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Drug induced neurodegeneration

Bharat Bhusan Subudhi, Pratap Kumar Sahu
Oxidative stress in brain underlies the major neurological disorders including Alzheimer's disease (AD) and Parkinson's disease (PD). Peripherally, Angiotensin-II is a major effector of inflammation. Identification of its capacity to access brain during hypertension, as well as location of central rennin angiotensin system have led to its recognition as the major effector of oxidative stress in brain. Clinical uses of antioxidants to antagonize this oxidative stress have mostly failed. In this scenario, AT1 blockers have been investigated to prevent neurodegeneration...
October 24, 2016: Mini Reviews in Medicinal Chemistry
Ranjit Singh, Ranju Bansal
Neuroinflammatory mechanisms mediated by activated glial and cytokines (TNF-α, IL-1β) might contribute neuronal degeneration leading to Alzheimer's (AD) and Parkinson's disease (PD). Lipopolysaccharide (LPS) is an inflammogen derived from the cell wall of Gram-negative bacteria, which promotes neuroinflammation and subsequent neurodegeneration. Dehydroepiandrosterone (DHEA) and testosterone have been reported as neuroprotective steroids useful for the treatment of various neurodegenerative disorders. In the present study, several 16-arylidene steroidal derivatives have been evaluated as neuroprotective agents in LPS-treated animal models...
October 24, 2016: ACS Chemical Neuroscience
Bing Zhang, Jia-Wei Zhang, Wei-Ping Wang, Rui-Fang Dong, Shuang Tian, Chao Zhang
PURPOSE: Lamotrigine (LTG) is a broad-spectrum antiepileptic drug that is widely used in clinic. However, the effect of LTG on cognition and neurodegeneration during epilepsy treatment remains controversial. In this study, we compared the cognitive effects of LTG and sodium valproate in pentylenetetrazole (PTZ)-kindled animal model, and the dose dependency was tested for LTG. METHODS: PTZ-kindled animals were divided into the following treatment groups: control group, treated with 3...
October 12, 2016: Synapse
Oyinbo A Charles, Igbigbi S Patrick, Avwioro O Godwin
BACKGROUND: Alcohol-induced neurodegeneration, a consequence of chronic ethanol exposure, is a neuroadaptation that drives the progression of alcohol use disorder (AUD). Unfortunately, conventional drugs for AUDs do not prevent neurodegeneration as part of their pharmacological repertoire. Multimodal neuroprotective therapeutic agents are hypothesized to have high therapeutic utility in the treatment of central nervous system. Interestingly, nutraceuticals by nature are multimodal in mechanisms of action...
September 2016: Annals of Neurosciences
Keiko Imamura, Naruhiko Sahara, Nicholas M Kanaan, Kayoko Tsukita, Takayuki Kondo, Yumiko Kutoku, Yutaka Ohsawa, Yoshihide Sunada, Koichi Kawakami, Akitsu Hotta, Satoshi Yawata, Dai Watanabe, Masato Hasegawa, John Q Trojanowski, Virginia M-Y Lee, Tetsuya Suhara, Makoto Higuchi, Haruhisa Inoue
Mutations in the gene MAPT encoding tau, a microtubules-associated protein, cause a subtype of familial neurodegenerative disorder, known as frontotemporal lobar degeneration tauopathy (FTLD-Tau), which presents with dementia and is characterized by atrophy in the frontal and temporal lobes of the brain. Although induced pluripotent stem cell (iPSC) technology has facilitated the investigation of phenotypes of FTLD-Tau patient neuronal cells in vitro, it remains unclear how FTLD-Tau patient neurons degenerate...
October 10, 2016: Scientific Reports
Modesto de Candia, Giorgia Zaetta, Nunzio Denora, Domenico Tricarico, Maria Majellaro, Saverio Cellamare, Cosimo D Altomare
Several 6-substituted 3,4,5,6-tetrahydroazepino[4,3-b]indol-1(2H)-one (THAI) derivatives were synthesized and evaluated for their activity as cholinesterase (ChE) inhibitors. The most potent inhibitors were identified among 6-(2-phenylethyl)-THAI derivatives, and in particular compounds 12b and 12d proved to be very active against human BChE (IC50 = 13 and 1.8 nM, respectively), with 1000-fold selectivity over AChE. Structure-activity relationships highlighted critical features (e.g., ring fusion [4,3-b], integrity of the lactam CONH function) and favorable physicochemical properties of the 6-(2-phenylethyl) group (i...
September 13, 2016: European Journal of Medicinal Chemistry
Rui Wang, P Hemachandra Reddy
Excitatory glutamatergic neurotransmission via N-methyl-d-aspartate receptor (NMDAR) is critical for synaptic plasticity and survival of neurons. However, excessive NMDAR activity causes excitotoxicity and promotes cell death, underlying a potential mechanism of neurodegeneration occurred in Alzheimer's disease (AD). Studies indicate that the distinct outcomes of NMDAR-mediated responses are induced by regionalized receptor activities, followed by different downstream signaling pathways. The activation of synaptic NMDARs initiates plasticity and stimulates cell survival...
September 23, 2016: Journal of Alzheimer's Disease: JAD
Willyan Franco Hilario, Alice Laschuk Herlinger, Lorena Bianchine Areal, Lívia Silveira de Moraes, Tamara Andrea Alarcon Ferreira, Tassiane Emanuelle Servane Andrade, Cristina Martins-Silva, Rita Gomes Wanderley Pires
Parkinson's disease (PD) is the second most common neurodegenerative disease in the world, being characterized by dopaminergic neurodegeneration of substantia nigra pars compacta. PD pharmacotherapy has been based on dopamine replacement in the striatum with the dopaminergic precursor 3,4-dihydroxyphenylalanine (L-DOPA) and/or with dopaminergic agonists, alongside anticholinergic drugs in order to mitigate the motor abnormalities. However, these practices neither prevent nor stop the progression of the disease...
September 22, 2016: Journal of Molecular Neuroscience: MN
Edward Málaga-Trillo, Katharina Ochs
Prions and Amyloid beta (Aβ) peptides induce synaptic damage via complex mechanisms that include the pathological alteration of intracellular signaling cascades. The host-encoded cellular prion protein (PrP(C)) acts as a high-affinity cell surface receptor for both toxic species and it can modulate the endocytic trafficking of the N-methyl D-aspartate (NMDA) receptor and E-cadherin adhesive complexes via Src family kinases (SFKs). Interestingly, SFK-mediated control of endocytosis is a widespread mechanism used to regulate the activity of important transmembrane proteins, including neuroreceptors for major excitatory and inhibitory neurotransmitters...
September 20, 2016: Prion
Mari Paz Serrano, Raquel Herrero-Labrador, Hunter S Futch, Julia Serrano, Alejandro Romero, Ana Patricia Fernandez, Abdelouahid Samadi, Mercedes Unzeta, Jose Marco-Contelles, Ricardo Martínez-Murillo
BACKGROUND: The heterogeneity of Alzheimer disease requires the development of multitarget drugs for treating the symptoms of the disease and its progression. Both cholinergic and monoamine oxidase dysfunctions are involved in the pathological process. Thus, we hypothesized that the development of therapies focused on these targets might be effective. We have developed and assessed a new product, coded ASS234, a multipotent acetyl and butyrylcholinesterase/monoamine oxidase A-B inhibitor with a potent inhibitory effect on amyloid-β aggregation as well as antioxidant and antiapoptotic properties...
September 20, 2016: Journal of Psychiatry & Neuroscience: JPN
Antonietta Gentile, Alessandra Musella, Silvia Bullitta, Diego Fresegna, Francesca De Vito, Roberta Fantozzi, Eleonora Piras, Francesca Gargano, Giovanna Borsellino, Luca Battistini, Anna Schubart, Georgia Mandolesi, Diego Centonze
BACKGROUND: Data from multiple sclerosis (MS) and the MS rodent model, experimental autoimmune encephalomyelitis (EAE), highlighted an inflammation-dependent synaptopathy at the basis of the neurodegenerative damage causing irreversible disability in these disorders. This synaptopathy is characterized by an imbalance between glutamatergic and GABAergic transmission and has been proposed to be a potential therapeutic target. Siponimod (BAF312), a selective sphingosine 1-phosphate1,5 receptor modulator, is currently under investigation in a clinical trial in secondary progressive MS patients...
2016: Journal of Neuroinflammation
Ming-Chang Chiang, Yi-Chuan Cheng, Shiang-Jiuun Chen, Chia-Hui Yen, Rong-Nan Huang
Alzheimer's disease (AD) is the general consequence of dementia and is diagnostic neuropathology by the cumulation of amyloid-beta (Aβ) protein aggregates, which are thought to promote mitochondrial dysfunction processes leading to neurodegeneration. AMP-activated protein kinase (AMPK), a critical regulator of energy homeostasis and a major player in lipid and glucose metabolism, is potentially implied in the mitochondrial deficiency of AD. Metformin, one of the widespread used anti- metabolic disease drugs, use its actions in part by stimulation of AMPK...
October 1, 2016: Experimental Cell Research
Elena Beltramo, Tatiana Lopatina, Aurora Mazzeo, Ana I Arroba, Angela M Valverde, Cristina Hernández, Rafael Simó, Massimo Porta
AIMS: Diabetic retinopathy is considered a microvascular disease, but recent evidence has underlined early involvement of the neuroretina with interactions between microvascular and neural alterations. Topical administration of somatostatin (SST), a neuroprotective molecule with antiangiogenic properties, prevents diabetes-induced retinal neurodegeneration in animals. The α2-adrenergic receptor agonist brimonidine (BRM) decreases vitreoretinal vascular endothelial growth factor and inhibits blood-retinal barrier breakdown in diabetic rats...
August 23, 2016: Acta Diabetologica
Hayate Javed, Sheikh Azimullah, Salema B Abul Khair, Shreesh Ojha, M Emdadul Haque
BACKGROUND: Parkinson disease (PD) is a movement disorder affecting 1 % of people over the age of 60. The etiology of the disease is unknown; however, accumulating evidence suggests that mitochondrial defects, oxidative stress, and neuroinflammation play important roles in developing the disease. Current medications for PD can only improve its symptoms, but are unable to halt its progressive nature. Although many therapeutic approaches are available, new drugs are urgently needed for the treatment of PD...
2016: BMC Neuroscience
Leila Simani, Nima Naderi, Fariba Khodagholi, Masoud Mehrpour, Sanaz Nasoohi
Statins are widely used in high-risk patients to reduce the stroke incidence. However, little has been investigated about the impact of chronic pretreatment with statins on cerebral ischemic insult following defined arterial occlusion. To address this in experimental rats, in the present work, atorvastatin was orally dosed for 1 month to evaluate the outcomes of the subsequent occlusive stroke induced by middle cerebral artery occlusion (MCAO). Our data was suggestive of potential escalating impact of chronic atorvastatin (Atv; 10 mg/kg) on neurological function, but not infarct volume...
August 19, 2016: Journal of Molecular Neuroscience: MN
João Bernardo, Patrícia Valentão, Clara Grosso, Paula Andrade
The central nervous system (CNS) is a mythical target for drug delivery. There is an ongoing debate over the brain accessibility of flavonoids, a group of plant-derived secondary metabolites widely known by their multifarious bioactivities achieved by distinct mechanisms. Recently, their applicability in the management of neurologic and psychiatric disorders, such as Alzheimer's and Parkinson's diseases, and major depression, has received particular attention. To reach their target, flavonoids must cross over the ultimate obstacle - the blood-brain barrier - at pharmacologically effective concentrations...
August 8, 2016: Current Medicinal Chemistry
Yanchun Pan, Takuji Daito, Yo Sasaki, Yong Hee Chung, Xiaoyun Xing, Santhi Pondugula, S Joshua Swamidass, Ting Wang, Albert H Kim, Hiroko Yano
Although epigenetic abnormalities have been described in Huntington's disease (HD), the causal epigenetic mechanisms driving neurodegeneration in HD cortex and striatum remain undefined. Using an epigenetic pathway-targeted drug screen, we report that inhibitors of DNA methyltransferases (DNMTs), decitabine and FdCyd, block mutant huntingtin (Htt)-induced toxicity in primary cortical and striatal neurons. In addition, knockdown of DNMT3A or DNMT1 protected neurons against mutant Htt-induced toxicity, together demonstrating a requirement for DNMTs in mutant Htt-triggered neuronal death and suggesting a neurodegenerative mechanism based on DNA methylation-mediated transcriptional repression...
2016: Scientific Reports
Tugay Atalay, Ismail Gulsen, Nese Colcimen, Hamit Hakan Alp, Enver Sosuncu, Ilker Alaca, Hakan Ak, Murat Cetin Ragbetli
AIM: Traumatic brain injury (TBI) is a complex process that increasing evidence has demonstrated that reactive oxygen species contribute to brain injury. Revesterol (RVT), which exhibits significant antioxidant properties, is neuroprotective against excitotoxicity, ischemia, and hypoxia. Our aim was to evaluate the neuroprotective effects of RVT on the hippocampus in a rat model of TBI. MATERIAL AND METHODS: Seven rats were divided into four. A moderate degree of head trauma was induced using Feeney's falling weight technique...
May 25, 2016: Turkish Neurosurgery
Christopher J Gaffney, Freya Shephard, Jeff Chu, David L Baillie, Ann Rose, Dumitru Constantin-Teodosiu, Paul L Greenhaff, Nathaniel J Szewczyk
BACKGROUND: Declines in skeletal muscle structure and function are found in various clinical populations, but the intramuscular proteolytic pathways that govern declines in these individuals remain relatively poorly understood. The nematode Caenorhabditis elegans has been developed into a model for identifying and understanding these pathways. Recently, it was reported that UNC-105/degenerin channel activation produced muscle protein degradation via an unknown mechanism. METHODS: Generation of transgenic and double mutant C...
May 2016: Journal of Cachexia, Sarcopenia and Muscle
Toshiharu Nagatsu, Ikuko Nagatsu
Tyrosine hydroxylase (TH), which was discovered at the National Institutes of Health (NIH) in 1964, is a tetrahydrobiopterin (BH4)-requiring monooxygenase that catalyzes the first and rate-limiting step in the biosynthesis of catecholamines (CAs), such as dopamine, noradrenaline, and adrenaline. Since deficiencies of dopamine and noradrenaline in the brain stem, caused by neurodegeneration of dopamine and noradrenaline neurons, are mainly related to non-motor and motor symptoms of Parkinson's disease (PD), we have studied human CA-synthesizing enzymes [TH; BH4-related enzymes, especially GTP-cyclohydrolase I (GCH1); aromatic L-amino acid decarboxylase (AADC); dopamine β-hydroxylase (DBH); and phenylethanolamine N-methyltransferase (PNMT)] and their genes in relation to PD in postmortem brains from PD patients, patients with CA-related genetic diseases, mice with genetically engineered CA neurons, and animal models of PD...
November 2016: Journal of Neural Transmission
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