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Cns diseases

Iara Barreto Neves Oliveira, Rodrigo Saar Gomes, Larissa Fonseca Gomides, Jéssica Cristina Dos Santos, Marcos Alexandre Diniz Carneiro, Fátima Ribeiro-Dias, Denise Sisterolli Diniz
OBJECTIVE: Multiple sclerosis (MS) is a multifactorial chronic disease that affects the central nervous system (CNS). Toll-like receptors (TLRs) play a central role in cytokine production after pathogen- and danger-associated molecular patterns (PAMPs and DAMPs) and contribute to CNS damage in MS patients. Here, we evaluated the effects of interferon (IFN)-β treatment in TLR2 and TLR4-dependent cytokine production and mRNA expression in whole-blood cell cultures from MS patients. METHODS: We evaluated cytokine production by ELISA from whole-blood cell culture supernatants and mRNA expression by real-time polymerase chain reaction in peripheral blood mononuclear cells (PBMCs)...
March 21, 2019: Neuroimmunomodulation
In Ki Cho, Bo Yang, Craig Forest, Lu Qian, Anthony W S Chan
Huntington's disease (HD) is a devastating monogenic, dominant, hereditary, neurodegenerative disease. HD is caused by the expansion of CAG repeats in exon 1 of the huntingtin (HTT) gene, IT15, resulting in an expanded polyglutamine (polyQ) residue in the N-terminus of the HTT protein. HD is characterized by the accumulation of mutant HTT (mHTT) in neural and somatic cells. Progressive brain atrophy occurs initially in the striatum and extends to different brain regions with progressive decline in cognitive, behavioral and motor functions...
2019: PloS One
Michael E Benros, Preben B Mortensen
An immunologic component to schizophrenia has been increasingly recognized, where infections and chronic inflammatory diseases as atopic disorders and autoimmune diseases could be involved in the pathogenesis of schizophrenia. Psychotic symptoms can be directly triggered by infections reaching the CNS, or be secondary to systemic inflammation indirectly affecting the brain through immune components, such as brain-reactive antibodies and cytokines. Large-scale epidemiological studies have consistently displayed that infections, autoimmune diseases, and atopic disorders are associated with increased risk of schizophrenia and that schizophrenia is associated with increased levels of immune markers at diagnosis...
March 21, 2019: Current Topics in Behavioral Neurosciences
Mohammad Mahdi Eftekharian, Alireza Komaki, Mehrdokht Mazdeh, Shahram Arsang-Jang, Mohammad Taheri, Soudeh Ghafouri-Fard
Multiple sclerosis (MS) as a chronic autoimmune disease of the central nervous system (CNS) has been associated with dysregulation of several genes including miRNAs. In the present study, we assessed transcript levels of seven miRNAs (miR-96-5p, miR-211-5p, miR-15a, miR-34a-5p, miR-204-5p, miR-501-5p, and miR-524-5p) in the peripheral blood of MS patients compared with healthy subjects in association with response to fingolimod treatment. Expression levels of miR-211-5p and miR-34a-5p were significantly decreased in MS patients compared with healthy subjects (P values of 0...
March 21, 2019: Journal of Molecular Neuroscience: MN
Sohair Geyer, Muazzam Jacobs, Nai-Jen Hsu
Bacterial infection of the central nervous system (CNS) is a severe and life-threatening condition with high mortality, and it may lead to permanent neurological deficits in survivors. Increasing evidence indicates that astrocytes, as the most abundant CNS glial cell population, regulate innate and adaptive immune responses in the CNS under pathological conditions in addition to their role in the maintenance of CNS homeostasis and neuronal function. Following antigen recognition, astrocytes participate in the initiation of innate immune responses, and prompt an adaptive immune response to recruit peripheral immune cells...
2019: Frontiers in Molecular Neuroscience
Mathilde Raverdeau, Maria Christofi, Anna Malara, Mieszko M Wilk, Alicja Misiak, Lucia Kuffova, Tian Yu, Aoife M McGinley, Shauna M Quinn, Chandirasegaran Massilamany, Jay Reddy, John V Forrester, Kingston Hg Mills
Regulatory T (Treg) cells help to maintain tolerance and prevent the development of autoimmune diseases. Retinoic acid (RA) can promote peripheral conversion of naïve T cells into Foxp3+ Treg cells. Here, we show that RA can act as an adjuvant to induce antigen-specific type 1 Treg (Tr1) cells, which is augmented by co-administration of IL-2. Immunization of mice with the model antigen KLH in the presence of RA and IL-2 induces T cells that secrete IL-10, but not IL-17 or IFN-γ, and express LAG-3, CD49b and PD-1 but not Foxp3, a phenotype typical of Tr1 cells...
March 20, 2019: EMBO Reports
Laurine Becquet, Catalina Abad, Mathilde Leclercq, Camille Miel, Laetitia Jean, Gaëtan Riou, Alain Couvineau, Olivier Boyer, Yossan-Var Tan
BACKGROUND: Orexins (hypocretins, Hcrt) A and B are GPCR-binding hypothalamic neuropeptides known to regulate sleep/wake states and feeding behavior. A few studies have shown that orexin A exhibits anti-inflammatory and neuroprotective properties, suggesting that it might provide therapeutic effects in inflammatory and neurodegenerative diseases like multiple sclerosis (MS). In MS, encephalitogenic Th1 and Th17 cells trigger an inflammatory response in the CNS destroying the myelin sheath...
March 20, 2019: Journal of Neuroinflammation
Miguel A Maia, Emília Sousa
Alzheimer's disease (AD) is a growing global health concern with a massive impact on affected individuals and society. Despite the considerable advances achieved in the understanding of AD pathogenesis, researchers have not been successful in fully identifying the mechanisms involved in disease progression. The amyloid hypothesis, currently the prevalent theory for AD, defends the deposition of β-amyloid protein (Aβ) aggregates as the trigger of a series of events leading to neuronal dysfunction and dementia...
March 19, 2019: Pharmaceuticals
Joseph D Panarese, Darren W Engers, Yong-Jin Wu, Joanne J Bronson, John E Macor, Aspen Chun, Alice L Rodriguez, Andrew S Felts, Julie L Engers, Matthew T Loch, Kyle A Emmitte, Arlindo L Castelhano, Michael J Kates, Michael A Nader, Carrie K Jones, Anna L Blobaum, P Jeffrey Conn, Colleen M Niswender, Corey R Hopkins, Craig W Lindsley
Herein, we report the discovery of a novel potent, selective, CNS penetrant, and orally bioavailable mGlu4 PAM, VU0652957 (VU2957, Valiglurax). VU2957 possessed attractive in vitro and in vivo pharmacological and DMPK properties across species. To advance toward the clinic, a spray-dried dispersion (SDD) formulation of VU2957 was developed to support IND-enabling toxicology studies. Based on its overall profile, VU2957 was evaluated as a preclinical development candidate for the treatment of Parkinson's disease...
March 14, 2019: ACS Medicinal Chemistry Letters
Simone Brogi, Giuseppe Campiani, Margherita Brindisi, Stefania Butini
The allosteric targeting of ionotropic glutamate receptors (iGluRs) is a valuable approach for treating various central nervous system (CNS) disorders. In this frame, this Innovations provides a summary of the state-of-the art in the development of allosteric modulators for iGluRs and offers an outlook regarding innovative strategies for treating neurological diseases.
March 14, 2019: ACS Medicinal Chemistry Letters
Ferdinando Nicoletti, Rosamaria Orlando, Luisa Di Menna, Milena Cannella, Serena Notartomaso, Giada Mascio, Luisa Iacovelli, Francesco Matrisciano, Francesco Fazio, Filippo Caraci, Agata Copani, Giuseppe Battaglia, Valeria Bruno
Metabotropic glutamate (mGlu) receptors are considered as candidate drug targets for the treatment of schizophrenia. These receptors form a family of eight subtypes (mGlu1 to -8), of which mGlu1 and -5 are coupled to Gq/11 , and all other subtypes are coupled to Gi/o . Here, we discuss the possibility that selective ligands of individual mGlu receptor subtypes may be effective in controlling the core symptoms of schizophrenia, and, in some cases, may impact mechanisms underlying the progression of the disorder...
2019: Frontiers in Psychiatry
Lei Liu, Logan M Locascio, Sylvain Doré
Ischemic stroke is one of the leading causes of death and long-term disability worldwide; however, effective clinical approaches are still limited. The transcriptional factor Nrf2 is a master regulator in cellular and organismal defense against endogenous and exogenous stressors by coordinating basal and stress-inducible activation of multiple cytoprotective genes. The Nrf2 network not only tightly controls redox homeostasis but also regulates multiple intermediary metabolic processes. Therefore, targeting Nrf2 has emerged as an attractive therapeutic strategy for the prevention and treatment of CNS diseases including stroke...
2019: Frontiers in Pharmacology
Eugenia Falomir-Lockhart, Franco Juan Cruz Dolcetti, Luis Miguel García-Segura, Claudia Beatriz Hereñú, Maria Jose Bellini
Microglial cells become dystrophic with aging; this phenotypic alteration contributes to basal central nervous system (CNS) neuroinflammation being a risk factor for age related neurodegenerative diseases. In previous studies we have observed that insulin like growth factor 1 (IGF1) gene therapy is a feasible approach to target brain cells, and that is effective to modify inflammatory response in vitro and to ameliorate cognitive or motor deficits in vivo . Based on these findings, the main aim of the present study is to investigate the effect of IGF1 gene therapy on microglia distribution and morphology in the senile rat...
2019: Frontiers in Aging Neuroscience
Elif G Umıt, Mehmet Baysal, Volkan Bas, Ismail Asker, Onur Kırkızlar, Ahmet M Demır
PURPOSE: Multiple myeloma is a chronic, uncurable hematological cancer with the involvement of multiple organ systems. As a disease affecting older patients, the treatment of multiple myeloma should be based on individual patient characteristics. Polypharmacy is an increasing problem in the care of older patients and in patients with multiple myeloma, polypharmacy is almost inevitable. We aimed to evaluate the applicability of polypharmacy definitions and the relation of polypharmacy with disease outcomes in patients with multiple myeloma...
March 19, 2019: Journal of Oncology Pharmacy Practice
Ursula K Rohlwink, Naomi F Walker, Alvaro A Ordonez, Yifan J Li, Elizabeth W Tucker, Paul T Elkington, Robert J Wilkinson, Katalin A Wilkinson
Tuberculosis (TB) remains the single biggest infectious cause of death globally, claiming almost two million lives and causing disease in over 10 million individuals annually. Matrix metalloproteinases (MMPs) are a family of proteolytic enzymes with various physiological roles implicated as key factors contributing to the spread of TB. They are involved in the breakdown of lung extracellular matrix and the consequent release of Mycobacterium tuberculosis bacilli into the airways. Evidence demonstrates that MMPs also play a role in central nervous system (CNS) tuberculosis, as they contribute to the breakdown of the blood brain barrier and are associated with poor outcome in adults with tuberculous meningitis (TBM)...
March 18, 2019: International Journal of Molecular Sciences
Kostas Iakovou, Kleopatra Schulpis
Introduction Classical Phenylketonuria (PKU) is a metabolic disease characterized by high phenylalanine (phe) levels in blood and brain. PKU patients are commonly treated with low phe diet supplemented with amino acid free formula. High Phe levels minimize brain tryptophan concentration, the pressure of serotonin, which is responsible for the appearance of depression symptoms. Both amino acids share the same pathway for entering CNS via BBB. Aimed to determine the effect of psychological support on different education status depressed PKU patients via adherence to their diet...
March 19, 2019: International Journal of Adolescent Medicine and Health
Hui-Xia Lin, Qing-Qing Tao, Qiao Wei, Cong-Xin Chen, Yu-Chao Chen, Hong-Fu Li, Aaron D Gitler, Zhi-Ying Wu
Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by selective involvement of motor neurons in the central nervous system (CNS). The most common causative gene of ALS in the Chinese population is the Cu/Zn superoxide dismutase 1 (SOD1) gene, which accounts for 20-42.9% of familial ALS (FALS) and 1-2% of sporadic ALS (SALS) cases. In this study, we identify three novel SOD1 mutations, Gly17Cys, Pro75Ser, and His121Gln, in four ALS pedigrees. A functional analysis was performed, and the results showed that all three mutations could lead to the formation of misfolded proteins...
March 19, 2019: Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration
Carine L Holz, Dodd G Sledge, Matti Kiupel, Rahul K Nelli, Lutz S Goehring, Gisela Soboll Hussey
Histopathological differences in horses infected with equine herpesvirus type 1 (EHV-1) of differing neuropathogenic potential [wild-type (Ab4), polymerase mutant (Ab4 N752), EHV-1/4 gD mutant (Ab4 gD4)] were evaluated to examine the impact of viral factors on clinical disease, tissue tropism and pathology. Three of 8 Ab4 infected horses developed Equine Herpesvirus Myeloencephalopathy (EHM) requiring euthanasia of 2 horses on day 9 post-infection. None of the other horses showed neurologic signs and all remaining animals were sacrificed 10 weeks post-infection...
2019: Frontiers in Veterinary Science
Sarah M Carpanini, Megan Torvell, Bryan Paul Morgan
The complement system plays critical roles in development, homeostasis, and regeneration in the central nervous system (CNS) throughout life; however, complement dysregulation in the CNS can lead to damage and disease. Complement proteins, regulators, and receptors are widely expressed throughout the CNS and, in many cases, are upregulated in disease. Genetic and epidemiological studies, cerebrospinal fluid (CSF) and plasma biomarker measurements and pathological analysis of post-mortem tissues have all implicated complement in multiple CNS diseases including multiple sclerosis (MS), neuromyelitis optica (NMO), neurotrauma, stroke, amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD)...
2019: Frontiers in Immunology
Amalie S Schøller, Masja Fonnes, Loulieta Nazerai, Jan P Christensen, Allan R Thomsen
While the brain is considered an immune-privileged site, the CNS may nevertheless be the focus of immune mediated inflammation in the case of infection and certain autoimmune diseases, e.g., multiple sclerosis. As in other tissues, it has been found that acute T-cell infiltration may be followed by establishment of persistent local T-cell memory. To improve our understanding regarding the regulation of putative tissue resident memory T (Trm) cells in CNS, we devised a new model system for studying the generation of Trm cells in this site...
2019: Frontiers in Immunology
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