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Drug induced neurodegeneration

Pradeep Phadnis, Purnima Dey Sarkar, Mithun Singh Rajput
BACKGROUND: Initial evidences have shown that diabetes mellitus occurs concomitantly with obsessive-compulsive disorder (OCD) symptomatology. Serotonergic psychiatric therapy posits that serotonin is a central character in the management of OCD. Hence, it is worth investigating novel chemical entities affecting the serotonergic system for targeting OCD. An isoflavonoid phytoestrogen, genistein, has been recognized as of great pharmacological value especially for protecting neurodegeneration, depression (serotonin regulation), and diabetes...
March 21, 2018: Journal of Basic and Clinical Physiology and Pharmacology
Kurt A Jellinger, Amos D Korczyn
BACKGROUND: Dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD), which share many clinical, neurochemical, and morphological features, have been incorporated into DSM-5 as two separate entities of major neurocognitive disorders with Lewy bodies. Despite clinical overlap, their diagnosis is based on an arbitrary distinction concerning the time of onset of motor and cognitive symptoms, namely as early cognitive impairment in DLB and later onset following that of motor symptoms in PDD...
March 6, 2018: BMC Medicine
Md Suhail Alam, Bruce Cooper, Joseph D Farris, Kasturi Haldar
Histone deacetylase (HDAC) inhibitors are of significant interest as drugs. However, their use to treat neurological disorders has raised concern because HDACs are required for brain function. We have previously shown that a triple combination formulation (TCF) of the pan HDACi vorinostat (Vo), 2-hydroxypropyl-beta-cyclodextrin (HPBCD) and polyethylene glycol (PEG) 400 improves pharmacokinetic exposure and entry of Vo into the brain. TCF treatment significantly delayed both neurodegeneration and death in the Npc1nmf164 murine model of Niemann-Pick Type C (NPC) disease...
March 1, 2018: Scientific Reports
Vrinda M, Arun S, Srikumar B N, Bindu M Kutty, Shankaranarayana Rao B S
Epilepsy is a neurological condition associated with seizures, neurodegeneration, circuit reorganization, and other structural and functional abnormalities. These elements ultimately lead to behavioural alterations such as anxiety, depression, and importantly cognitive impairment like learning disability and memory impairment. These factors can attribute to acceleration of aging and cognitive impairment in middle-aged people, which is otherwise evident in dementia and Alzheimer's disease among elderly people...
February 19, 2018: Journal of Chemical Neuroanatomy
Patrizia Ambrogini, Maria Cristina Albertini, Michele Betti, Claudia Galati, Davide Lattanzi, David Savelli, Michael Di Palma, Stefania Saccomanno, Desirée Bartolini, Pierangelo Torquato, Gabriele Ruffolo, Fabiola Olivieri, Francesco Galli, Eleonora Palma, Andrea Minelli, Riccardo Cuppini
Seizure-triggered maladaptive neural plasticity and neuroinflammation occur during the latent period as a key underlying event in epilepsy chronicization. Previously, we showed that α-tocopherol (α-T) reduces hippocampal neuroglial activation and neurodegeneration in the rat model of kainic acid (KA)-induced status epilepticus (SE). These findings allowed us to postulate an antiepileptogenic potential for α-T in hippocampal excitotoxicity, in line with clinical evidence showing that α-T improves seizure control in drug-resistant patients...
February 22, 2018: Molecular Neurobiology
Peng Feng, Xiangjian Zhang, Dongfang Li, Chenhui Ji, Ziyue Yuan, Ruifang Wang, Guofang Xue, Guanglai Li, Christian Hölscher
Type 2 diabetes mellitus (T2DM) is a risk factors for developing Parkinson's disease (PD). Insulin desensitization is observed in the brains of PD patients, which may be an underlying mechanism that promotes neurodegeneration. Incretin hormones are growth factors that can re-sensitize insulin signalling. We have previously shown that analogues of the incretins GLP-1 or GIP have neuroprotective effects in the MPTP mouse model of PD. Novel dual GLP-1/GIP receptor agonists have been developed as treatments for T2DM...
February 17, 2018: Neuropharmacology
Andrew Octavian Sasmita, Anna Pick Kiong Ling, Kenny Gah Leong Voon, Rhun Yian Koh, Ying Pei Wong
Neurodegeneration is typically preceded by neuroinflammation generated by the nervous system to protect itself from tissue damage, however, excess neuroinflammation may inadvertently cause more harm to the surrounding tissues. Attenuating neuroinflammation with non‑steroidal anti‑inflammatory drugs can inhibit neurodegeneration. However, such treatments induce chronic side effects, including stomach ulcers. Madecassoside, a triterpene derived from Centella asiatica, is considered to be an alternative treatment of inflammation...
February 9, 2018: International Journal of Molecular Medicine
Sudip Mondal, Evan Hegarty, James J Sahn, Luisa L Scott, Sertan K Gökçe, Christopher Martin, Navid Ghorashian, Praveen Navoda Satarasinghe, Sangeetha Iyer, Wisath Sae-Lee, Timothy Hodges, Jonathan T Pierce, Stephen F Martin, Adela Ben-Yakar
The nematode Caenorhabditis elegans, with tractable genetics and a well-defined nervous system, provides a unique whole-animal model system to identify novel drug targets and therapies for neurodegenerative diseases. Large-scale drug or target screens in models that recapitulate the subtle age- and cell-specific aspects of neurodegenerative diseases are limited by a technological requirement for high-throughput analysis of neuronal morphology. Recently we developed a model of amyloid precursor protein-induced neurodegeneration that exhibits progressive degeneration of select cholinergic neurons...
February 9, 2018: ACS Chemical Neuroscience
Giusy T Coppolino, Davide Marangon, Camilla Negri, Gianluca Menichetti, Marta Fumagalli, Paolo Gelosa, Leda Dimou, Roberto Furlan, Davide Lecca, Maria P Abbracchio
Promoting remyelination is recognized as a novel strategy to foster repair in neurodegenerative demyelinating diseases, such as multiple sclerosis. In this respect, the receptor GPR17, recently emerged as a new target for remyelination, is expressed by early oligodendrocyte precursors (OPCs) and after a certain differentiation stage it has to be downregulated to allow progression to mature myelinating oligodendrocytes. Here, we took advantage of the first inducible GPR17 reporter mouse line (GPR17-iCreERT2 xCAG-eGFP mice) allowing to follow the final fate of GPR17+ cells by tamoxifen-induced GFP-labeling to unveil the destiny of these cells in two demyelination models: experimental autoimmune encephalomyelitis (EAE), characterized by marked immune cell activation and inflammation, and cuprizone induced demyelination, where myelin dysfunction is achieved by a toxic insult...
February 9, 2018: Glia
Flávia Pereira Dias Viegas, Matheus de Freitas Silva, Miguel Divino da Rocha, Maísa Rosa Castelli, Mariana Máximo Riquiel, Rafael Pereira Machado, Sarah Macedo Vaz, Laís Medeiros Simões de Lima, Karla Cristine Mancini, Patrícia Cruz Marques de Oliveira, Élida Parreira Morais, Vanessa Silva Gontijo, Fernanda Motta R da Silva, Dora D'Alincourt da Fonseca Peçanha, Newton Gonçalves Castro, Gilda A Neves, Alexandre Giusti-Paiva, Fabiana Cardoso Vilela, Lidiane Orlandi, Ihosvany Camps, Márcia Paranho Veloso, Luis Felipe Leomil Coelho, Marisa Ionta, Guilherme Álvaro Ferreira-Silva, Rodrigo Machado Pereira, Laurent E Dardenne, Isabella Alvim Guedes, Wellerson de Oliveira Carneiro Junior, Paula Maria Quaglio Bellozi, Antônio Carlos Pinheiro de Oliveira, Fábio Furlan Ferreira, Letizia Pruccoli, Andrea Tarozzi, Claudio Viegas
A new series of sixteen multifunctional N-benzyl-piperidine-aryl-acylhydrazones hybrid derivatives was synthesized and evaluated for multi-target activities related to Alzheimer's disease (AD). The molecular hybridization approach was based on the combination, in a single molecule, of the pharmacophoric N-benzyl-piperidine subunit of donepezil, the substituted hydroxy-piperidine fragment of the AChE inhibitor LASSBio-767, and an acylhydrazone linker, a privileged structure present in a number of synthetic aryl- and aryl-acylhydrazone derivatives with significant AChE and anti-inflammatory activities...
January 31, 2018: European Journal of Medicinal Chemistry
Xiuju Yan, Lixiao Xu, Chenchen Bi, Dongyu Duan, Liuxiang Chu, Xin Yu, Zimei Wu, Aiping Wang, Kaoxiang Sun
Introduction: Efficient delivery of rotigotine into the brain is crucial for obtaining maximum therapeutic efficacy for Parkinson's disease (PD). Therefore, in the present study, we prepared lactoferrin-modified rotigotine nanoparticles (Lf-R-NPs) and studied their biodistribution, pharmacodynamics, and neuroprotective effects following nose-to-brain delivery in the rat 6-hydroxydopamine model of PD. Materials and methods: The biodistribution of rotigotine nanoparticles (R-NPs) and Lf-R-NPs after intranasal administration was assessed by liquid extraction surface analysis coupled with tandem mass spectrometry...
2018: International Journal of Nanomedicine
Jaume Folch, Miren Ettcheto, Oriol Busquets, Elena Sánchez-López, Rubén D Castro-Torres, Ester Verdaguer, Patricia R Manzine, Saghar Rabiei Poor, María Luisa García, Jordi Olloquequi, Carlos Beas-Zarate, Carme Auladell, Antoni Camins
Alzheimer's disease (AD) is progressive neurodegenerative disorder characterized by brain accumulation of the amyloid β peptide (Aβ), which form senile plaques, neurofibrillary tangles (NFT) and, eventually, neurodegeneration and cognitive impairment. Interestingly, epidemiological studies have described a relationship between type 2 diabetes mellitus (T2DM) and this pathology, being one of the risk factors for the development of AD pathogenesis. Information as it is, it would point out that, impairment in insulin signalling and glucose metabolism, in central as well as peripheral systems, would be one of the reasons for the cognitive decline...
January 29, 2018: Pharmaceuticals
Dinesh Upadhya, Olagide W Castro, Raghavendra Upadhya, Ashok K Shetty
The hippocampus is one of the most susceptible regions in the brain to be distraught with status epilepticus (SE) induced injury. SE can occur from numerous causes and is more frequent in children and the elderly population. Administration of a combination of antiepileptic drugs can abolish acute seizures in most instances of SE but cannot prevent the morbidity typically seen in survivors of SE such as cognitive and mood impairments and spontaneous recurrent seizures. This is primarily due to the inefficiency of antiepileptic drugs to modify the evolution of SE-induced initial precipitating injury into a series of epileptogenic changes followed by a state of chronic epilepsy...
January 25, 2018: Molecular Neurobiology
Sarah-Lena Offenburger, Elisabeth Jongsma, Anton Gartner
The loss of dopaminergic neurons is a hallmark of Parkinson's disease, the aetiology of which is associated with increased levels of oxidative stress. We used C. elegans to screen for genes that protect dopaminergic neurons against oxidative stress and isolated glit-1 (gliotactin (Drosophila neuroligin-like) homologue). Loss of the C. elegans neuroligin-like glit-1 causes increased dopaminergic neurodegeneration after treatment with 6-hydroxydopamine (6-OHDA), an oxidative-stress inducing drug that is specifically taken up into dopaminergic neurons...
January 2018: PLoS Genetics
Ashiq Hussain, Atefeh Pooryasin, Mo Zhang, Laura F Loschek, Marco La Fortezza, Anja B Friedrich, Catherine-Marie Blais, Habibe K Üçpunar, Vicente A Yépez, Martin Lehmann, Nicolas Gompel, Julien Gagneur, Stephan J Sigrist, Ilona C Grunwald Kadow
Loss of the sense of smell is among the first signs of natural aging and neurodegenerative diseases such as Alzheimer's and Parkinson's. Cellular and molecular mechanisms promoting this smell loss are not understood. Here, we show that Drosophila melanogaster also loses olfaction before vision with age. Within the olfactory circuit, cholinergic projection neurons show a reduced odor response accompanied by a defect in axonal integrity and reduction in synaptic marker proteins. Using behavioral functional screening, we pinpoint that expression of the mitochondrial reactive oxygen scavenger SOD2 in cholinergic projection neurons is necessary and sufficient to prevent smell degeneration in aging flies...
January 18, 2018: ELife
Liubov S Kalinichenko, Erich Gulbins, Johannes Kornhuber, Christian P Müller
Psychoactive drug use is a common behavior in many societies worldwide, frequently associated with drug instrumentalization. Regular use may develop into drug addiction, which is a severe psychiatric disorder with multiple pathological effects to virtually all organ systems. Treatment strategies for addiction are often insufficient with no broadly working pharmaco-treatment available. Recently, lipids, and particularly sphingolipids, have been considered as new mediators in the pathogenic pathways and as possible therapeutic targets for the treatment of addictive states...
January 10, 2018: Journal of Neural Transmission
Robert E Becker, Nigel H Greig, Debomoy K Lahiri, Joseph Bledsoe, Sarah Majercik, Clive Ballard, Dag Aarsland, Lon S Schneider, Douglas Flanagan, Ramprakash Govindarajan, Mary Sano, Luigi Ferrucci, Dimitrios Kapogiannis
BACKGROUND: Concussion (mild) and other moderate traumatic brain injury (TBI) and Alzheimer's disease (AD) share overlapping neuropathologies, including neuronal pre-programmed cell death (PPCD), and clinical impairments and disabilities. Multiple clinical trials targeting mechanisms based on the Amyloid Hypothesis of AD have so far failed, indicating that it is prudent for new drug developments to also pursue mechanisms independent of the Amyloid Hypothesis. To address these issue, we have proposed the use of an animal model of concussion/TBI as a supplement to AD transgenic mice to provide an indication of an AD drug candidate's potential for preventing PPCD and resulting progression towards dementia in AD...
January 10, 2018: Current Alzheimer Research
Juhee Lim, Yeojin Bang, Jong-Hyun Choi, Arum Han, Min-Soo Kwon, Kwang Hyeon Liu, Hyun Jin Choi
Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most common genetic cause of Parkinson's disease (PD). The neuropathology of LRRK2 mutation-related PD is indistinguishable from that of idiopathic PD, including increased dopaminergic neurodegeneration and Lewy bodies, but its subtle non-motor phenotypes have not been fully evaluated. In the present study, we examined anxiety/depression-like behaviors and accompanying neurochemical changes in differently aged transgenic (Tg) mice expressing human mutant LRRK2 G2019S...
January 5, 2018: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Yaowaporn Sangsen, Thongchai Sooksawate, Kittisak Likhitwitayawuid, Boonchoo Sritularak, Ruedeekorn Wiwattanapatapee
The polyphenol compound, oxyresveratrol (OXY) possesses potent antioxidant and neuroprotective properties of potential utility in the treatment of Alzheimer's disease. However, the low oral bioavailability limits its neuroprotective effect and clinical application. The neuroprotective effect of orally administered OXY-loaded self-microemulsifying drug delivery system (OXY-SMEDDS) was compared with free OXY in vivo. Mice were orally administered either free OXY or OXY-SMEDDS once daily at a dose of 90, 180, or 360 mg/kg for 14 d...
January 4, 2018: Planta Medica
Laraib Liaquat, Zehra Batool, Sadia Sadir, Sahar Rafiq, SidrahShahzad, Tahira Perveen, Saida Haider
AIMS: Free radical mediated neurotoxicity is a leading cause of neurodegenerative disorders. Neurodegeneration due to oxidative stress can produce cognitive dysfunctions. Flavonoids and curcuminoids are naturally occurring polyphenolic compounds that display a variety of therapeutic importance against oxidative stress. MAIN METHODS: This study was designed to assess potential role of polyphenolic compounds in neurocognitive functions and prevention against oxidative stress...
December 26, 2017: Life Sciences
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