article and Previous Related Reviews 5346 2. Introduction 5346 2.1. Destruction 5347 2.2. Sensing 5347 2.3. Historical Context 5348 2.3.1. Brief History and Molecular Structure 5348 2.4. Related Compounds and Nomenclature 5348 2.4.1. Phosphorus(V) Parent Compounds and Fundamental Chemistry 5348 2.4.2. Pesticides 5349 2.4.3. Simulants 5349 2.4.4. Decomposition Products 5350 2.5. Toxicology 5351 2.5.1. Acetylcholine Esterase (AChE) Inhibition 5351 2.5.2. Endocannabinoid System Activation 5352 2.6. Critical Needs To Decontaminate and Detect 5353 2.7. Treaties and Conventions 5354 3. Stockpile Destruction 5355 3.1. Agent Storage 5355 3.2. Protection Protocols and Logistics 5355 3.3. Background 5355 3.4. Methods Currently Employed 5355 3.4.1. Incineration 5355 3.4.2. Neutralization by Base Hydrolysis 5356 4. Decomposition Reactions 5357 4.1. Hydrolysis 5357 4.2. Autocatalytic Hydrolysis or Hydrolysis Byproducts 5358 4.3. Use of Peroxide 5359 4.4. Oxidation with Bleach and Related Reagents 5360 4.5. Alkoxide as Nucleophile 5360 4.5.1. Basic Media 5360 4.5.2. Metal-Catalyzed Reactions 5361 4.5.3. Metal-Assisted Reactions 5363 4.5.4. Biotechnological Degradation 5363 4.5.5. Cyclodextrin-Assisted Reactions 5370 4.6. Halogen as the Nucleophile 5370 4.6.1. Use of BrOx 5370 4.6.2. Use of Other Halogens 5371 4.6.3. Use of Group 13 Chelates 5371 4.7. Surface Chemistry 5371 4.7.1. Bare Metals and Solid Nanoparticles 5371 4.7.2. Metal Oxides 5371 4.7.3. Representative Elements 5372 4.7.4. d-Block (Groups 4 10) 5373 4.7.5. Solid Metal Oxides of Group 3 and the Lanthanides 5375 4.7.6. Porous Silicon and Related Systems 5375 4.7.7. Zeolites 5375 4.7.8. Comparative IR Data 5375 4.8. Other Types of Systems 5375 5. Decontamination 5376 5.1. Overview: Ability to React with All Types of Agents, Ease of Application, and Compatibility with Treated Objects 5376 6. Agent Fate and Disposal 5378 6.1. Indoor 5378 6.2. Concrete and Construction Surfaces 5378 6.3. Landfills 5379 7. Sensing and Detection 5379 7.1. Possible Metal Ion Binding Modes in Solution 5379 7.1.1. Early Reports of Phosph(on)ate [R3PdO 3 3 3M nþ] Interactions (R= Alkyl, Alkoxyl) 5380 7.1.2. Coordination Chemistry of Downstream Non-P-Containing Products of Decomposition 5380 7.2. Colorimetric Detection 5381 7.3. Chemiluminescence: Fluorescence and Phosphorescence 5382 7.3.1. Lanthanide-Based Catalysts 5382 7.3.2. Organometallic-Based Sensors 5382 7.3.3. Organic Design 5382 7.3.4. Biologically-Based Luminescence Detection 5382 7.3.5. Polymer and Bead Supports 5382 7.4. Porous Silicon 5383 7.5. Carbon Nanotubes 5383

Exploiting Quorum Sensing To Confuse Bacterial Pathogens

Abstract: Cell-cell communication, or quorum sensing, is a widespread phenomenon in bacteria that is used to coordinate gene expression among local populations. Its use by bacterial pathogens to regulate genes that promote invasion, defense, and spread has been particularly well documented. With the ongoing emergence of antibiotic-resistant pathogens, there is a current need for development of alternative therapeutic strategies. An antivirulence approach by which quorum sensing is impeded has caught on as a viable means to manipulate bacterial processes, especially pathogenic traits that are harmful to human and animal health and agricultural productivity. The identification and development of chemical compounds and enzymes that facilitate quorum-sensing inhibition (QSI) by targeting signaling molecules, signal biogenesis, or signal detection are reviewed here. Overall, the evidence suggests that QSI therapy may be efficacious against some, but not necessarily all, bacterial pathogens, and several failures and ongoing concerns that may steer future studies in productive directions are discussed. Nevertheless, various QSI successes have rightfully perpetuated excitement surrounding new potential therapies, and this review highlights promising QSI leads in disrupting pathogenesis in both plants and animals.

Applying low-molecular weight supramolecular gelators in an environmental setting – self-assembled gels as smart materials for pollutant removal

Abstract: This review explores supramolecular gels as materials for environmental remediation. These soft materials are formed by self-assembling low-molecular-weight building blocks, which can be programmed with molecular-scale information by simple organic synthesis. The resulting gels often have nanoscale ‘solid-like’ networks which are sample-spanning within a ‘liquid-like’ solvent phase. There is intimate contact between the solvent and the gel nanostructure, which has a very high effective surface area as a result of its dimensions. As such, these materials have the ability to bring a solid-like phase into contact with liquids in an environmental setting. Such materials can therefore remediate unwanted pollutants from the environment including: immobilisation of oil spills, removal of dyes, extraction of heavy metals or toxic anions, and the detection or removal of chemical weapons. Controlling the interactions between the gel nanofibres and pollutants can lead to selective uptake and extraction. Furthermore, if suitably designed, such materials can be recyclable and environmentally benign, while the responsive and tunable nature of the self-assembled network offers significant advantages over other materials solutions to problems caused by pollution in an environmental setting.