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Parkinson Disease: HELP
Articles by Nigel H. Greig
Based on 18 articles published since 2010
(Why 18 articles?)
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Between 2010 and 2020, N. H. Greig wrote the following 18 articles about Parkinson Disease.
 
+ Citations + Abstracts
1 Editorial Are Alzheimer's disease and other neurodegenerative disorders caused by impaired signalling of insulin and other hormones? 2018

Hölscher, Christian / De Felice, Fernanda G / Greig, Nigel H / Ferreira, Sergio T. ·Biomedical and Life Sciences, Lancaster University, Lancaster, UK. Electronic address: c.holscher@lancaster.ac.uk. · Centre for Neuroscience Studies, Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada. · Drug Design & Development Section, Translational Gerontology Branch, National Institute on Aging, National Institutes of Health, Baltimore, USA. · Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil. ·Neuropharmacology · Pubmed #29782874.

ABSTRACT: -- No abstract --

2 Review A New Treatment Strategy for Parkinson's Disease through the Gut-Brain Axis: The Glucagon-Like Peptide-1 Receptor Pathway. 2017

Kim, Dong Seok / Choi, Ho-Il / Wang, Yun / Luo, Yu / Hoffer, Barry J / Greig, Nigel H. ·1 Peptron Inc., Yuseong-gu, Daejeon, Republic of Korea. · 2 Drug Design and Development Section, Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA. · 3 Center for Neuropsychiatric Research, National Health Research Institutes, Zhunan, Miaoli County, Taiwan. · 4 Department of Neurosurgery, Case Western Reserve University School of Medicine, Cleveland, OH, USA. ·Cell Transplant · Pubmed #29113464.

ABSTRACT: Molecular communications in the gut-brain axis, between the central nervous system and the gastrointestinal tract, are critical for maintaining healthy brain function, particularly in aging. Epidemiological analyses indicate type 2 diabetes mellitus (T2DM) is a risk factor for neurodegenerative disorders including Alzheimer's disease (AD) and Parkinson's diseases (PD) for which aging shows a major correlative association. Common pathophysiological features exist between T2DM, AD, and PD, including oxidative stress, inflammation, insulin resistance, abnormal protein processing, and cognitive decline, and suggest that effective drugs for T2DM that positively impact the gut-brain axis could provide an effective treatment option for neurodegenerative diseases. Glucagon-like peptide-1 (GLP-1)-based antidiabetic drugs have drawn particular attention as an effectual new strategy to not only regulate blood glucose but also decrease body weight by reducing appetite, which implies that GLP-1 could affect the gut-brain axis in normal and pathological conditions. The neurotrophic and neuroprotective effects of GLP-1 receptor (R) stimulation have been characterized in numerous in vitro and in vivo preclinical studies using GLP-1R agonists and dipeptidyl peptidase-4 inhibitors. Recently, the first open label clinical study of exenatide, a long-acting GLP-1 agonist, in the treatment of PD showed long-lasting improvements in motor and cognitive function. Several double-blind clinical trials of GLP-1R agonists including exenatide in PD and other neurodegenerative diseases are already underway or are about to be initiated. Herein, we review the physiological role of the GLP-1R pathway in the gut-brain axis and the therapeutic strategy of GLP-1R stimulation for the treatment of neurodegenerative diseases focused on PD, for which age is the major risk factor.

3 Review Commonalities in Biological Pathways, Genetics, and Cellular Mechanism between Alzheimer Disease and Other Neurodegenerative Diseases: An In Silico-Updated Overview. 2017

Ahmad, Khurshid / Baig, Mohammad Hassan / Mushtaq, Gohar / Kamal, Mohammad Amjad / Greig, Nigel H / Choi, Inho. ·Department of Medical Biotechnology, Yeungnam University, Gyeongsan. Korea. · Department of Medical Biotechnology, Yeungnam University, 280 Daehak-ro, Gyeongsan, Gyeongbuk 712-749. Korea. · Department of Biochemistry, College of Science, King Abdulaziz University, Jeddah 21589. Saudi Arabia. · King Fahd Medical Research Centre, King Abdulaziz University, P.O. Box 80216, Jeddah 21589. Saudi Arabia. · Drug Design & Development Section, Translational Gerontology Branch, Intramural Research Program, National, Institute on Aging, National Institutes of Health, Biomedical Research Center, 251 Bayview Boulevard, Baltimore, MD 21224. United States. ·Curr Alzheimer Res · Pubmed #28164765.

ABSTRACT: BACKGROUND: Alzheimer's disease (AD) is the most common and well-studied neurodegenerative disease (ND). Biological pathways, pathophysiology and genetics of AD show commonalities with other NDs viz. Parkinson's disease (PD), Amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), Prion disease and Dentatorubral-pallidoluysian atrophy (DRPLA). Many of the NDs, sharing the common features and molecular mechanisms suggest that pathology may be directly comparable and be implicated in disease prevention and development of highly effective therapies. METHOD: In this review, a brief description of pathophysiology, clinical symptoms and available treatment of various NDs have been explored with special emphasis on AD. Commonalities in these fatal NDs provide support for therapeutic advancements and enhance the understanding of disease manifestation. CONCLUSION: The studies concentrating on the commonalities in biological pathways, cellular mechanisms and genetics may provide the scope to researchers to identify few novel common target(s) for disease prevention and development of effective common drugs for multi-neurodegenerative diseases.

4 Review miRNAs as Circulating Biomarkers for Alzheimer's Disease and Parkinson's Disease. 2016

Mushtaq, Gohar / Greig, Nigel H / Anwar, Firoz / Zamzami, Mazin A / Choudhry, Hani / Shaik, Munvar M / Tamargo, Ian A / Kamal, Mohammad A. ·Drug Design and Development Section, Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA. greign@mail.nih.gov. ·Med Chem · Pubmed #26527155.

ABSTRACT: Detection of biomarkers for neurodegenerative disorders (NDDs) within brain tissues of Alzheimer's disease (AD) and Parkinson's disease (PD) patients has always been hampered by our inability to access and biopsy tissue of key brain regions implicated in disease occurrence and progression. Currently, diagnosis of NDDs is principally based on clinical observations of symptoms that present at later stages of disease progression, followed by neuroimaging and, possibly, CSF evaluation. One way to potentially detect and diagnose NDDs at a far earlier stage is to screen for abnormal levels of specific disease markers within the peripheral circulation of patients with NDDs. Increasing evidence suggests that there is dysregulation of microRNAs (miRNAs) in NDDs. Peripheral blood mononuclear cells, as well as biofluids, such as plasma, serum, urine and cerebrospinal fluid, contain miRNAs that can be identified and quantified. Circulating miRNAs within blood and other biofluids may thus be characterized and used as non-invasive, diagnostic biomarkers that facilitate the early detection of disease and potentially the continual monitoring of disease progression for NDDs such as AD and PD. Plainly, such a screen is only possible with a clear understanding of which miRNAs change with disease, and when these changes occur during the progression of AD and PD. Such information is becoming increasingly available and, in the near future, may not only support disease diagnosis, but provide the opportunity to evaluate therapeutic interventions earlier in the disease process.

5 Review miRNAs: Key Players in Neurodegenerative Disorders and Epilepsy. 2015

Karnati, Hanuma Kumar / Panigrahi, Manas Kumar / Gutti, Ravi Kumar / Greig, Nigel H / Tamargo, Ian A. ·Department of Biochemistry, School of Life Sciences, University of Hyderabad, Gachibowli, Hyderabad, Telangana, India. · Department of Neurosurgery, Krishna Institute of Medical Sciences (KIMS), Hyderabad, Telangana, India. · Drug Design & Development Section, Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA. ·J Alzheimers Dis · Pubmed #26402105.

ABSTRACT: MicroRNAs (miRNAs) are endogenous, ∼22 nucleotide, non-coding RNA molecules that function as post-transcriptional regulators of gene expression. miRNA dysregulation has been observed in cancer and in neurodegenerative disorders such as Alzheimer's, Parkinson's, and Huntington's diseases, amyotrophic lateral sclerosis, and the neurological disorder, epilepsy. Neuronal degradation and death are important hallmarks of neurodegenerative disorders. Additionally, abnormalities in metabolism, synapsis and axonal transport have been associated with Alzheimer's disease, Parkinson's disease, and frontotemporal dementia. A number of recently published studies have demonstrated the importance of miRNAs in the nervous system and have contributed to the growing body of evidence on miRNA dysregulation in neurological disorders. Knowledge of the expressions and activities of such miRNAs may aid in the development of novel therapeutics. In this review, we discuss the significance of miRNA dysregulation in the development of neurodegenerative disorders and the use of miRNAs as targets for therapeutic intervention.

6 Review Alzheimer's disease and type 2 diabetes: exploring the association to obesity and tyrosine hydroxylase. 2012

Priyadarshini, Medha / Kamal, Mohammad A / Greig, Nigel H / Reale, Marcella / Abuzenadah, Adel M / Chaudhary, Adeel G A / Damanhouri, Ghazi A. ·Department of Biochemistry, Faculty of Life Sciences, Aligarh Muslim University, UP, India. medha.priyadarshini@gmail.com ·CNS Neurol Disord Drug Targets · Pubmed #22583431.

ABSTRACT: Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM) are two debilitating health disorders afflicting millions worldwide. Recent research has revealed similarities between AD and T2DM. Both these protein conformational disorders are associated with obesity, insulin resistance, inflammation and endoplasmic reticulum stress, en-route initiation and/or stage aggravation. In this mini review we have tried to summarize studies describing obesity, insulin resistance and glucocorticoid imbalance as common patho-mechanisms in T2DM and AD. A reduction in tyrosine hydroxylase (TH) in the brain has been found to occur in Parkinson's disease (PD). AD, T2DM and PD share common risk factors like depression. Thus, whether TH is involved in the 'state of cognitive depression' that is the hallmark of AD and often accompanies PD and T2DM is also explored.

7 Review A synopsis on the role of tyrosine hydroxylase in Parkinson's disease. 2012

Tabrez, Shams / Jabir, Nasimudeen R / Shakil, Shazi / Greig, Nigel H / Alam, Qamre / Abuzenadah, Adel M / Damanhouri, Ghazi A / Kamal, Mohammad A. ·King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia. ·CNS Neurol Disord Drug Targets · Pubmed #22483313.

ABSTRACT: Parkinson's disease (PD) is a common chronic progressive neurodegenerative disorder in elderly people. A consistent neurochemical abnormality in PD is degeneration of dopaminergic neurons in substantia nigra pars compacta, leading to a reduction of striatal dopamine (DA) levels. As tyrosine hydroxylase (TH) catalyses the formation of L-dihydroxyphenylalanine (L-DOPA), the rate-limiting step in the biosynthesis of DA, the disease can be considered as a TH-deficiency syndrome of the striatum. Problems related to PD usually build up when vesicular storage of DA is altered by the presence of either α-synuclein protofibrils or oxidative stress. Phosphorylation of three physiologically-regulated specific sites of N-terminal domain of TH is vital in regulating its kinetic and protein interaction. The concept of physiological significance of TH isoforms is another interesting aspect to be explored further for a comprehensive understanding of its role in PD. Thus, a logical and efficient strategy for PD treatment is based on correcting or bypassing the enzyme deficiency by the treatment with L-DOPA, DA agonists, inhibitors of DA metabolism or brain grafts with cells expressing a high level of TH. Neurotrophic factors are also attracting the attention of neuroscientists because they provide the essential neuroprotective and neurorestorative properties to the nigrostriatal DA system. PPAR-γ, a key regulator of immune responses, is likewise a promising target for the treatment of PD, which can be achieved by the use of agonists with the potential to impact the expression of pro- and anti-inflammatory cytokines at the transcriptional level in immune cells via expression of TH. Herein, we review the primary biochemical and pathological features of PD, and describe both classical and developing approaches aimed to ameliorate disease symptoms and its progression.

8 Review N-methyl D-aspartate (NMDA) receptor antagonists and memantine treatment for Alzheimer's disease, vascular dementia and Parkinson's disease. 2012

Olivares, David / Deshpande, Varun K / Shi, Ying / Lahiri, Debomoy K / Greig, Nigel H / Rogers, Jack T / Huang, Xudong. ·Service of Clinical Pharmacology, Hospital Clinico San Carlos, C/Professor Martin Lagos s/n, 28040, Madrid, Spain. ·Curr Alzheimer Res · Pubmed #21875407.

ABSTRACT: Memantine, a partial antagonist of N-methyl-D-aspartate receptor (NMDAR), approved for moderate to severe Alzheimer's disease (AD) treatment within the U.S. and Europe under brand name Namenda (Forest), Axura and Akatinol (Merz), and Ebixa and Abixa (Lundbeck), may have potential in alleviating additional neurological conditions, such as vascular dementia (VD) and Parkinson's disease (PD). In various animal models, memantine has been reported to be a neuroprotective agent that positively impacts both neurodegenerative and vascular processes. While excessive levels of glutamate result in neurotoxicity, in part through the over-activation of NMDARs, memantine-as a partial NMDAR antagonist, blocks the NMDA glutamate receptors to normalize the glutamatergic system and ameliorate cognitive and memory deficits. The key to memantine's therapeutic action lies in its uncompetitive binding to the NMDAR through which low affinity and rapid off-rate kinetics of memantine at the level of the NMDAR-channel preserves the physiological function of the receptor, underpinning memantine's tolerability and low adverse event profile. As the biochemical pathways evoked by NMDAR antagonism also play a role in PD and since no other drug is sufficiently effective to substitute for the first-line treatment of L-dopa despite its side effects, memantine may be useful in PD treatment with possibly fewer side effects. In spite of the relative modest nature of its adverse effects, memantine has been shown to provide only a moderate decrease in clinical deterioration in AD and VD, and hence efforts are being undertaken in the design of new and more potent memantine-based drugs to hopefully provide greater efficacy.

9 Review Targeting TNF-α to elucidate and ameliorate neuroinflammation in neurodegenerative diseases. 2011

Frankola, Kathryn A / Greig, Nigel H / Luo, Weiming / Tweedie, David. ·Drug Design & Development Section, Laboratory of Neurosciences, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA. ·CNS Neurol Disord Drug Targets · Pubmed #21288189.

ABSTRACT: Inflammatory signals generated within the brain and peripheral nervous system direct diverse biological processes. Key amongst the inflammatory molecules is tumor necrosis factor-α (TNF-α), a potent pro-inflammatory cytokine that, via binding to its associated receptors, is considered to be a master regulator of cellular cascades that control a number of diverse processes coupled to cell viability, gene expression, synaptic integrity and ion homeostasis. Whereas a self-limiting neuroinflammatory response generally results in the resolution of an intrinsically or extrinsically triggered insult by the elimination of toxic material or injured tissue to restore brain homeostasis and function, in the event of an unregulated reaction, where the immune response persists, inappropriate chronic neuroinflammation can ensue. Uncontrolled neuroinflammatory activity can induce cellular dysfunction and demise, and lead to a self-propagating cascade of harmful pathogenic events. Such chronic neuroinflammation is a typical feature across a range of debilitating common neurodegenerative diseases, epitomized by Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis, in which TNF-α expression appears to be upregulated and may represent a valuable target for intervention. Elaboration of the protective homeostasis signaling cascades from the harmful pathogenic ones that likely drive disease onset and progression could aid in the clinical translation of approaches to lower brain and peripheral nervous system TNF-α levels, and amelioration of inappropriate neuroinflammation.

10 Article Glucagon-like peptide-1 (GLP-1)-based receptor agonists as a treatment for Parkinson's disease. 2020

Glotfelty, Elliot J / Olson, Lars / Karlsson, Tobias E / Li, Yazhou / Greig, Nigel H. ·Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA. · Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden. ·Expert Opin Investig Drugs · Pubmed #32412796.

ABSTRACT:

11 Article Utility of Neuronal-Derived Exosomes to Examine Molecular Mechanisms That Affect Motor Function in Patients With Parkinson Disease: A Secondary Analysis of the Exenatide-PD Trial. 2019

Athauda, Dilan / Gulyani, Seema / Karnati, Hanuma Kumar / Li, Yazhou / Tweedie, David / Mustapic, Maja / Chawla, Sahil / Chowdhury, Kashfia / Skene, Simon S / Greig, Nigel H / Kapogiannis, Dimitrios / Foltynie, Thomas. ·Department of Clinical and Movement Neurosciences, University College London Institute of Neurology, The National Hospital for Neurology and Neurosurgery, London, United Kingdom. · Laboratory of Neurosciences, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, Maryland. · Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, Maryland. · University College London Comprehensive Clinical Trials Unit, London, United Kingdom. · School of Biosciences and Medicine, University of Surrey, Kent, United Kingdom. ·JAMA Neurol · Pubmed #30640362.

ABSTRACT: Importance: Exenatide, a glucagon-like peptide 1 agonist used in type 2 diabetes, was recently found to have beneficial effects on motor function in a randomized, placebo-controlled trial in Parkinson disease (PD). Accumulating evidence suggests that impaired brain insulin and protein kinase B (Akt) signaling play a role in PD pathogenesis; however, exploring the extent to which drugs engage with putative mechnisms in vivo remains a challenge. Objective: To assess whether participants in the Exenatide-PD trial have augmented activity in brain insulin and Akt signaling pathways. Design, Setting, and Participants: Serum samples were collected from 60 participants in the single-center Exenatide-PD trial (June 18, 2014, to June 16, 2016), which compared patients with moderate PD randomized to 2 mg of exenatide once weekly or placebo for 48 weeks followed by a 12-week washout period. Serum extracellular vesicles, including exosomes, were extracted, precipitated, and enriched for neuronal source by anti-L1 cell adhesion molecule antibody absorption, and proteins of interest were evaluated using electrochemiluminescence assays. Statistical analysis was performed from May 1, 2017, to August 31, 2017. Main Outcomes and Measures: The main outcome was augmented brain insulin signaling that manifested as a change in tyrosine phosphorylated insulin receptor substrate 1 within neuronal extracellular vesicles at the end of 48 weeks of exenatide treatment. Additional outcome measures were changes in other insulin receptor substrate proteins and effects on protein expression in the Akt and mitogen-activated protein kinase pathways. Results: Sixty patients (mean [SD] age, 59.9 [8.4] years; 43 [72%] male) participated in the study: 31 in the exenatide group and 29 in the placebo group (data from 1 patient in the exenatide group were excluded). Patients treated with exenatide had augmented tyrosine phosphorylation of insulin receptor substrate 1 at 48 weeks (0.27 absorbance units [AU]; 95% CI, 0.09-0.44 AU; P = .003) and 60 weeks (0.23 AU; 95% CI, 0.05-0.41 AU; P = .01) compared with patients receiving placebo. Exenatide-treated patients had elevated expression of downstream substrates, including total Akt (0.35 U/mL; 95% CI, 0.16-0.53 U/mL; P < .001) and phosphorylated mechanistic target of rapamycin (mTOR) (0.22 AU; 95% CI, 0.04-0.40 AU; P = .02). Improvements in Movement Disorders Society Unified Parkinson's Disease Rating Scale part 3 off-medication scores were associated with levels of total mTOR (F4,50 = 5.343, P = .001) and phosphorylated mTOR (F4,50 = 4.384, P = .04). Conclusions and Relevance: The results of this study are consistent with target engagement of brain insulin, Akt, and mTOR signaling pathways by exenatide and provide a mechanistic context for the clinical findings of the Exenatide-PD trial. This study suggests the potential of using exosome-based biomarkers as objective measures of target engagement in clinical trials using drugs that target neuronal pathways.

12 Article Glucose-Dependent Insulinotropic Polypeptide Mitigates 6-OHDA-Induced Behavioral Impairments in Parkinsonian Rats. 2018

Yu, Yu-Wen / Hsueh, Shih-Chang / Lai, Jing-Huei / Chen, Yen-Hua / Kang, Shuo-Jhen / Chen, Kai-Yun / Hsieh, Tsung-Hsun / Hoffer, Barry J / Li, Yazhou / Greig, Nigel H / Chiang, Yung-Hsiao. ·The Ph.D. Program for Neural Regenerative Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan. yvonneyu524@hotmail.com. · Center for Neurotrauma and Neuroregeneration, Taipei Medical University, Taipei 11031, Taiwan. yvonneyu524@hotmail.com. · The Ph.D. Program for Neural Regenerative Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan. d620103001@tmu.edu.tw. · Center for Neurotrauma and Neuroregeneration, Taipei Medical University, Taipei 11031, Taiwan. d620103001@tmu.edu.tw. · Center for Neurotrauma and Neuroregeneration, Taipei Medical University, Taipei 11031, Taiwan. m105095006@tmu.edu.tw. · Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan. m105095006@tmu.edu.tw. · Center for Neurotrauma and Neuroregeneration, Taipei Medical University, Taipei 11031, Taiwan. swallows3366@gmail.com. · Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan. swallows3366@gmail.com. · Center for Neurotrauma and Neuroregeneration, Taipei Medical University, Taipei 11031, Taiwan. terbiun@gmail.com. · Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan. terbiun@gmail.com. · The Ph.D. Program for Neural Regenerative Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan. chenkathryn@hotmail.com. · Center for Neurotrauma and Neuroregeneration, Taipei Medical University, Taipei 11031, Taiwan. chenkathryn@hotmail.com. · The Ph.D. Program for Neural Regenerative Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan. hsiehth@mail.cgu.edu.tw. · Center for Neurotrauma and Neuroregeneration, Taipei Medical University, Taipei 11031, Taiwan. hsiehth@mail.cgu.edu.tw. · Department of Physical Therapy and Graduate Institute of Rehabilitation Science, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan. hsiehth@mail.cgu.edu.tw. · The Ph.D. Program for Neural Regenerative Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan. bjh82@case.edu. · Department of Neurosurgery, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA. bjh82@case.edu. · Drug Design & Development Section, Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD 20892, USA. yazhou.Li@nih.gov. · Drug Design & Development Section, Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD 20892, USA. greign@grc.nia.nih.gov. · The Ph.D. Program for Neural Regenerative Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan. ychiang@tmu.edu.tw. · Center for Neurotrauma and Neuroregeneration, Taipei Medical University, Taipei 11031, Taiwan. ychiang@tmu.edu.tw. · Department of Neurosurgery, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA. ychiang@tmu.edu.tw. · Department of Neurosurgery, Taipei Medical University Hospital, Taipei 11031, Taiwan. ychiang@tmu.edu.tw. ·Int J Mol Sci · Pubmed #29641447.

ABSTRACT: In the present study, the effectiveness of glucose-dependent insulinotropic polypeptide (GIP) was evaluated by behavioral tests in 6-hydroxydopamine (6-OHDA) hemi-parkinsonian (PD) rats. Pharmacokinetic measurements of GIP were carried out at the same dose studied behaviorally, as well as at a lower dose used previously. GIP was delivered by subcutaneous administration (s.c.) using implanted ALZET micro-osmotic pumps. After two days of pre-treatment, male Sprague Dawley rats received a single unilateral injection of 6-OHDA into the medial forebrain bundle (MFB). The neuroprotective effects of GIP were evaluated by apomorphine-induced contralateral rotations, as well as by locomotor and anxiety-like behaviors in open-field tests. Concentrations of human active and total GIP were measured in plasma during a five-day treatment period by ELISA and were found to be within a clinically translatable range. GIP pretreatment reduced behavioral abnormalities induced by the unilateral nigrostriatal dopamine (DA) lesion produced by 6-OHDA, and thus may be a novel target for PD therapeutic development.

13 Article Exenatide once weekly versus placebo in Parkinson's disease: a randomised, double-blind, placebo-controlled trial. 2017

Athauda, Dilan / Maclagan, Kate / Skene, Simon S / Bajwa-Joseph, Martha / Letchford, Dawn / Chowdhury, Kashfia / Hibbert, Steve / Budnik, Natalia / Zampedri, Luca / Dickson, John / Li, Yazhou / Aviles-Olmos, Iciar / Warner, Thomas T / Limousin, Patricia / Lees, Andrew J / Greig, Nigel H / Tebbs, Susan / Foltynie, Thomas. ·Sobell Department of Motor Neuroscience, University College London Institute of Neurology and the National Hospital for Neurology and Neurosurgery, London, UK. · Comprehensive Clinical Trials Unit, University College London, London, UK. · Leonard Wolfson Experimental Neuroscience Centre, London, UK. · Institute of Nuclear Medicine, University College London Hospitals NHS Trust, London, UK. · Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA. · Queen Square Brain Bank, London, UK. · Sobell Department of Motor Neuroscience, University College London Institute of Neurology and the National Hospital for Neurology and Neurosurgery, London, UK. Electronic address: t.foltynie@ucl.ac.uk. ·Lancet · Pubmed #28781108.

ABSTRACT: BACKGROUND: Exenatide, a glucagon-like peptide-1 (GLP-1) receptor agonist, has neuroprotective effects in preclinical models of Parkinson's disease. We investigated whether these effects would be apparent in a clinical trial. METHODS: In this single-centre, randomised, double-blind, placebo-controlled trial, patients with moderate Parkinson's disease were randomly assigned (1:1) to receive subcutaneous injections of exenatide 2 mg or placebo once weekly for 48 weeks in addition to their regular medication, followed by a 12-week washout period. Eligible patients were aged 25-75 years, had idiopathic Parkinson's disease as measured by Queen Square Brain Bank criteria, were on dopaminergic treatment with wearing-off effects, and were at Hoehn and Yahr stage 2·5 or less when on treatment. Randomisation was by web-based randomisation with a two strata block design according to disease severity. Patients and investigators were masked to treatment allocation. The primary outcome was the adjusted difference in the Movement Disorders Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) motor subscale (part 3) in the practically defined off-medication state at 60 weeks. All efficacy analyses were based on a modified intention-to-treat principle, which included all patients who completed any post-randomisation follow-up assessments. The study is registered at ClinicalTrials.gov (NCT01971242) and is completed. FINDINGS: Between June 18, 2014, and March 13, 2015, 62 patients were enrolled and randomly assigned, 32 to exenatide and 30 to placebo. Our primary analysis included 31 patients in the exenatide group and 29 patients in the placebo group. At 60 weeks, off-medication scores on part 3 of the MDS-UPDRS had improved by 1·0 points (95% CI -2·6 to 0·7) in the exenatide group and worsened by 2·1 points (-0·6 to 4·8) in the placebo group, an adjusted mean difference of -3·5 points (-6·7 to -0·3; p=0·0318). Injection site reactions and gastrointestinal symptoms were common adverse events in both groups. Six serious adverse events occurred in the exenatide group and two in the placebo group, although none in either group were judged to be related to the study interventions. INTERPRETATION: Exenatide had positive effects on practically defined off-medication motor scores in Parkinson's disease, which were sustained beyond the period of exposure. Whether exenatide affects the underlying disease pathophysiology or simply induces long-lasting symptomatic effects is uncertain. Exenatide represents a major new avenue for investigation in Parkinson's disease, and effects on everyday symptoms should be examined in longer-term trials. FUNDING: Michael J Fox Foundation for Parkinson's Research.

14 Article Dopaminergic neuron-specific deletion of p53 gene is neuroprotective in an experimental Parkinson's disease model. 2016

Qi, Xin / Davis, Brandon / Chiang, Yung-Hsiao / Filichia, Emily / Barnett, Austin / Greig, Nigel H / Hoffer, Barry / Luo, Yu. ·Department of Physiology & Biophysics, Case Western Reserve University, Cleveland, Ohio, USA. · Department of Neurological Surgery, Case Western Reserve University, Cleveland, Ohio, USA. · Division of Neurosurgery, Department of Surgery, College of Medicine, Taipei Medical University, Taipei, Taiwan. · Drug Design & Development Section, Translational Gerontology Branch, Intramural Research Program, National Institute of Aging, Baltimore, Maryland, USA. ·J Neurochem · Pubmed #27317935.

ABSTRACT: p53, a stress response gene, is involved in diverse cell death pathways and its activation has been implicated in the pathogenesis of Parkinson's disease (PD). However, whether the neuronal p53 protein plays a direct role in regulating dopaminergic (DA) neuronal cell death is unknown. In this study, in contrast to the global inhibition of p53 function by pharmacological inhibitors and in traditional p53 knock-out (KO) mice, we examined the effect of DA specific p53 gene deletion in DAT-p53KO mice. These DAT-p53KO mice did not exhibit apparent changes in the general structure and neuronal density of DA neurons during late development and in aging. However, in DA-p53KO mice treated with the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), we found that the induction of Bax and p53 up-regulated modulator of apoptosis (PUMA) mRNA and protein levels by MPTP were diminished in both striatum and substantia nigra of these mice. Notably, deletion of the p53 gene in DA neurons significantly reduced dopaminergic neuronal loss in substantia nigra, dopaminergic neuronal terminal loss at striatum and, additionally, decreased motor deficits in mice challenged with MPTP. In contrast, there was no difference in astrogliosis between WT and DAT-p53KO mice in response to MPTP treatment. These findings demonstrate a specific contribution of p53 activation in DA neuronal cell death by MPTP challenge. Our results further support the role of programmed cell death mediated by p53 in this animal model of PD and identify Bax, BAD and PUMA genes as downstream targets of p53 in modulating DA neuronal death in the in vivo MPTP-induced PD model. We deleted p53 gene in dopaminergic neurons in late developmental stages and found that DA specific p53 deletion is protective in acute MPTP animal model possibly through blocking MPTP-induced BAX and PUMA up-regulation. Astrocyte activation measured by GFAP positive cells and GFAP gene up-regulation in the striatum shows no difference between wt and DA-p53 ko mice.

15 Article Transgenerational latent early-life associated regulation unites environment and genetics across generations. 2016

Lahiri, Debomoy K / Maloney, Bryan / Bayon, Baindu L / Chopra, Nipun / White, Fletcher A / Greig, Nigel H / Nurnberger, John I. ·Department of Psychiatry, Stark Neurosciences Research Institute, Indiana University School of Medicine, 320 West 15th Street, Indianapolis, IN 46202, USA. · Department of Medical & Molecular Genetics, Indiana University School of Medicine, 320 West 15th Street, Indianapolis, IN 46202, USA. · Department of Anesthesia, Stark Neurosciences Research Institute, Indiana University School of Medicine, 320 West 15th Street, Indianapolis, IN 46202, USA. · Translational Gerontology Branch, National Institute on Aging, NIH, Baltimore, MD 21224, USA. ·Epigenomics · Pubmed #26950428.

ABSTRACT: The origin of idiopathic diseases is still poorly understood. The latent early-life associated regulation (LEARn) model unites environmental exposures and gene expression while providing a mechanistic underpinning for later-occurring disorders. We propose that this process can occur across generations via transgenerational LEARn (tLEARn). In tLEARn, each person is a 'unit' accumulating preclinical or subclinical 'hits' as in the original LEARn model. These changes can then be epigenomically passed along to offspring. Transgenerational accumulation of 'hits' determines a sporadic disease state. Few significant transgenerational hits would accompany conception or gestation of most people, but these may suffice to 'prime' someone to respond to later-life hits. Hits need not produce symptoms or microphenotypes to have a transgenerational effect. Testing tLEARn requires longitudinal approaches. A recently proposed longitudinal epigenome/envirome-wide association study would unite genetic sequence, epigenomic markers, environmental exposures, patient personal history taken at multiple time points and family history.

16 Article Blast traumatic brain injury-induced cognitive deficits are attenuated by preinjury or postinjury treatment with the glucagon-like peptide-1 receptor agonist, exendin-4. 2016

Tweedie, David / Rachmany, Lital / Rubovitch, Vardit / Li, Yazhou / Holloway, Harold W / Lehrmann, Elin / Zhang, Yongqing / Becker, Kevin G / Perez, Evelyn / Hoffer, Barry J / Pick, Chaim G / Greig, Nigel H. ·Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA. Electronic address: tweedieda@grc.nia.nih.gov. · Department of Anatomy and Anthropology, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel. · Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA. · Laboratory of Genetics, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA. · Laboratory of Behavioral Neuroscience, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA. · Department of Neurosurgery, Case Western Reserve University School of Medicine, Cleveland, OH, USA; Graduate Program in Neuroregeneration, Taipei Medical University, Taipei, Taiwan. · Department of Anatomy and Anthropology, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel; Sagol School of Neuroscience, Tel-Aviv University, Tel-Aviv, Israel. ·Alzheimers Dement · Pubmed #26327236.

ABSTRACT: INTRODUCTION: Blast traumatic brain injury (B-TBI) affects military and civilian personnel. Presently, there are no approved drugs for blast brain injury. METHODS: Exendin-4 (Ex-4), administered subcutaneously, was evaluated as a pretreatment (48 hours) and postinjury treatment (2 hours) on neurodegeneration, behaviors, and gene expressions in a murine open field model of blast injury. RESULTS: B-TBI induced neurodegeneration, changes in cognition, and genes expressions linked to dementia disorders. Ex-4, administered preinjury or postinjury, ameliorated B-TBI-induced neurodegeneration at 72 hours, memory deficits from days 7-14, and attenuated genes regulated by blast at day 14 postinjury. DISCUSSION: The present data suggest shared pathologic processes between concussive and B-TBI, with end points amenable to beneficial therapeutic manipulation by Ex-4. B-TBI-induced dementia-related gene pathways and cognitive deficits in mice somewhat parallel epidemiologic studies of Barnes et al. who identified a greater risk in US military veterans who experienced diverse TBIs, for dementia in later life.

17 Article Molecular docking study of catecholamines and [4-(propan-2-yl) phenyl]carbamic acid with tyrosine hydroxylase. 2012

Parveen, Zahida / Nawaz, Muhammad Sulaman / Shakil, Shazi / Greig, Nigel H / Kamal, Mohammad A. ·National Center for Bioinformatics, Quaid-I-Azam University, Islamabad, Pakistan. ·CNS Neurol Disord Drug Targets · Pubmed #22583429.

ABSTRACT: Parkinson's disease is a major age-related neurodegenerative disorder. As the classical disease-related motor symptoms are associated with the loss of dopamine-generating cells within the substantia nigra, tyrosine hydroxylase (TH), the rate-limiting enzyme in the synthesis of catecholamines has become an important target in the development of Parkinson's disease drug candidates, with the focus to augment TH levels or its activity. By contrast, TH inhibitors are of relevance in the treatment of conditions associated with catecholamine over-production, as occurs in pheochromocytomas. To aid characterizing new drug candidates, a molecular docking study of catecholamines and a novel hypothetical compound [4-(propan-2-yl) phenyl]carbamic acid (PPCA) with TH is described. Docking was performed using Autodock4.2 and results were analyzed using Chimera1.5.2. All the studied ligands were found to bind within a deep narrow groove lined with polar aromatic and acidic residues within TH. Our results corroborated a 'hexa interacting amino acids unit' located in this deep narrow groove crucial to the interaction of PPCA and the studied catecholamines with TH, whereby the 'His361-His336 dyad' was found to be even more crucial to these binding interactions. PPCA displayed a binding interaction with human TH that was comparable to the original TH substrate, L-tyrosine. Hence PPCA may warrant in vitro and in vivo characterization with TH to assess its potential as a candidate therapeutic.

18 Article Enhanced survival of dopaminergic neuronal transplants in hemiparkinsonian rats by the p53 inactivator PFT-α. 2011

Chou, J / Greig, N H / Reiner, D / Hoffer, B J / Wang, Y. ·National Institute on Drug Abuse, Baltimore, MD 21224, USA. ·Cell Transplant · Pubmed #21294958.

ABSTRACT: A key limiting factor impacting the success of cell transplantation for Parkinson's disease is the survival of the grafted cells, which are often short lived. The focus of this study was to examine a novel strategy to optimize the survival of exogenous fetal ventromesencephalic (VM) grafts by treatment with the p53 inhibitor, pifithrin-α (PFT-α), to improve the biological outcome of parkinsonian animals. Adult male Sprague-Dawley rats were given 6-hydroxydopamine into the left medial forebrain bundle to induce a hemiparkinsonian state. At 7 weeks after lesioning, animals were grafted with fetal VM or cortical tissue into the lesioned striatum and, thereafter, received daily PFT-α or vehicle injections for 5 days. Apomorphine-induced rotational behavior was examined at 2, 6, 9, and 12 weeks after grafting. Analysis of TUNEL or tyrosine hydroxylase (TH) immunostaining was undertaken at 5 days or 4 months after grafting. The transplantation of fetal VM tissue into the lesioned striatum reduced rotational behavior. A further reduction in rotation was apparent in animals receiving PFT-α and VM transplants. By contrast, no significant reduction in rotation was evident in animals receiving cortical grafts or cortical grafts + PFT-α. PFT-α treatment reduced TUNEL labeling and increased TH(+) cell and fiber density in the VM transplants. In conclusion, our data indicate that early postgrafting treatment with PFT-α enhances the survival of dopamine cell transplants and augments behavioral recovery in parkinsonian animals.