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      Statins and the Brain: More than Lipid Lowering Agents?

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          Abstract

          Background:

          Statins represent a class of medications widely prescribed to efficiently treat dyslipidemia. These drugs inhibit 3-βhydroxy 3β-methylglutaryl Coenzyme A reductase (HMGR), the rate-limiting enzyme of mevalonate (MVA) pathway. Besides cholesterol, MVA pathway leads to the production of several other compounds, which are essen-tial in the regulation of a plethora of biological activities, including in the central nervous system. For these reasons, statins are able to induce pleiotropic actions, and acquire increased interest as potential and novel modulators in brain processes, es-pecially during pathological conditions.

          Objective:

          The purpose of this review is to summarize and examine the current knowledge about pharmacokinetic and phar-macodynamic properties of statins in the brain. In addition, effects of statin on brain diseases are discussed providing the most up-to-date information.

          Methods:

          Relevant scientific information was identified from PubMed database using the following keywords: statins and brain, central nervous system, neurological diseases, neurodegeneration, brain tumors, mood, stroke.

          Results:

          315 scientific articles were selected and analyzed for the writing of this review article. Several papers highlighted that statin treatment is effective in preventing or ameliorating the symptomatology of a number of brain pathologies. Howev-er, other studies failed to demonstrate a neuroprotective effect.

          Conclusion:

          Even though considerable research studies suggest pivotal functional outcomes induced by statin therapy, addi-tional investigation is required to better determine the pharmacological effectiveness of statins in the brain, and support their clinical use in the management of different neuropathologies.

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          Most cited references256

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          Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2.

          Rett syndrome (RTT, MIM 312750) is a progressive neurodevelopmental disorder and one of the most common causes of mental retardation in females, with an incidence of 1 in 10,000-15,000 (ref. 2). Patients with classic RTT appear to develop normally until 6-18 months of age, then gradually lose speech and purposeful hand use, and develop microcephaly, seizures, autism, ataxia, intermittent hyperventilation and stereotypic hand movements. After initial regression, the condition stabilizes and patients usually survive into adulthood. As RTT occurs almost exclusively in females, it has been proposed that RTT is caused by an X-linked dominant mutation with lethality in hemizygous males. Previous exclusion mapping studies using RTT families mapped the locus to Xq28 (refs 6,9,10,11). Using a systematic gene screening approach, we have identified mutations in the gene (MECP2 ) encoding X-linked methyl-CpG-binding protein 2 (MeCP2) as the cause of some cases of RTT. MeCP2 selectively binds CpG dinucleotides in the mammalian genome and mediates transcriptional repression through interaction with histone deacetylase and the corepressor SIN3A (refs 12,13). In 5 of 21 sporadic patients, we found 3 de novo missense mutations in the region encoding the highly conserved methyl-binding domain (MBD) as well as a de novo frameshift and a de novo nonsense mutation, both of which disrupt the transcription repression domain (TRD). In two affected half-sisters of a RTT family, we found segregation of an additional missense mutation not detected in their obligate carrier mother. This suggests that the mother is a germline mosaic for this mutation. Our study reports the first disease-causing mutations in RTT and points to abnormal epigenetic regulation as the mechanism underlying the pathogenesis of RTT.
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            Identification of a gene (FMR-1) containing a CGG repeat coincident with a breakpoint cluster region exhibiting length variation in fragile X syndrome.

            Fragile X syndrome is the most frequent form of inherited mental retardation and is associated with a fragile site at Xq27.3. We identified human YAC clones that span fragile X site-induced translocation breakpoints coincident with the fragile X site. A gene (FMR-1) was identified within a four cosmid contig of YAC DNA that expresses a 4.8 kb message in human brain. Within a 7.4 kb EcoRI genomic fragment, containing FMR-1 exonic sequences distal to a CpG island previously shown to be hypermethylated in fragile X patients, is a fragile X site-induced breakpoint cluster region that exhibits length variation in fragile X chromosomes. This fragment contains a lengthy CGG repeat that is 250 bp distal of the CpG island and maps within a FMR-1 exon. Localization of the brain-expressed FMR-1 gene to this EcoRI fragment suggests the involvement of this gene in the phenotypic expression of the fragile X syndrome.
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              Small GTP-binding proteins.

              Small GTP-binding proteins (G proteins) exist in eukaryotes from yeast to human and constitute a superfamily consisting of more than 100 members. This superfamily is structurally classified into at least five families: the Ras, Rho, Rab, Sar1/Arf, and Ran families. They regulate a wide variety of cell functions as biological timers (biotimers) that initiate and terminate specific cell functions and determine the periods of time for the continuation of the specific cell functions. They furthermore play key roles in not only temporal but also spatial determination of specific cell functions. The Ras family regulates gene expression, the Rho family regulates cytoskeletal reorganization and gene expression, the Rab and Sar1/Arf families regulate vesicle trafficking, and the Ran family regulates nucleocytoplasmic transport and microtubule organization. Many upstream regulators and downstream effectors of small G proteins have been isolated, and their modes of activation and action have gradually been elucidated. Cascades and cross-talks of small G proteins have also been clarified. In this review, functions of small G proteins and their modes of activation and action are described.
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                Author and article information

                Journal
                Curr Neuropharmacol
                Curr Neuropharmacol
                CN
                Current Neuropharmacology
                Bentham Science Publishers
                1570-159X
                1875-6190
                January 2019
                January 2019
                : 17
                : 1
                : 59-83
                Affiliations
                Department of Science, University of Rome “Roma Tre” , Italy; Medical Genetics Unit, University Hospital of Rome “Tor Vergata” , Italy; Institute of Cell Biology and Neurobiology, National Research Council (CNR) , Rome, , Italy; Université Libre de Bruxelles (ULB), IRIBHM, Bruxelles, , Belgium; Department of Sense Organs, Sapienza University of Rome , Italy
                Author notes
                [* ]Address correspondence to this author at the Department of Sense Organs, Sapienza University, viale del Policlinico 155, 00186 Rome, Italy; E-mail: marco.segatto@ 123456uniroma3.it
                [#]

                These authors equally contributed to this work and appear in alphabetical order

                Article
                CN-17-59
                10.2174/1570159X15666170703101816
                6341496
                28676012
                4b96c3ce-3263-4fc5-9be5-5e592cb49a92
                © 2019 Bentham Science Publishers

                This is an open access article licensed under the terms of the Creative Commons Attribution-Non-Commercial 4.0 International Public License (CC BY-NC 4.0) ( https://creativecommons.org/licenses/by-nc/4.0/legalcode), which permits unrestricted, non-commercial use, distribution and reproduction in any medium, provided the work is properly cited.

                History
                : 08 April 2017
                : 24 May 2017
                : 26 June 2017
                Categories
                Article

                Pharmacology & Pharmaceutical medicine
                statins,brain,neurodegeneration,neurological disorders,mood,brain tumors

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