A novel biomechanical analysis of gait changes in the MPTP mouse model of Parkinson's disease.
Locomotion; MPTP; Behavior; Gait; Gender-bias
Parkinson's disease (PD) is an age-associated neurodegenerative disorder hallmarked by a loss of mesencephalic dopaminergic neurons. Accurate recapitulation of the PD movement phenotype in animal models of the disease is critical for understanding disease etiology and developing novel therapeutic treatments. However, most existing behavioral assays currently applied to such animal models fail to adequately detect and subsequently quantify the subtle changes associated with the progressive stages of PD. In this study, we used a video-based analysis system to develop and validate a novel protocol for tracking locomotor performance in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. We anticipated that (1) treated mice should use slower, shorter, and less frequent strides and (2) that gait deficits should monotonically increase following MPTP administration, as the effects of neurodegeneration become manifest. Video-based biomechanical analyses, utilizing behavioral measures motivated by the comparative biomechanics literature, were used to quantify gait dynamics over a seven-day period following MPTP treatment. Analyses revealed shuffling behaviors consistent with the gait symptoms of advanced PD in humans. Here we also document dramatic gender-based differences in locomotor performance during the progression of the MPTP-induced lesion, despite male and female mice showing similar losses of striatal dopaminergic cells following MPTP administration. Whereas female mice appeared to be protected against gait deficits, males showed multiple changes in gait kinematics, consistent with the loss of locomotor agility and stability. Overall, these data show that the novel video analysis protocol presented here is a robust method capable of detecting subtle changes in gait biomechanics in a mouse model of PD. Our findings indicate that this method is a useful means by which to easily and economically screen preclinical therapeutic compounds for protecting against or reversing neuropathology associated with PD neurodegeneration.
Geldenhuys Werner J; Guseman Tamara L; Pienaar Ilse S; Dluzen Dean E; Young Jesse W
PeerJ
2015
1905-07
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.7717/peerj.1175" target="_blank" rel="noreferrer noopener">10.7717/peerj.1175</a>
Evolution of a Natural Products and Nutraceuticals Course in the Pharmacy Curriculum.
Humans; *Biological Products/therapeutic use; *Clinical Competence; *Dietary Supplements; course curriculum; Curriculum/*trends; dietary supplements; Educational Measurement/methods; evidence-based medicine; herbal products; nutraceuticals; Education; *Students; Pharmacy; Pharmacy/methods/*trends
Objective. To develop, implement, and modify a required, second-year pharmacy course that provides an understanding of the scientific, therapeutic, and clinical principles, as well as the evidence-based medicine underlying the use of natural products. Design. A 28-hour, multi-faculty course was developed and offered in 2008. The course was modified over the years to enhance students' practice skills in the use of natural products. A course evaluation and survey were administered to assess the students' opinions. Assessment. Students performed well in the course and provided favorable evaluations, especially for the latest offering. Students reported significantly improved skills in providing advice to patients regarding the use of natural products. Conclusion. The course increased the students' knowledge and application of information and counseling skills regarding natural products.
Geldenhuys Werner J; Cudnik Michelle L; Krinsky Daniel L; Darvesh Altaf S
American journal of pharmaceutical education
2015
2015-08
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.5688/ajpe79682" target="_blank" rel="noreferrer noopener">10.5688/ajpe79682</a>
Molecular determinants of blood-brain barrier permeation.
Humans; Animals; *Drug Delivery Systems; Blood-Brain Barrier/*metabolism; Brain/drug effects; Computer Simulation; high-throughput; in silico; logPS; nutrient transporters; Permeability; virtual screening
The blood-brain barrier (BBB) is a microvascular unit which selectively regulates the permeability of drugs to the brain. With the rise in CNS drug targets and diseases, there is a need to be able to accurately predict a priori which compounds in a company database should be pursued for favorable properties. In this review, we will explore the different computational tools available today, as well as underpin these to the experimental methods used to determine BBB permeability. These include in vitro models and the in vivo models that yield the dataset we use to generate predictive models. Understanding of how these models were experimentally derived determines our accurate and predicted use for determining a balance between activity and BBB distribution.
Geldenhuys Werner J; Mohammad Afroz S; Adkins Chris E; Lockman Paul R
Therapeutic delivery
2015
1905-7
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.4155/tde.15.32" target="_blank" rel="noreferrer noopener">10.4155/tde.15.32</a>
Exploring Adenosine Receptor Ligands: Potential Role in the Treatment of Cardiovascular Diseases.
Humans; Animals; Protein Binding; Signal Transduction; atherosclerosis; *Drug Discovery; *Ligands; Adenosine/metabolism; cardiac death; Cardiovascular Diseases/drug therapy/metabolism; Cardiovascular System/metabolism; Hydrogen Bonding; Molecular Structure; myocardial infarction; Structure-Activity Relationship; vascular tone; Receptors; Models; Molecular; Purinergic P1/*chemistry/*metabolism
Cardiovascular diseases remain the number one diseases affecting patients' morbidity and mortality. The adenosine receptors are G-protein coupled receptors which have been of interest for drugs target for the treatment of multiple diseases ranging from cardiovascular to neurological. Adenosine receptors have been connected to several biological pathways affecting the physiology and pathology of the cardiovascular system. In this review, we will cover the different adenosine receptor ligands that have been identified to interact with adenosine receptors and affect the vascular system. These ligands will be evaluated from clinical as well as medicinal chemistry perspectives with more emphasis on how structural changes in structure translate into ligand potency and efficacy. Adenosine receptors represent a novel therapeutic target for development of treatment options treating a wide variety of diseases, including vascular disease and obesity.
Geldenhuys Werner J; Hanif Ahmad; Yun June; Nayeem Mohammed A
Molecules (Basel, Switzerland)
2017
2017-06
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.3390/molecules22060917" target="_blank" rel="noreferrer noopener">10.3390/molecules22060917</a>
The blood-brain barrier choline transporter.
Humans; Animals; Drug Delivery Systems/*methods; Blood-Brain Barrier/drug effects/*metabolism; Membrane Transport Proteins/*metabolism; Organic Cation Transport Proteins/metabolism; Organic Cation Transporter 1/metabolism; Organic Cation Transporter 2
Drug delivery to the brain is made difficult by the blood-brain barrier (BBB) which is selectively permeable to organic drug compounds. Several membrane solute and nutrient transporters are expressed in the BBB vasculature, which may be utilized as mechanism of delivery of drugs to the brain. Of interest to us, are the organic cation transporters which could be used to transport cationic compounds into the CNS. In this mini-review, we will review the current understanding of the structural requirements for designing compounds which could effectively use organic cation transporters (OCT). For the first time, structural requirements for both OCT1 and OCT2 versus the BBB choline transporter (BBBCHT) are discussed and compared. The information gained here could increase the success rate in successful CNS drug delivery and therapeutics.
Geldenhuys Werner J; Allen David D
Central nervous system agents in medicinal chemistry
2012
2012-06
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.2174/187152412800792670" target="_blank" rel="noreferrer noopener">10.2174/187152412800792670</a>
Serotonin 5-HT6 receptor antagonists for the treatment of Alzheimer's disease.
Humans; Molecular Structure; Serotonin/*metabolism; Alzheimer Disease/*drug therapy; Serotonin Antagonists/chemistry/*therapeutic use; Nootropic Agents/chemistry/*therapeutic use; Receptors
Recently, the serotonin 5-HT(6) receptor has been identified as a drug target for attenuating cognitive deficits associated with Alzheimer's disease (AD). Additionally, this receptor may also play a role in schizophrenia, anxiety and obesity. Reports in the literature suggest that the production of selective antagonists for the 5-HT(6) receptor has increased during the last 10 years, with some compounds currently in clinical trials for the treatment of AD. In this review, we will address the rationale for using 5-HT(6) receptor antagonists in AD, as well as report on current advances in the understanding of the structure-activity relationships required to synthesize 5-HT(6) receptor antagonists.
Geldenhuys Werner J; Van der Schyf Cornelis J
Current topics in medicinal chemistry
2008
2008
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.2174/156802608785161420" target="_blank" rel="noreferrer noopener">10.2174/156802608785161420</a>
Identification of Novel Agents for the Treatment of Brain Metastases of Breast Cancer.
Female; Humans; Animals; Mice; Apoptosis; Cell Line; ADME; Antineoplastic Agents/*therapeutic use; brain cancer; Brain Neoplasms/*drug therapy/pathology/*secondary; Breast Neoplasms/*pathology; chemotherapy; CNS; distribution; drug discovery; Drug resistance; Tumor
BACKGROUND: Brain cancer from metastasized breast cancer has a high mortality rate in women. The treatment of lesions is hampered in large part by the blood-brain barrier (BBB), which prevents adequate distribution of anti-cancer compounds to brain metastases. METHOD: In this study we used a novel screening method to identify candidate molecules that are well-suited to utilizing the BBB choline transporter for distribution into the brain parenchyma. RESULTS: From our screen we identified two compounds, Ch-1 and Ch-2 that were able to reduce the brain tumor burden in a murine mouse model of brain metastasis of breast cancer. These compounds also significantly increased the survival of mice by more than 10 days. Mechanistic studies indicated that Ch-1 is able to prevent the activation of the pro-survival mitogen-activated kinases (MAPKs) by osteoactivin (OA; Glycoprotein nonmetastatic melanoma protein B GPNMB). CONCLUSION: The results from this study show that nutrient transporter virtual screening is a viable novel alternative to traditional drug screening programs to identify anti-cancer compounds for the treatment of brain cancers.
Venishetty Vinay K; Geldenhuys Werner J; Terell-Hall Tori B; Griffith Jessica I G; Sondag Gregory R; Safadi Fayez F; Lockman Paul R
Current cancer drug targets
2017
1905-7
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.2174/1568009617666161121123948" target="_blank" rel="noreferrer noopener">10.2174/1568009617666161121123948</a>
Novel multifunctional anti-Alzheimer drugs with various CNS neurotransmitter targets and neuroprotective moieties.
Humans; Animals; Drug Design; Alzheimer Disease/pathology/*prevention & control; Central Nervous System/chemistry/*drug effects/metabolism; Neuroprotective Agents/*chemistry/pharmacology/*therapeutic use; Neurotransmitter Agents/chemistry/*metabolism; Biological; Models
Traditionally, drug design programs are focused on optimizing the specificity of lead compounds against a carefully selected drug target. Disappointingly, this approach to discover a "magic bullet" drug has not met with the expected success for CNS disorders. Transcriptomics and proteomic profiling of neurodegenerative diseases have indicated that they are poly-etiological in origin and that the processes leading to neuronal death are multifactorial. An emerging concept is the design of drug ligands that modulate multiple drug targets identified for a particular disease. In this review we explore some examples of multifunctional drugs which may be useful in the treatment of neurodegenerative diseases, such as Alzheimer's and Parkinson's disease.
Van der Schyf Cornelis J; Mandel Silvia; Geldenhuys Werner J; Amit Tamar; Avramovich Yael; Zheng Hailin; Fridkin Mati; Gal Shunit; Weinreb Orly; Bar Am Orit; Sagi Yotam; Youdim Moussa B H
Current Alzheimer research
2007
2007-12
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.2174/156720507783018226" target="_blank" rel="noreferrer noopener">10.2174/156720507783018226</a>
Alteration of hepatic proinflammatory cytokines is involved in the resveratrol-mediated chemoprevention of chemically-induced hepatocarcinogenesis.
Female; Animals; Rats; Gene Expression Regulation/drug effects; Liver/drug effects/metabolism; Resveratrol; Diethylnitrosamine; Anticarcinogenic Agents/pharmacology/*therapeutic use; Cytokines/genetics/*metabolism; Phenobarbital; Stilbenes/pharmacology/*therapeutic use; Sprague-Dawley; RNA; Messenger/metabolism; Liver Neoplasms; Experimental/chemically induced/metabolism/*prevention & control
Hepatocellular carcinoma (HCC), one of the most common cancers in the world, is a leading cause of cancerrelated mortality. HCC develops most frequently in the background of oxidative stress and chronic hepatic inflammation due to viral infections, alcohol abuse as well as exposure to environmental and dietary carcinogens. As the prognosis of HCC is extremely poor and mostly unresponsive to current chemotherapeutic treatment regimens, novel preventive approaches like chemoprevention are urgently needed. We have recently found that resveratrol, a dietary polyphenol present in grapes, berries, peanuts as well as red wine, prevents diethylnitrosamine (DENA)-initiated hepatocarcinogenesis in rats through suppression of inflammation and oxidative stress. As cytokines are considered to be important mediators of inflammation, the objective of the present study was to investigate the effects of resveratrol on hepatic cytokines during DENA-initiated hepatocarcinogenesis in rats. Liver samples were harvested from our previous study in which resveratrol (50, 100 and 300 mg/kg) was found to exert a chemopreventive action against rat liver tumorigenesis induced by DENA. The levels of proinflammatory cytokines, namely tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta) and interleukin- 6 (IL-6), were measured using enzyme-linked immunosorbent assays. The mRNA expression of these cytokines was studied by reverse transcriptase-polymerase chain reaction for comparison. Resveratrol treatment reversed the DENAinduced alteration of the level and expression of hepatic TNF-alpha, IL-1beta and IL-6. From the current results in conjunction with our previous findings, it can be concluded that resveratrol-mediated chemoprevention of rat liver carcinogenesis is related to alteration of proinflammatory cytokines.
Mbimba Thomas; Awale Prabha; Bhatia Deepak; Geldenhuys Werner J; Darvesh Altaf S; Carroll Richard T; Bishayee Anupam
Current pharmaceutical biotechnology
2012
2012-01
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.2174/138920112798868575" target="_blank" rel="noreferrer noopener">10.2174/138920112798868575</a>
Natural products of dietary origin as lead compounds in virtual screening and drug design.
Humans; Animals; Diet; Resveratrol; *Drug Design; *Biological Products/pharmacology; Caffeine/pharmacology; Curcumin/pharmacology; Genistein/pharmacology; Stilbenes/pharmacology
Natural products have been found to be useful in the treatment of several diseases across the ages. In this article, we review the use of natural products, obtained from dietary sources, as lead compounds in developing novel therapeutic agents. These compounds have shown tremendous promise in the prevention and as well as treatment of a variety of chronic ailments. In addition, to being patentable and biocompatible, these compounds are a rich source of novel scaffolds to invigorate the pipelines of the pharmaceutical industry. In this communication, we also focus on studies which show how natural products have proved useful as lead compounds in virtual screening and structure-based drug design programs. Natural dietary constituents, such as resveratrol, curcumin and caffeine as well as other compounds, are discussed to illustrate this approach.
Geldenhuys Werner J; Bishayee Anupam; Darvesh Altaf S; Carroll Richard T
Current pharmaceutical biotechnology
2012
2012-01
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.2174/138920112798868548" target="_blank" rel="noreferrer noopener">10.2174/138920112798868548</a>
Role of serotonin in Alzheimer's disease: a new therapeutic target?
Humans; Animals; Serotonin/*metabolism; Clinical Trials as Topic; Alzheimer Disease/*drug therapy/*metabolism; Serotonin/*pharmacology/*therapeutic use; Clinical Trials; Receptors; Drug Evaluation; Preclinical; Alzheimer's Disease – Drug Therapy; Alzheimer's Disease – Metabolism; Cell Surface – Metabolism; Serotonin – Pharmacodynamics; Serotonin – Therapeutic Use
Mounting evidence accumulated over the past few years indicates that the neurotransmitter serotonin plays a significant role in cognition. As a drug target, serotonin receptors have received notable attention due in particular to the role of several serotonin-receptor subclasses in cognition and memory. The intimate anatomical and neurochemical association of the serotonergic system with brain areas that regulate memory and learning has directed current drug discovery programmes to focus on this system as a major therapeutic drug target. Thus far, none of these programmes has yielded unambiguous data that suggest that any of the new drug entities possesses disease-modifying properties, and significantly more research in this promising area of investigation is required. Compounds are currently being investigated for activity against serotonin 5-HT(1), 5-HT(4) and
Geldenhuys Werner J; Van der Schyf Cornelis J
CNS Drugs
2011
2011-09
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.2165/11590190-000000000-00000" target="_blank" rel="noreferrer noopener">10.2165/11590190-000000000-00000</a>
Oxidative stress and Alzheimer's disease: dietary polyphenols as potential therapeutic agents.
Humans; Animals; Oxidative Stress/drug effects/*physiology; Alzheimer Disease/*physiopathology/*therapy; Antioxidants/*administration & dosage/chemistry/pharmacology; Flavonoids/*administration & dosage/chemistry/pharmacology; Mitochondria/drug effects/physiology; Neurodegenerative Diseases/physiopathology; Phenols/*administration & dosage/chemistry/pharmacology; Polyphenols
Oxidative stress has been strongly implicated in the pathophysiology of neurodegenerative disorders such as Alzheimer's disease (AD). In recent years, antioxidants - especially those of dietary origin - have been suggested as possible agents useful for the prevention and treatment of AD. This article reviews the role of oxidative stress and the contribution of free radicals in the development of AD, and also discusses the use of antioxidants as a therapeutic strategy in the amelioration of this illness. The antioxidant potential of polyphenolic compounds obtained from dietary sources, such as anthocyanins from berries, catechins and theaflavins from tea, curcumin from turmeric, resveratrol from grapes and peanuts, the dihydrochalcones aspalathin and nothofagin from rooibos and the xanthone mangiferin from honeybush, are discussed in this review. The neuroprotective effects of these phytochemicals in preclinical models of AD are highlighted. Finally, innovative concepts, novel hypotheses, current challenges and future directions in the use of dietary polyphenols for the treatment of AD are discussed.
Darvesh Altaf S; Carroll Richard T; Bishayee Anupam; Geldenhuys Werner J; Van der Schyf Cornelis J
Expert review of neurotherapeutics
2010
2010-05
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1586/ern.10.42" target="_blank" rel="noreferrer noopener">10.1586/ern.10.42</a>
The serotonin 5-HT6 receptor: a viable drug target for treating cognitive deficits in Alzheimer's disease.
Humans; Animals; Structure-Activity Relationship; Serotonin/*metabolism; Drug Design; Alzheimer Disease/*complications; Cognition Disorders/*drug therapy/*etiology; Serotonin Antagonists/chemistry/*therapeutic use; Receptors; Biological; Models
The serotonin 6 receptor is attracting attention as an etiological contributor in cognition deficits in diseases such as Alzheimer's disease, anxiety/depression and schizophrenia. In this review, we discuss the role of this recently discovered G protein-coupled receptor in cognition and memory, particularly in Alzheimer's disease. A surge in publications that describe the development of ligands for this receptor have recently come to light, underscoring the emerging interest in this receptor as a drug target. We also explore the current status of structure-activity relationship studies that have focused on the design of novel antagonists for the serotonin 6 receptor.
Geldenhuys Werner J; Van der Schyf Cornelis J
Expert review of neurotherapeutics
2009
2009-07
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1586/ern.09.51" target="_blank" rel="noreferrer noopener">10.1586/ern.09.51</a>
Pharmacotherapy of Alzheimer's disease: current and future trends.
Humans; Alzheimer's disease; Alzheimer Disease/*drug therapy; anti-inflammatory agents; antioxidants; cholinesterase inhibitors; dementia; Drug Therapy/*methods/*trends; immunotherapy; memantine; multi-targeted drugs; natural products; pharmacotherapy
Alzheimer's disease (AD) and its related dementia has shown an alarming rise in the global population. Although considerable efforts have been made to develop effective therapeutic agents for AD therapy, drug development has not met significant clinical success. Current pharmacotherapy of AD is limited to cholinesterase inhibitors and the N-methyl-D-aspartate antagonist memantine. Considerable research is underway to develop newer agents for the management of AD. Since amyloid-beta (Abeta) has been implicated in AD pathogenesis, the use of beta secretase inhibitors as well as immunotherapy against Abeta has been investigated. A considerable effort has been spent investigating the therapeutic potential of antioxidants and anti-inflammatory agents, several of natural products and dietary origin, in AD treatment. Numerous drug targets have also been investigated for AD treatment and a modest drug pipeline is available. Despite these efforts, drug development for AD has proved extremely difficult and most clinical trials have afforded disappointing results.
Geldenhuys Werner J; Darvesh Altaf S
Expert review of neurotherapeutics
2015
2015-01
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1586/14737175.2015.990884" target="_blank" rel="noreferrer noopener">10.1586/14737175.2015.990884</a>
Designing drugs with multi-target activity: the next step in the treatment of neurodegenerative disorders.
Humans; Clinical Trials as Topic; *Drug Design; Central Nervous System Diseases/*drug therapy; Neurodegenerative Diseases/*drug therapy; Neuroprotective Agents/*chemistry/therapeutic use
INTRODUCTION: Neurodegenerative diseases have had devastating effects on patients' quality of life. These complex diseases have several pathways that are affected to initiate cell death. Current therapies, designed to address only a single target, fall short in mitigating or preventing disease progression, and disease-modifying drugs are desperately needed. Over the past several years, a new paradigm has emerged which has as a goal the targeting of multiple disease etiological pathways. Such "multi-targeted designed drugs" (MTDD) have shown great promise in preclinical studies as neuroprotective agents, as well as being able to afford symptomatic relief to blunt the day-to-day burden of these illnesses. AREAS COVERED: In this review, the authors evaluate the use of chemical scaffolds that led themselves exquisitely to the development of MTDDs in central nervous system disorders. Some of the examples discussed have also transitioned into the clinic, which underscores the importance of pursuing drug discovery programs within the multifunctional arena. EXPERT OPINION: Currently, very little can be done to slow the progress of neurodegeneration. The multifaceted profile of neurodegeneration necessitates a change in paradigm toward the design of compounds that address several drug targets simultaneously. With successful compounds in clinical trials as well as compounds moving into the clinic, support is growing and the feasibility of this approach is now becoming recognized. This review shows that several small molecule scaffolds can be successfully utilized to design MTDD compounds with good CNS pharmacokinetics.
Geldenhuys Werner J; Van der Schyf Cornelis J
Expert opinion on drug discovery
2013
2013-02
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1517/17460441.2013.744746" target="_blank" rel="noreferrer noopener">10.1517/17460441.2013.744746</a>
In vivo brain microdialysis: advances in neuropsychopharmacology and drug discovery.
INTRODUCTION: Microdialysis is an important in vivo sampling technique, useful in the assay of extracellular tissue fluid. The technique has both pre-clinical and clinical applications but is most widely used in neuroscience. The in vivo microdialysis technique allows measurement of neurotransmitters such as acetycholine (ACh), the biogenic amines including dopamine (DA), norepinephrine (NE) and serotonin (5-HT), amino acids such as glutamate (Glu) and gamma aminobutyric acid (GABA), as well as the metabolites of the aforementioned neurotransmitters, and neuropeptides in neuronal extracellular fluid in discrete brain regions of laboratory animals such as rodents and non-human primates. AREAS COVERED: In this review we present a brief overview of the principles and procedures related to in vivo microdialysis and detail the use of this technique in the pre-clinical measurement of drugs designed to be used in the treatment of chemical addiction, neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD) and as well as psychiatric disorders such as attention-deficit/hyperactivity disorder (ADHD) and schizophrenia. This review offers insight into the tremendous utility and versatility of this technique in pursuing neuropharmacological investigations as well its significant potential in rational drug discovery. EXPERT OPINION: In vivo microdialysis is an extremely versatile technique, routinely used in the neuropharmacological investigation of drugs used for the treatment of neurological disorders. This technique has been a boon in the elucidation of the neurochemical profile and mechanism of action of several classes of drugs especially their effects on neurotransmitter systems. The exploitation and development of this technique for drug discovery in the near future will enable investigational new drug candidates to be rapidly moved into the clinical trial stages and to market thus providing new successful therapies for neurological diseases that are currently in demand.
Darvesh Altaf S; Carroll Richard T; Geldenhuys Werner J; Gudelsky Gary A; Klein Jochen; Meshul Charles K; Van der Schyf Cornelis J
Expert opinion on drug discovery
2011
2011-02
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1517/17460441.2011.547189" target="_blank" rel="noreferrer noopener">10.1517/17460441.2011.547189</a>
Novel models for assessing blood-brain barrier drug permeation.
Humans; Animals; Blood-Brain Barrier/*metabolism; *Capillary Permeability; Drosophila melanogaster/metabolism; Grasshoppers/metabolism; High-Throughput Screening Assays; Pharmaceutical Preparations/*metabolism; Zebrafish/metabolism; Models; Animal
INTRODUCTION: The blood-brain barrier (BBB) is a selectively permeable micro-vascular unit which prevents many central nervous system (CNS)-targeted compounds from reaching the brain. A significant problem in CNS drug development is the ability to model BBB permeability in a timely, reproducible and cost-effective manner. Through the years, several models have been used such as artificial membranes, cell culture and animal models. AREAS COVERED: In this focused review, the authors cover novel models which have been developed or are in the process of being developed which can be used in modeling BBB. These models can either be used to determine BBB permeability or whether a compound may be disrupting the BBB. Many of these models lend themselves to high-throughput screening. The main model organisms covered here are the grasshopper (Locusta migratoria), fruit fly (Drosophila melanogaster) and zebrafish (Danio rerio). EXPERT OPINION: Many of the models covered here have only recently been utilized for BBB studies and still needs to be fully studied for its impact on reducing costs during drug development. The strength of these models lay in the fact that a whole organism experiment can be done in high throughput fashion as compared with classical vertebrate models such as micro-dialysis.
Geldenhuys Werner J; Allen David D; Bloomquist Jeffrey R
Expert opinion on drug metabolism & toxicology
2012
2012-06
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1517/17425255.2012.677433" target="_blank" rel="noreferrer noopener">10.1517/17425255.2012.677433</a>
Curcumin and neurodegenerative diseases: a perspective.
Humans; Animals; Oxidative Stress/drug effects; Neurodegenerative Diseases/*drug therapy/metabolism; Curcumin/adverse effects/pharmacokinetics/*pharmacology/*therapeutic use; Neuroprotective Agents/adverse effects/pharmacokinetics/*pharmacology/*therapeutic use; Drug Evaluation; Preclinical
INTRODUCTION: Curcumin, a dietary polyphenol found in the curry spice turmeric, possesses potent antioxidant and anti-inflammatory properties and an ability to modulate multiple targets implicated in the pathogenesis of chronic illness. Curcumin has shown therapeutic potential for neurodegenerative diseases including Alzheimer's disease (AD) and Parkinson's disease (PD). AREAS COVERED: This article highlights the background and epidemiological evidence of curcumin's health benefits and its pharmacodynamic and pharmacokinetic profile. Curcumin's ability to counteract oxidative stress and inflammation and its capacity to modulate several molecular targets is reviewed. We highlight the neuroprotective properties of curcumin including pre-clinical evidence for its pharmacological effects in experimental models of AD and PD. The bioavailability and safety of curcumin, the development of semi-synthetic curcuminoids as well as novel formulations of curcumin are addressed. EXPERT OPINION: Curcumin possesses therapeutic potential in the amelioration of a host of neurodegenerative ailments as evidenced by its antioxidant, anti-inflammatory and anti-protein aggregation effects. However, issues such as limited bioavailability and a paucity of clinical studies examining its therapeutic effectiveness in illnesses such as AD and PD currently limit its therapeutic outreach. Considerable effort will be required to adapt curcumin as a neuroprotective agent to be used in the treatment of AD, PD and other neurodegenerative diseases.
Darvesh Altaf S; Carroll Richard T; Bishayee Anupam; Novotny Nicholas A; Geldenhuys Werner J; Van der Schyf Cornelis J
Expert opinion on investigational drugs
2012
2012-08
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1517/13543784.2012.693479" target="_blank" rel="noreferrer noopener">10.1517/13543784.2012.693479</a>
Parkinson's disease biomarker: a patent evaluation of WO2013153386.
Humans; Disease Progression; Biomarkers/metabolism; Phosphorylation; Mitochondria/pathology; mitophagy; autophagy; clinical testing; Dopaminergic Neurons/pathology; mitochondrial membrane potential; Parkinson Disease/*diagnosis/physiopathology; Patents as Topic; Protein Kinases/*metabolism; Ubiquitin-Protein Ligases/*metabolism
INTRODUCTION: Parkinson's disease (PD) is a neurodegenerative movement disorder resultant from the loss of dopaminergic neurons in the brain. There is an urgent need for effective biomarkers that can be used in the early diagnosis of PD. Mitochondrial dysfunction plays a significant role in PD pathology, which has led to the evaluation of mitophagy markers, PTEN-induced putative kinase 1 (PINK1), and PARKIN as possible biomarkers for the early diagnosis of PD. AREAS COVERED: The current patent describes the use of phosphorylation of PINK1 and PARKIN as a diagnostic measure. Specifically, Ser65 on PARKIN, which is phosphorylated by PINK1, and the autophosphorylation of PINK1 at Thr257 are described. EXPERT OPINION: This patent describes a much needed methodology that can easily be adapted in the clinical setting by which a biological sample, such as serum or cerebrospinal fluid, is collected and analyzed for the phosphorylation markers. Here, the phosphorylation activity seen in PINK1 and PARKIN can differentiate between age-matched controls and PD patients. This patent presents a novel diagnostic measure in early PD, as well as determines which medications would have a beneficial effect on a patient's disease progression.
Geldenhuys Werner J; Abdelmagid Samir M; Gallegos Patrick J; Safadi Fayez F
Expert opinion on therapeutic patents
2014
2014-08
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1517/13543776.2014.931375" target="_blank" rel="noreferrer noopener">10.1517/13543776.2014.931375</a>
Biocompatibility, efficacy and biodistribution of Gelucire-stabilized nanoparticles engineered for docetaxel delivery.
*Biocompatible Materials; *Nanoparticles; Animals; Antineoplastic Agents/*administration & dosage/pharmacokinetics/pharmacology; Docetaxel; Macrophage Activation/drug effects; Platelet Aggregation/drug effects; Rats; Reactive Oxygen Species/metabolism; Taxoids/*administration & dosage/pharmacokinetics/pharmacology; Tissue Distribution
Docetaxel is a potent anticancer agent that will benefit greatly from alternative delivery systems that can overcome several reported adverse effects due to the drug itself and/or the solvent system in the current clinical formulation. In this regard, a new nanoparticle delivery system for docetaxel was prepared from Gelucire-based nanoemulsions by using binary mixtures of Gelucire 44/14 and cetyl alcohol as NP matrix materials. Various amounts of docetaxel (50-1000 microg/ml) were added to the oil phase of the nanoemulsions prior to obtaining solid nanoparticles. The nanoparticles (100-140 nm) achieved high entrapment efficiency (\textgreater or = 89%) of docetaxel which was maintained upon storage at 4 degrees C and 25 degrees C. Additional data indicated the Gelucire component in NP played influential roles in drug release possibly by facilitating diffusion from NPs and/or accelerating erosion of NP matrix. Docetaxel-loaded nanoparticles did not cause any significant red blood cell lysis or platelet aggregation nor activate macrophages. Also in-vitro antitumor efficacy in human lung adenocarcinoma cells was demonstrated based on cell cytotoxicity, production of reactive oxygen species and reduction of mitochondrial potential. Enhancement of in-vitro antitumor effects of docetaxel with Gelucire-based NPs could be ascribed to improved particle dispersion and efficient cell permeability. Studies in BALB/c mice demonstrated the stability/retention of NPs in blood circulation and the potential in facilitating docetaxel absorption across the peritoneal cavity. The nanoparticles reported herein may be effective as novel biocompatible and effective delivery systems for docetaxel.
Wehrung Daniel; Geldenhuys Werner J; Bi Lipeng; Oyewumi Moses O
Journal of nanoscience and nanotechnology
2012
2012-03
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1166/jnn.2012.5789" target="_blank" rel="noreferrer noopener">10.1166/jnn.2012.5789</a>
Antitumor efficacy and tolerability of systemically administered gallium acetylacetonate-loaded gelucire-stabilized nanoparticles.
*Lethal Dose 50; Adenocarcinoma/*drug therapy/pathology; Animals; Antineoplastic Agents/administration & dosage/pharmacokinetics/toxicity; Cell Line; Dose-Response Relationship; Drug; Drug Stability; Drug Tolerance; Gallium/*administration & dosage/pharmacokinetics/*toxicity; Humans; Metabolic Clearance Rate; Mice; Nanocapsules/*administration & dosage/chemistry/*toxicity; Nude; Organ Specificity; Tissue Distribution; Treatment Outcome; Triglycerides/chemistry; Tumor
The widespread clinical success with most gallium compounds in cancer therapy is markedly hampered by lack of tumor specific accumulation, poor tumor permeability and undesirable toxicity to healthy tissues. The aim of this work was to investigate for the first time antitumor mechanism of a new gallium compound (gallium acetylacetonate; GaAcAc) while assessing effectiveness of gelucire-stabilized nanoparticles (NPs) for potential application in gallium-based lung cancer therapy. NPs loaded with GaAcAc (Ga-NPs) were prepared using mixtures of cetyl alcohol with Gelucire 44/14 (Ga-NP-1) or Gelucire 53/13 (Ga-NP-2) as matrix materials. Of special note from this work is the direct evidence of involvement of microtubule disruption in antitumor effects of GaAcAc on human lung adenocarcinoma (A549). In-vivo tolerability studies were based on plasma ALT, creatinine levels and histopathological examination of tissues. The superior in-vivo antitumor efficacy of Ga-NPs over GaAcAc was depicted in marked reduction of tumor weight and tumor volume as well as histological assessment of excised tumors. Compared to free GaAcAc, Ga-NPs showed a 3-fold increase in tumor-to-blood gallium concentrations with minimized overall exposure to healthy tissues. Overall, enhancement of antitumor effects of GaAcAc by gelucire-stabilized NPs coupled with reduced exposure of healthy tissues to gallium would likely ensure desired therapeutic outcomes and safety of gallium-based cancer treatment.
Wehrung Daniel; Bi Lipeng; Geldenhuys Werner J; Oyewumi Moses O
Journal of biomedical nanotechnology
2013
2013-06
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1166/jbn.2013.1598" target="_blank" rel="noreferrer noopener">10.1166/jbn.2013.1598</a>
Development and validation of a novel RP-HPLC method for the analysis of reduced glutathione.
Chromatography; Glutathione/*analysis; High Pressure Liquid/*methods; Limit of Detection; Linear Models; Nanoparticles/chemistry; Pharmaceutical Preparations/chemistry; Reproducibility of Results; Reverse-Phase/*methods; Spectrophotometry; Ultraviolet
The objective of this study was the development, optimization, and validation of a novel reverse-phase high-pressure liquid chromatography (RP-HPLC) method for the quantification of reduced glutathione in pharmaceutical formulations utilizing simple UV detection. The separation utilized a C18 column at room temperature and UV absorption was measured at 215 nm. The mobile phase was an isocratic flow of a 50/50 (v/v) mixture of water (pH 7.0) and acetonitrile flowing at 1.0 mL/min. Validation of the method assessed the methods ability in seven categories: linearity, range, limit of detection, limit of quantification, accuracy, precision, and selectivity. Analysis of the system suitability showed acceptable levels of suitability in all categories. Likewise, the method displayed an acceptable degree of linearity (r(2) = 0.9994) over a concentration range of 2.5-60 microg/mL. The detection limit and quantification limit were 0.6 and 1.8 microg/mL respectively. The percent recovery of the method was 98.80-100.79%. Following validation the method was employed in the determination of glutathione in pharmaceutical formulations in the form of a conjugate and a nanoparticle. The proposed method offers a simple, accurate, and inexpensive way to quantify reduced glutathione.
Sutariya Vijaykumar; Wehrung Daniel; Geldenhuys Werner J
Journal of chromatographic science
2012
2012-03
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1093/chromsci/bmr055" target="_blank" rel="noreferrer noopener">10.1093/chromsci/bmr055</a>
Generation and characterization of ATP analog-specific protein kinase Cdelta.
Adenosine Triphosphate/*analogs & derivatives/*chemistry; Amino Acid; Amino Acid Sequence; Animals; ATP; Catalysis; Cercopithecus aethiops; Chemical Biology; COS Cells; Glutamine/chemistry; Humans; Inbred C57BL; Leucine/chemistry; Lysine/chemistry; Mice; Molecular Sequence Data; Neutrophils/metabolism; Phenylalanine/chemistry; Phosphorylation; Protein Binding; Protein Kinase C (PKC); Protein Kinase C-delta/*metabolism; Protein Phosphorylation; Purines/chemistry; Sequence Homology; Signal Transduction; Stroke; Substrate Specificity; Superoxides/chemistry; Transgenic
To better study the role of PKCdelta in normal function and disease, we developed an ATP analog-specific (AS) PKCdelta that is sensitive to specific kinase inhibitors and can be used to identify PKCdelta substrates. AS PKCdelta showed nearly 200 times higher affinity (Km) and 150 times higher efficiency (kcat/Km) than wild type (WT) PKCdelta toward N(6)-(benzyl)-ATP. AS PKCdelta was uniquely inhibited by 1-(tert-butyl)-3-(1-naphthyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1NA-PP1) and
Kumar Varun; Weng Yi-Chinn; Geldenhuys Werner J; Wang Dan; Han Xiqian; Messing Robert O; Chou Wen-Hai
The Journal of biological chemistry
2015
2015-01
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1074/jbc.M114.598698" target="_blank" rel="noreferrer noopener">10.1074/jbc.M114.598698</a>
Osteoactivin inhibition of osteoclastogenesis is mediated through CD44-ERK signaling.
*MAP Kinase Signaling System; *Signal Transduction; Animals; Cell Differentiation; Cells; Cultured; Eye Proteins/*metabolism; Hyaluronan Receptors/*metabolism; Inbred C57BL; Male; Membrane Glycoproteins/*metabolism; Mice; Osteoclasts/*cytology/metabolism; RANK Ligand/metabolism; Recombinant Proteins/metabolism
Osteoactivin is a heavily glycosylated protein shown to have a role in bone remodeling. Previous studies from our lab have shown that mutation in Osteoactivin enhances osteoclast differentiation but inhibits their function. To date, a classical receptor and a signaling pathway for Osteoactivin-mediated osteoclast inhibition has not yet been characterized. In this study, we examined the role of Osteoactivin treatment on osteoclastogenesis using bone marrow-derived osteoclast progenitor cells and identify a signaling pathway relating to Osteoactivin function. We reveal that recombinant Osteoactivin treatment inhibited osteoclast differentiation in a dose-dependent manner shown by qPCR, TRAP staining, activity and count. Using several approaches, we show that Osteoactivin binds CD44 in osteoclasts. Furthermore, recombinant Osteoactivin treatment inhibited ERK phosphorylation in a CD44-dependent manner. Finally, we examined the role of Osteoactivin on receptor activator of nuclear factor-kappa B ligand (RANKL)-induced osteolysis in vivo. Our data indicate that recombinant Osteoactivin inhibits RANKL-induced osteolysis in vivo and this effect is CD44-dependent. Overall, our data indicate that Osteoactivin is a negative regulator of osteoclastogenesis in vitro and in vivo and that this process is regulated through CD44 and ERK activation.
Sondag Gregory R; Mbimba Thomas S; Moussa Fouad M; Novak Kimberly; Yu Bing; Jaber Fatima A; Abdelmagid Samir M; Geldenhuys Werner J; Safadi Fayez F
Experimental & molecular medicine
2016
2016-09
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1038/emm.2016.78" target="_blank" rel="noreferrer noopener">10.1038/emm.2016.78</a>
Virtual screening to identify novel antagonists for the G protein-coupled NK3 receptor.
*Models; *Narcotic Antagonists; *Quantitative Structure-Activity Relationship; Animals; Binding; Calcium Signaling/drug effects; CHO Cells; Competitive; Cricetinae; Cricetulus; Databases; Factual; Humans; Ligands; Molecular; Neurokinin-3/*antagonists & inhibitors/chemistry; Opioid/chemistry; Quinolines/*chemistry/pharmacology; Radioligand Assay; Receptors
The NK(3) subtype of tachykinin receptor is a G protein-coupled receptor that is a potential therapeutic target for several neurological diseases, including schizophrenia. In this study, we have screened compound databases for novel NK(3) receptor antagonists using a virtual screening protocol of similarity analysis. The lead compound for this study was the potent NK(3) antagonist talnetant. Compounds of the quinoline type found in the virtual screen were additionally evaluated in a comparative molecular field analysis model to predict activity a priori to testing in vitro. Selected members of this latter set were tested for their ability to inhibit ligand binding to the NK(3) receptor as well as to inhibit senktide-induced calcium responses in cells expressing the human NK(3) receptor. Two novel compounds were identified that inhibited NK(3) receptor agonist binding, with potencies in the nM range and antagonized NK(3) receptor-mediated increases in intracellular calcium. These results demonstrate the utility of similarity analysis in identifying novel antagonist ligands for neuropeptide receptors.
Geldenhuys Werner J; Kuzenko Stephanie R; Simmons Mark A
Journal of medicinal chemistry
2010
2010-11
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1021/jm1010012" target="_blank" rel="noreferrer noopener">10.1021/jm1010012</a>
MitoNEET (CISD1) Knockout Mice Show Signs of Striatal Mitochondrial Dysfunction and a Parkinson's Disease Phenotype.
*aging; *Disease Models; *drug discovery; *mitochondrial dysfunction; *mitoNEET; Animal; Animals; Corpus Striatum/*metabolism/*pathology; Inbred C57BL; Iron-Binding Proteins/genetics/*metabolism; Knockout; Male; Membrane Proteins/genetics/*metabolism; Mice; Mitochondria/*metabolism/*pathology; Parkinson Disease/*metabolism/pathology
Mitochondrial dysfunction is thought to play a significant role in neurodegeneration observed in Parkinson's disease (PD), yet the mechanisms underlying this pathology remain unclear. Here, we demonstrate that loss of mitoNEET (CISD1), an iron-sulfur containing protein that regulates mitochondrial bioenergetics, results in mitochondrial dysfunction and loss of striatal dopamine and tyrosine hydroxylase. Mitochondria isolated from mice lacking mitoNEET were dysfunctional as revealed by elevated reactive oxygen species (ROS) and reduced capacity to produce ATP. Gait analysis revealed a shortened stride length and decreased rotarod performance in knockout mice, consistent with the loss of striatal dopamine. Together, these data suggest that mitoNEET KO mice exhibit many of the characteristics of early neurodegeneration in PD and may provide a novel drug discovery platform to evaluate compounds for enhancing mitochondrial function in neurodegenerative disorders.
Geldenhuys Werner J; Benkovic Stanley A; Lin Li; Yonutas Heather M; Crish Samuel D; Sullivan Patrick G; Darvesh Altaf S; Brown Candice M; Richardson Jason R
ACS chemical neuroscience
2017
2017-12
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1021/acschemneuro.7b00287" target="_blank" rel="noreferrer noopener">10.1021/acschemneuro.7b00287</a>
The emergence of designed multiple ligands for neurodegenerative disorders.
*Drug Design; *Ligands; Amyloid beta-Peptides/metabolism; Antiparkinson Agents/therapeutic use; Clinical Trials as Topic; Humans; Molecular Structure; Neurodegenerative Diseases/*drug therapy; Neuroprotective Agents/*therapeutic use
The incidence of neurodegenerative diseases has seen a constant increase in the global population, and is likely to be the result of extended life expectancy brought about by better health care. Despite this increase in the incidence of neurodegenerative diseases, there has been a dearth in the introduction of new disease-modifying therapies that are approved to prevent or delay the onset of these diseases, or reverse the degenerative processes in brain. Mounting evidence in the peer-reviewed literature shows that the etiopathology of these diseases is extremely complex and heterogeneous, resulting in significant comorbidity and therefore unlikely to be mitigated by any drug acting on a single pathway or target. A recent trend in drug design and discovery is the rational design or serendipitous discovery of novel drug entities with the ability to address multiple drug targets that form part of the complex pathophysiology of a particular disease state. In this review we discuss the rationale for developing such multifunctional drugs (also called designed multiple ligands or DMLs), and why these drug candidates seem to offer better outcomes in many cases compared to single-targeted drugs in pre-clinical studies for neurodegenerative diseases such as Alzheimer's and Parkinson's disease. Examples are drawn from the literature of drug candidates that have already reached the market, some unsuccessful attempts, and others that are still in the drug development pipeline.
Geldenhuys Werner J; Youdim Moussa B H; Carroll Richard T; Van der Schyf Cornelis J
Progress in neurobiology
2011
2011-09
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/j.pneurobio.2011.04.010" target="_blank" rel="noreferrer noopener">10.1016/j.pneurobio.2011.04.010</a>
Polycyclic compounds: ideal drug scaffolds for the design of multiple mechanism drugs?
*Drug Design; Adamantane/chemistry/pharmacology; Animals; Central Nervous System Diseases/*drug therapy; Humans; Molecular Structure; Neuroprotective Agents/chemistry/*pharmacology/therapeutic use; Polycyclic Compounds/*chemistry/pharmacology/therapeutic use; Psychotropic Drugs/chemistry/*pharmacology/therapeutic use; Quantitative Structure-Activity Relationship
Recently there has been a resurging interest in developing multi-functional drugs to treat diseases with complex pathological mechanisms. Such drug molecules simultaneously target multiple etiologies that have been found to be important modulators in specific diseases. This approach has significant promise and may be more effective than using one compound specific for one drug target or, by a polypharmaceutical approach, using a cocktail of two or more drugs. Polycyclic ring structures are useful as starting scaffolds in medicinal chemistry programs to develop multi-functional drugs, and may also be useful moieties added to existing structures to improve the pharmacokinetic properties of drugs currently used in the clinic or under development. This review attempts to provide a synopsis of current published research to exemplify the use of polycyclic compounds as starting molecules to develop multi-functional drugs.
Van der Schyf Cornelis J; Geldenhuys Werner J
Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics
2009
2009-01
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/j.nurt.2008.10.037" target="_blank" rel="noreferrer noopener">10.1016/j.nurt.2008.10.037</a>
Markers associated with testosterone enhancement of methamphetamine-induced striatal dopaminergic neurotoxicity.
Animals; Biomarkers/metabolism; Blotting; Body Temperature/drug effects; Body Weight/drug effects; Corpus Striatum/*drug effects/metabolism; Dopamine Plasma Membrane Transport Proteins/metabolism; Dopamine/*metabolism; Drug Synergism; HSP70 Heat-Shock Proteins/metabolism; Inbred Strains; Male; Methamphetamine/*toxicity; Mice; Neurotoxicity Syndromes/*etiology/metabolism; Oxidative Stress/drug effects; Testosterone Propionate/*pharmacology; Vesicular Monoamine Transport Proteins/metabolism; Western
Intact male CD-1 mice received an injection of testosterone propionate (TP–5 ug), progesterone (P–5 mg), the oil vehicle or remained untreated (control). At 24 hours after hormonal treatments the mice received an injection of methamphetamine (MA–40 mg/kg) and rectal temperatures were measured. At 5 days post-MA, assays were performed to assess effects of these treatments. Maximal increases in body temperatures, that were significantly greater than oil-treated controls, were obtained in TP-treated mice. At 5 days post-MA, maximal weight reductions were obtained with TP-treated mice, while P-treated mice showed no significant decrease between the pre- versus post-MA determinations. Striatal dopamine concentrations showed maximal reductions and heat-shock protein-70 maximal increases in the TP group, with both differing significantly as compared with all other groups. Protein levels of dopamine transporters were significantly decreased in P-treated mice, while vesicular monoamine transporter-2 was significantly decreased in TP-treated mice. Taken together, these results suggest that testosterone exacerbates the deleterious effects of MA within male mice as indicated by a number of markers related to neurotoxicity. The changes in markers as associated with this enhanced neurotoxicity suggest that TP may increase thermal/energy responses and/or oxidative stress to produce this effect.
Buletko A Blake; Dluzen Dean E; McDermott Janet L; Darvesh Altaf S; Geldenhuys Werner J
Neurotoxicology and teratology
2012
2012-06
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/j.ntt.2012.03.003" target="_blank" rel="noreferrer noopener">10.1016/j.ntt.2012.03.003</a>
Dimebon attenuates methamphetamine, but not MPTP, striatal dopamine depletion.
Animals; Corpus Striatum/*drug effects/metabolism; Dopamine/*metabolism; Drug Synergism; Inbred C57BL; Indoles/*pharmacology; Methamphetamine/*pharmacology; Mice
Dimebon is an anti-histamine with central nervous system activity. In this report the effects of dimebon as a neuroprotectant in animal models of Parkinson's disease were tested as assessed in methamphetamine- and MPTP-induced striatal dopaminergic toxicity. Dimebon (1mg/kg) administered at 30 min prior to methamphetamine (40mg/kg) significantly reduced the amount of striatal dopamine depletion in mice, without altering the initial methamphetamine-induced increase in body temperature. In contrast, dimebon at either 1 or 25mg/kg administered at 30 min prior to MPTP (35 mg/kg) was unable to prevent MPTP-induced striatal dopamine loss as determined at 7 days post-methamphetamine/MPTP. These data suggest that dimebon may be exerting a neurotoxin specific neuroprotective effect upon the striatal dopaminergic system and may serve as an important tool for discriminating the mechanistic basis of these two dopaminergic neurotoxins.
Geldenhuys Werner J; Darvesh Altaf S; Dluzen Dean E
Neurochemistry international
2012
2012-06
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/j.neuint.2012.03.013" target="_blank" rel="noreferrer noopener">10.1016/j.neuint.2012.03.013</a>
Development and validation of an LC-MS/MS method for determination of the L-type voltage-gated calcium channel/NMDA receptor antagonist NGP1-01 in mouse serum.
Animals; Bridged-Ring Compounds/*blood; Calcium Channel Blockers/*blood; Chromatography; LC-MS/MS; Limit of Detection; Liquid/*methods; Mice; Mouse serum; Multifunctional drug; N-Methyl-D-Aspartate/*antagonists & inhibitors; Neuroprotective agent; NGP1-01; Pentacycloundecylamine; Receptors; Reproducibility of Results; Tandem Mass Spectrometry/*methods
NGP1-01 (8-benzylamino-8,11-oxapentacyclo[5.4.0.0(2,6).0(3,10).0(5,9)]undecane) is a heterocyclic cage compound with multifunctional calcium channel blocking activity that has been demonstrated to be neuroprotective in several neurodegenerative models. A sensitive internal standard LC-MS/MS method was developed and validated to quantify NGP1-01 in mouse serum. The internal standard (IS) was
Jogiraju Harini; Zhou Xiang; Gobburi Ashta Lakshmi Prasad; Pedada Kiran K; Geldenhuys Werner J; Van der Schyf Cornelis J; Crish Samuel D; Anderson David J
Journal of chromatography. B, Analytical technologies in the biomedical and life sciences
2014
2014-07
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/j.jchromb.2014.05.048" target="_blank" rel="noreferrer noopener">10.1016/j.jchromb.2014.05.048</a>
A quantitative LC-MS/MS method for determination of thiazolidinedione mitoNEET ligand NL-1 in mouse serum suitable for pharmacokinetic studies.
%CV; %RE; 1-methyl-4-phenyl-1; 2; 3; 3-thiazolidine-2; 4-dione; 5-[3; 5-[4-hydroxy-3; 5-di-tert-butyl-4-hydroxyphenyl)methyl]-1; 5-dimethyl-phenyl)methyl]thiazolidine-2; 6-tetrahydropyridine; Animals; Carry-over; Chromatography; High Pressure Liquid/*methods; internal standard; IS; LC-MS/MS; Limit of Detection; LLOQ; lower limit of quantification; Methanol; Mice; mitoNEET; Mouse serum; MPTP; MRM; multiple reaction monitoring; NL-1; NL-2; percent coefficient of variation; peroxisome proliferator activated receptor-gamma; pharmacokinetic; PK; PPAR-gamma; QC; quality control; relative error; relative matrix effect; RME; SD; standard deviation; Tandem Mass Spectrometry/*methods; thiazolidinedione; Thiazolidinedione (TZD); Thiazolidinediones/*blood; TZD
Thiazolidinedione (TZD) compounds have shown promise as antidiabetic, antibiotics, antifungal and neuroprotective agents. The mitochondrial effect of a novel mitoNEET ligand, NL-1 {5-[(3,5-di-tert-butyl-4-hydroxyphenyl)methyl]-1,3-thiazolidine-2,4-dione}, and other TZD compounds, is a newly proposed mechanism for the neuroprotective action of these TZD compounds. In this work, a sensitive LC-MS/MS assay has been developed and validated for quantification of NL-1 in mouse serum. Sample preparation involved an acetonitrile protein precipitation procedure with addition of an internal standard NL-2 {5-[(4-hydroxy-3,5-dimethyl-phenyl)methyl]thiazolidine-2,4-dione}. LC-MS/MS analysis utilized a Columbus C-18 HPLC column (2mmx50mm, 5mum). Chromatography employed a multiple step gradient program that featured a steep linear gradient (25-95% in 0.5min) of 15muM ammonium acetate (additive for eliminating carry-over) in 2% methanol mixing with increasing proportions of 100% methanol. The HPLC was interfaced to a QTrap 5500 mass spectrometer (AB Sciex) equipped with an electrospray ionization source used in a negative ionization mode. Multiple reaction monitoring (MRM) of m/z 334–\textgreater263 for NL-1 and m/z 250–\textgreater179 for NL-2 was done. The method had a linear range of at least 1-100ng/mL in serum. The intra-assay and inter-assay percent coefficient of variation (%CV) were less than 4% and accuracies (%RE) ranged from -2.7% to 2.0%. The analytical procedure gave 96-115% absolute extraction recovery of NL-1. The relative matrix effect was measured and found to be insignificant. The analyte in serum was confirmed to be stable during storage and treatment. The method is suitable for pharmacokinetic (PK) studies of the parent drug NL-1 based on the preliminary serum results from dosed NL-1 mouse studies.
Pedada Kiran K; Zhou Xiang; Jogiraju Harini; Carroll Richard T; Geldenhuys Werner J; Lin Li; Anderson David J
Journal of chromatography. B, Analytical technologies in the biomedical and life sciences
2014
2014-01
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/j.jchromb.2013.11.048" target="_blank" rel="noreferrer noopener">10.1016/j.jchromb.2013.11.048</a>
4-Hydroxynonenal dependent alteration of TRPV1-mediated coronary microvascular signaling.
*4-Hydroxynonenal; *Coronary regulation; *Lipid peroxidation; *Post-translational modification; *Protein Processing; *Reactive oxygen species; *Signal Transduction; *TRPV1; Action Potentials/drug effects; Aldehydes/antagonists & inhibitors/metabolism/*pharmacology; Animal; Animals; Blood Flow Velocity; Calcium Signaling/drug effects; Capsaicin/*pharmacology; Cardiovascular Agents/*pharmacology; Coronary Circulation/drug effects; Coronary Vessels/metabolism/physiopathology; Cysteine/genetics/metabolism; Diabetes Mellitus/drug therapy/*metabolism/physiopathology; Disease Models; Femoral Artery/metabolism/physiopathology; HEK293 Cells; Humans; Inbred C57BL; Lipid Peroxidation; Male; Mice; Patch-Clamp Techniques; Post-Translational; TRPV Cation Channels/genetics/*metabolism; Vasodilation/drug effects
We demonstrated previously that TRPV1-dependent regulation of coronary blood flow (CBF) is disrupted in diabetes. Further, we have shown that endothelial TRPV1 is differentially regulated, ultimately leading to the inactivation of TRPV1, when exposed to a prolonged pathophysiological oxidative environment. This environment has been shown to increase lipid peroxidation byproducts including
DelloStritto Daniel J; Sinharoy Pritam; Connell Patrick J; Fahmy Joseph N; Cappelli Holly C; Thodeti Charles K; Geldenhuys Werner J; Damron Derek S; Bratz Ian N
Free radical biology & medicine
2016
2016-12
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/j.freeradbiomed.2016.09.021" target="_blank" rel="noreferrer noopener">10.1016/j.freeradbiomed.2016.09.021</a>
Effects of a novel dopamine uptake inhibitor upon extracellular dopamine from superfused murine striatal tissue.
Animals; Biological Transport/drug effects; Buffers; Calcium Channels/metabolism; Dopamine Plasma Membrane Transport Proteins/metabolism; Dopamine Uptake Inhibitors/*pharmacology; Dopamine/*metabolism; Extracellular Space/*drug effects/*metabolism; In Vitro Techniques; Male; Methamphetamine/pharmacology; Mice; Neostriatum/*cytology/drug effects; PC12 Cells; Perfusion; Potassium Channel Blockers/pharmacology; Potassium Channels; Potassium Chloride/pharmacology; Rats; Voltage-Gated/antagonists & inhibitors
The dopamine transporter (DAT) plays an important role in substance abuse, schizophrenia, and dopaminergic toxicity associated with the Parkinsonian animal model toxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Accordingly, the DAT serves as a critical component in regulating dopaminergic function in health and disease states. We have been working with a novel cage compound,
Geldenhuys Werner J; Bezuidenhout Lois-May; Dluzen Dean E
European journal of pharmacology
2009
2009-10
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/j.ejphar.2009.08.012" target="_blank" rel="noreferrer noopener">10.1016/j.ejphar.2009.08.012</a>
Emerging strategies of targeting lipoprotein lipase for metabolic and cardiovascular diseases.
Animals; Cardiovascular Diseases/drug therapy/*enzymology; Humans; Lipoprotein Lipase/chemistry/*metabolism; Metabolic Diseases/drug therapy/*enzymology
Although statins and other pharmacological approaches have improved the management of lipid abnormalities, there exists a need for newer treatment modalities especially for the management of hypertriglyceridemia. Lipoprotein lipase (LPL), by promoting hydrolytic cleavage of the triglyceride core of lipoproteins, is a crucial node in the management of plasma lipid levels. Although LPL expression and activity modulation is observed as a pleiotropic action of some the commonly used lipid lowering drugs, the deliberate development of drugs targeting LPL has not occurred yet. In this review, we present the biology of LPL, highlight the LPL modulation property of currently used drugs and review the novel emerging approaches to target LPL.
Geldenhuys Werner J; Lin Li; Darvesh Altaf S; Sadana Prabodh
Drug Discovery Today
2017
2017-02
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/j.drudis.2016.10.007" target="_blank" rel="noreferrer noopener">10.1016/j.drudis.2016.10.007</a>
mitoNEET as a novel drug target for mitochondrial dysfunction.
Animals; Drug Delivery Systems; Energy Metabolism; Humans; Mitochondria/*metabolism; Mitochondrial Proteins/chemistry/*metabolism; Protein Conformation; Thiazolidinediones/pharmacology
Mitochondrial dysfunction plays an important part in the pathology of several diseases, including Alzheimer's disease and Parkinson's disease. Targeting mitochondrial proteins shows promise in treating and attenuating the neurodegeneration seen in these diseases, especially considering their complex and pleiotropic origins. Recently, the mitochondrial protein mitoNEET [also referred to as CDGSH iron sulfur domain 1 (CISD1)] has emerged as the mitochondrial target of thiazolidinedione drugs such as the antidiabetic pioglitazone. In this review, we evaluate the current understanding regarding how mitoNEET regulates cellular bioenergetics as well as the structural requirements for drug compound association with mitoNEET. With a clear understanding of mitoNEET function, it might be possible to develop therapeutic agents useful in several different diseases including neurodegeneration, breast cancer, diabetes and inflammation.
Geldenhuys Werner J; Leeper Thomas C; Carroll Richard T
Drug Discovery Today
2014
2014-10
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/j.drudis.2014.05.001" target="_blank" rel="noreferrer noopener">10.1016/j.drudis.2014.05.001</a>
Effects of gelucire content on stability, macrophage interaction and blood circulation of nanoparticles engineered from nanoemulsions.
Animals; ATP Binding Cassette Transporter; Calorimetry; Differential Scanning; Drug Carriers/*chemical synthesis/pharmacokinetics; Drug Stability; Emulsions/chemistry; Fatty Alcohols/*chemistry; Fourier Transform Infrared; Humans; Inbred BALB C; Macrophages/*drug effects/metabolism; Member 1/metabolism; Mice; Nanoparticles/*chemistry/ultrastructure; Oils/chemistry; Paclitaxel/pharmacokinetics; Particle Size; Polyethylene Glycols/*chemistry; Reactive Oxygen Species/metabolism; Rhodamine 123/metabolism; Spectroscopy; Subfamily B; Water/chemistry
The main objective of the study is to investigate the efficacy of Gelucire 44/14 (gelucire) in facilitating formation of cetyl alcohol (CA)-based nanoparticle (NP) and to assess the effects on key NP properties and functions. NPs from oil-in-water nanoemulsion precursors were prepared using binary mixtures of CA and gelucire (CA/gelucire) containing gelucire at 0, 25, 50 and 75% (w/w). The sizes of gelucire-based NPs (128-183 nm) were five times lower than control NPs (made without gelucire). All the NPs (with or without gelucire component) did not activate macrophages as monitored by reactive oxygen species production. Results from differential scanning calorimetry, FT-IR and multimodal light scattering measurements demonstrated the involvement of gelucire component in achieving homogeneous CA/gelucire particle populations that were stable on storage. The
Wehrung Daniel; Geldenhuys Werner J; Oyewumi Moses O
Colloids and surfaces. B, Biointerfaces
2012
2012-06
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/j.colsurfb.2012.02.005" target="_blank" rel="noreferrer noopener">10.1016/j.colsurfb.2012.02.005</a>
Novel compounds that target lipoprotein lipase and mediate growth arrest in acute lymphoblastic leukemia.
*Acute lymphoblastic leukemia; *Cancer; *Co-culture model; *Lipids; *Lipoprotein lipase; *Metabolism; Amides/chemistry/metabolism/pharmacology; Antineoplastic Agents/*chemistry/metabolism/pharmacology; Binding Sites; Cell Line; Cell Proliferation/drug effects; Coculture Techniques; Dyslipidemias/complications/metabolism/pathology; Humans; Lipoprotein Lipase/antagonists & inhibitors/*metabolism; Mesenchymal Stem Cells/cytology/metabolism; Molecular Docking Simulation; Precursor Cell Lymphoblastic Leukemia-Lymphoma/complications/metabolism/pathology; Protein Binding; Protein Structure; Serum Albumin/chemistry/metabolism; Tertiary; Tumor
Over the past decade, the therapeutic strategies employed to treat B-precursor acute lymphoblastic leukemia (ALL) have been progressively successful in treating the disease. Unfortunately, the treatment associated dyslipidemia, either acute or chronic, is very prevalent and a cause for decreased quality of life in the surviving patients. To overcome this hurdle, we tested a series of cylopropanecarboxamides, a family demonstrated to target lipid metabolism, for their anti-leukemic activity in ALL. Several of the compounds tested showed anti-proliferative activity, with one, compound 22, inhibiting both Philadelphia chromosome negative REH and Philadelphia chromosome positive SupB15 ALL cell division. The novel advantage of these compounds is the potential synergy with standard chemotherapeutic agents, while concomitantly blunting the emergence of dyslipidemia. Thus, the cylopropanecarboxamides represent a novel class of compounds that can be potentially used in combination with the present standard-of-care to limit treatment associated dyslipidemia in ALL patients.
Nair Rajesh R; Geldenhuys Werner J; Piktel Debbie; Sadana Prabodh; Gibson Laura F
Bioorganic & medicinal chemistry letters
2018
2018-06
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/j.bmcl.2018.03.061" target="_blank" rel="noreferrer noopener">10.1016/j.bmcl.2018.03.061</a>
High-content screen using zebrafish (Danio rerio) embryos identifies a novel kinase activator and inhibitor.
*Cancer; *Compound library; *Kinase; *Notochord; *Phenotypic screen; *Somites; *Zebrafish; Animals; Antineoplastic Agents/chemistry/pharmacology; Antitumor/methods; Benzoic Acid/chemistry/pharmacology; Death-Associated Protein Kinases/metabolism; Drug Discovery/*methods; Drug Screening Assays; Embryo; Enzyme Activation/drug effects; Enzyme Activators/*chemistry/*pharmacology; Neoplasms/drug therapy/enzymology; Nonmammalian/*drug effects/enzymology; Protein Kinase Inhibitors/*chemistry/*pharmacology; Protein-Serine-Threonine Kinases/antagonists & inhibitors/metabolism; Zebrafish Proteins/antagonists & inhibitors/metabolism; Zebrafish/*embryology
In this report we utilized zebrafish (Danio rerio) embryos in a phenotypical high-content screen (HCS) to identify novel leads in a cancer drug discovery program. We initially validated our HCS model using the flavin adenosine dinucleotide (FAD) containing endoplasmic reticulum (ER) enzyme, endoplasmic reticulum oxidoreductase (ERO1) inhibitor EN460. EN460 showed a dose response effect on the embryos with a dose of 10muM being significantly lethal during early embryonic development. The HCS campaign which employed a small library identified a promising lead compound, a naphthyl-benzoic acid derivative coined compound 1 which had significant dosage and temporally dependent effects on notochord and muscle development in zebrafish embryos. Screening a 369 kinase member panel we show that compound 1 is a PIM3 kinase inhibitor (IC50=4.078muM) and surprisingly a DAPK1 kinase agonist/activator (EC50=39.525muM). To our knowledge this is the first example of a small molecule activating DAPK1 kinase. We provide a putative model for increased phosphate transfer in the ATP binding domain when compound 1 is virtually docked with DAPK1. Our data indicate that observable phenotypical changes can be used in future zebrafish screens to identify compounds acting via similar molecular signaling pathways.
Geldenhuys Werner J; Bergeron Sadie A; Mullins Jackie E; Aljammal Rowaa; Gaasch Briah L; Chen Wei-Chi; Yun June; Hazlehurst Lori A
Bioorganic & medicinal chemistry letters
2017
2017-05
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/j.bmcl.2017.02.068" target="_blank" rel="noreferrer noopener">10.1016/j.bmcl.2017.02.068</a>
Structure-activity and in vivo evaluation of a novel lipoprotein lipase (LPL) activator.
*Diabetes; *High-fat diet; *Homology modeling; *Hyperlipidemia; *Lipoprotein lipase; *Liver cirrhosis; *Obesity; Animals; Benzeneacetamides/chemical synthesis/chemistry/*pharmacology; Dose-Response Relationship; Drug; Imidazoles/chemical synthesis/chemistry/*pharmacology; Lipoprotein Lipase/*metabolism; Mice; Molecular Docking Simulation; Molecular Structure; Structure-Activity Relationship
Elevated triglycerides (TG) contribute towards increased risk for cardiovascular disease. Lipoprotein lipase (LPL) is an enzyme that is responsible for the metabolism of core triglycerides of very-low density lipoproteins (VLDL) and chylomicrons in the vasculature. In this study, we explored the structure-activity relationships of our lead compound (C10d) that we have previously identified as an LPL agonist. We found that the cyclopropyl moiety of C10d is not absolutely necessary for LPL activity. Several substitutions were found to result in loss of LPL activity. The compound C10d was also tested in vivo for its lipid lowering activity. Mice were fed a high-fat diet (HFD) for four months, and treated for one week at 10mg/kg. At this dose, C10d exhibited in vivo biological activity as indicated by lower TG and cholesterol levels as well as reduced body fat content as determined by ECHO-MRI. Furthermore, C10d also reduced the HFD induced fat accumulation in the liver. Our study has provided insights into the structural and functional characteristics of this novel LPL activator.
Geldenhuys Werner J; Caporoso Joel; Leeper Thomas C; Lee Yoon-Kwang; Lin Li; Darvesh Altaf S; Sadana Prabodh
Bioorganic & medicinal chemistry letters
2017
2017-01
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/j.bmcl.2016.11.053" target="_blank" rel="noreferrer noopener">10.1016/j.bmcl.2016.11.053</a>