Journal of Literature Pharmacy Sciences

Deneysel Nöroinflamatuar Hastalık Modelleri: Sistematik Derleme
Experimental Models in Neuroinflammatory Diseases: Systematic Review
Ömer BAHÇELİa, Şefika Pınar ŞENOLa, Bahar TUNÇTANa
aMersin Üniversitesi Eczacılık Fakültesi, Farmakoloji ABD, Mersin, TÜRKİYE
J Lit Pharm Sci. 2021;10(2):153-65
doi: 10.5336/pharmsci.2020-79790
Article Language: TR
Full Text
ÖZET
 Santral sinir sisteminde, inflamasyon gelişmesi nörolojik hastalıkların önemli ancak iyi anlaşılmamış bir durumudur. Akut beyin zedelenmesi veya enfeksiyonun ardından, astrositler ve mikrogliyanın etkinleşmesine ek olarak, kompleman faktörleri, sitokinler ve akut faz proteinlerinin oluşumundaki artmayı içeren karmaşık bir inflamatuar yanıt ortaya çıkmaktadır. T lenfositler ve antikorlar da ortaya çıkan bu yanıta katkıda bulunabilir. Zedelenmenin düzeltilmesinin daha güç, ancak kalıcı olduğu nörodejeneratif hastalıklarda inflamatuar yanıt süreklidir. Sürekli olan bu yanıtın başlıca amacı, ölen hücreler veya kümelenmiş proteinlerin temizlenmesi ile onarım işleminin başlatılmasının yanı sıra, dejenerasyon ve hücre ölümüne katkıda bulunma girişimidir. Hayvan modelleri, özgül inflamatuar mediyatörlerin nöroinflamatuar hastalıkların patojenezine katkısını araştırmak ve bu konuda yapılacak olan klinik araştırmalara temel oluşturabilecek bilgiler edinebilmek amacıyla kullanılmaktadır. Nöroinflamatuar hastalıkların oluşum mekanizmalarının ortaya konulması ve yeni tedavilerin geliştirilmesi ancak bu hastalıkların, deney hayvanlarında çalışılabilmesine olanak sağlayabilecek, deneysel modellerin oluşturulmasıyla gerçekleştirilebilir. Nörodejeneratif inflamatuar hastalıklar ile ilgili olarak elde edilecek daha fazla yeni veri, nöroinflamatuar hastalıkların insanlardaki klinik durumu en iyi derecede yansıtabilecek uygun deneysel modellerinin geliştirilmesine olanak tanıyabilecektir. Bu derlemede, en sık görülen Alzheimer hastalığı, Parkinson hastalığı, Hungtington hastalığı ile amyotrofik lateral skleroz gibi nöroinflamatuar hastalıkların kliniğinin yanı sıra, deneysel modellemesinde sıklıkla kullanılan transgenik ve transgenik olmayan yöntemler üzerinde durulmuştur. Ayrıca bu yöntemlerin sınırlamaları, avantajları ve dezavantajlarına değinilmiştir.

Anahtar Kelimeler: Santral sinir sistemi hastalıkları; nöroinflamasyon; deneysel hayvan modelleri
ABSTRACT
 Inflammation in the central nervous system is an substantial, but not well understood condition of neurological diseases. Following acute brain injury or infection, a complex inflammatory response occurs involving activation of astrocytes and microglia in addition to enhanced formation of complement factors, cytokines, and acute phase proteins. T lymphocytes and antibodies may also contribute to this response. In neurodegenerative diseases, where injury is more subtle but consistent, the inflammatory response is continuous. The main purpose of this response may enterprise to clear dying cells or aggregated proteins and initiate repair process, but also contribute to degeneration and cell death. Animal models are useful to investigate the contribution of specific inflammatory mediators to the pathogenesis of neuroinflammatory diseases and obtain basic information that can be used for clinical research on this subject. The emergence mechanisms of neuroinflammatory diseases and development of new therapies are only possible by establishing experimental models capable of work in experimental animals. Further novel data about neurodegenerative inflammatory diseases will allow for the development of more appropriate experimental models that can best reflect the clinical situation of these diseases in humans. This review is focused on the clinical features of the most common neuroinflammatory diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis, in addition to transgenic and non-trangenic methods frequently used in the experimental models of certain neurodegenerative diseases. The limitations, advantages, and disadvantages of these methods are also mentioned.

Keywords: Central nervous system diseases; neuroinflammation; experimental animal models
REFERENCES:
  1. DiSabato DJ, Quan N, Godbout JP. Neuroinflammation: the devil is in the details. J Neurochem. 2016;139 Suppl 2(Suppl 2):136-53. [Crossref] [PubMed] [PMC] 
  2. Carson MJ, Thrash JC, Walter B. The cellular response in neuroinflammation: The role of leukocytes, microglia and astrocytes in neuronal death and survival. Clin Neurosci Res. 2006;6(5):237-45. [Crossref] [PubMed] [PMC] 
  3. Ray WJ, Buggia-Prevot V. Novel Targets for Alzheimer's Disease: A View Beyond Amyloid. Annu Rev Med. 2021;72:15-28. [Crossref] [PubMed] 
  4. Viola KL, Klein WL. Amyloid β oligomers in Alzheimer's disease pathogenesis, treatment, and diagnosis. Acta Neuropathol. 2015;129(2):183-206. [Crossref] [PubMed] [PMC] 
  5. Wirths O, Zampar S. Neuron Loss in Alzheimer's Disease: Translation in Transgenic Mouse Models. Int J Mol Sci. 2020;21(21):8144. [Crossref] [PubMed] [PMC] 
  6. Wu Z, Yu J, Zhu A, Nakanishi H. Nutrients, Microglia Aging, and Brain Aging. Oxid Med Cell Longev. 2016;2016:7498528. [Crossref] [PubMed] [PMC] 
  7. Gong Y, Meyer EM, Meyers CA, Klein RL, King MA, Hughes JA. Memory-related deficits following selective hippocampal expression of Swedish mutation amyloid precursor protein in the rat. Exp Neurol. 2006;200(2):371-7. [Crossref]  [PubMed] 
  8. Lawlor PA, Bland RJ, Das P, Price RW, Holloway V, Smithson L, et al. Novel rat Alzheimer's disease models based on AAV-mediated gene transfer to selectively increase hippocampal Abeta levels. Mol Neurodegener. 2007;2:11. [Crossref] [PubMed] [PMC] 
  9. Jaworski T, Dewachter I, Lechat B, Croes S, Termont A, Demedts D, et al. AAV-tau mediates pyramidal neurodegeneration by cell-cycle re-entry without neurofibrillary tangle formation in wild-type mice. PLoS One. 2009;4(10):e7280. [Crossref] [PubMed] [PMC] 
  10. Drummond E, Wisniewski T. Alzheimer's disease: experimental models and reality. Acta Neuropathol. 2017;133(2):155-75. [Crossref]  [PubMed]  [PMC] 
  11. Chong FP, Ng KY, Koh RY, Chye SM. Tau Proteins and Tauopathies in Alzheimer's Disease. Cell Mol Neurobiol. 2018;38(5):965-80. [Crossref]  [PubMed] 
  12. Selkoe DJ, Hardy J. The amyloid hypothesis of Alzheimer's disease at 25 years. EMBO Mol Med. 2016;8(6):595-608. [Crossref] [PubMed] [PMC] 
  13. Ferretti MT, Partridge V, Leon WC, Canneva F, Allard S, Arvanitis DN, et al. Transgenic mice as a model of pre-clinical Alzheimer's disease. Curr Alzheimer Res. 2011;8(1):4-23. [Crossref] [PubMed] 
  14. Hsiao K, Chapman P, Nilsen S, Eckman C, Harigaya Y, Younkin S, et al. Correlative memory deficits, Abeta elevation, and amyloid plaques in transgenic mice. Science. 1996;274(5284):99-102. [Crossref] [PubMed] 
  15. Dineley KT, Jahrling JB, Denner L. Insulin resistance in Alzheimer's disease. Neurobiol Dis. 2014;72 Pt A:92-103. [Crossref] [PubMed] [PMC] 
  16. Castillo-Carranza DL, Sengupta U, Guerrero-Mu-oz MJ, Lasagna-Reeves CA, Gerson JE, Singh G, et al. Passive immunization with Tau oligomer monoclonal antibody reverses tauopathy phenotypes without affecting hyperphosphorylated neurofibrillary tangles. J Neurosci. 2014;34(12):4260-72. [Crossref] [PubMed] [PMC] 
  17. Hoefer M, Allison SC, Schauer GF, Neuhaus JM, Hall J, Dang JN, et al. Fear conditioning in frontotemporal lobar degeneration and Alzheimer's disease. Brain. 2008;131(Pt 6):1646-57. [Crossref] [PubMed] [PMC] 
  18. Games D, Adams D, Alessandrini R, Barbour R, Berthelette P, Blackwell C, et al. Alzheimer-type neuropathology in transgenic mice overexpressing V717F beta-amyloid precursor protein. Nature. 1995;373(6514):523-7. [Crossref]  [PubMed] 
  19. Do Carmo S, Cuello AC. Modeling Alzheimer's disease in transgenic rats. Mol Neurodegener. 2013;8:37. [Crossref] [PubMed] [PMC] 
  20. Echeverria V, Ducatenzeiler A, Dowd E, Jänne J, Grant SM, Szyf M, et al. Altered mitogen-activated protein kinase signaling, tau hyperphosphorylation and mild spatial learning dysfunction in transgenic rats expressing the beta-amyloid peptide intracellularly in hippocampal and cortical neurons. Neuroscience. 2004;129(3):583-92. [Crossref] [PubMed] 
  21. Ruiz-Opazo N, Kosik KS, Lopez LV, Bagamasbad P, Ponce LR, Herrera VL. Attenuated hippocampus-dependent learning and memory decline in transgenic TgAPPswe Fischer-344 rats. Mol Med. 2004;10(1-6):36-44. [Crossref] [PubMed] [PMC] 
  22. Flood DG, Lin YG, Lang DM, Trusko SP, Hirsch JD, Savage MJ, et al. A transgenic rat model of Alzheimer's disease with extracellular Abeta deposition. Neurobiol Aging. 2009;30(7):1078-90. [Crossref] [PubMed] 
  23. Leon WC, Canneva F, Partridge V, Allard S, Ferretti MT, DeWilde A, et al. A novel transgenic rat model with a full Alzheimer's-like amyloid pathology displays pre-plaque intracellular amyloid-beta-associated cognitive impairment. J Alzheimers Dis. 2010;20(1):113-26. [Crossref] [PubMed] 
  24. Cohen RM, Rezai-Zadeh K, Weitz TM, Rentsendorj A, Gate D, Spivak I, et al. A transgenic Alzheimer rat with plaques, tau pathology, behavioral impairment, oligomeric aβ, and frank neuronal loss. J Neurosci. 2013;33(15):6245-56. [Crossref] [PubMed] [PMC] 
  25. Kumar A, Aggarwal A, Singh A, Naidu PS. Animal Models in Drug Discovery of Alzheimer's Disease: A Mini Review. EC Pharmacol Toxicol. 2016;60-79. [Link] 
  26. Sadigh-Eteghad S, Sabermarouf B, Majdi A, Talebi M, Farhoudi M, Mahmoudi J. Amyloid-beta: a crucial factor in Alzheimer's disease. Med Princ Pract. 2015;24(1):1-10. [Crossref] [PubMed] [PMC] 
  27. Lecanu L, Greeson J, Papadopoulos V. Beta-amyloid and oxidative stress jointly induce neuronal death, amyloid deposits, gliosis, and memory impairment in the rat brain. Pharmacology. 2006;76(1):19-33. [Crossref] [PubMed] 
  28. Xiaoguang W, Jianjun C, Qinying C, Hui Z, Lukun Y, Yazhen S. Establishment of a Valuable Mimic of Alzheimer's Disease in Rat Animal Model by Intracerebroventricular Injection of Composited Amyloid Beta Protein. J Vis Exp. 2018;(137):56157. [Crossref] [PubMed] [PMC] 
  29. Stranahan AM, Arumugam TV, Cutler RG, Lee K, Egan JM, Mattson MP. Diabetes impairs hippocampal function through glucocorticoid-mediated effects on new and mature neurons. Nat Neurosci. 2008;11(3):309-17. [Crossref]  [PubMed]  [PMC] 
  30. Wang JQ, Yin J, Song YF, Zhang L, Ren YX, Wang DG, et al. Brain aging and AD-like pathology in streptozotocin-induced diabetic rats. J Diabetes Res. 2014;2014:796840. [Crossref] [PubMed] [PMC] 
  31. Chen Y, Liang Z, Blanchard J, Dai CL, Sun S, Lee MH, et al. A non-transgenic mouse model (icv-STZ mouse) of Alzheimer's disease: similarities to and differences from the transgenic model (3xTg-AD mouse). Mol Neurobiol. 2013;47(2):711-25. [Crossref] [PubMed] [PMC] 
  32. Kraska A, Santin MD, Dorieux O, Joseph-Mathurin N, Bourrin E, Petit F, et al. In vivo cross-sectional characterization of cerebral alterations induced by intracerebroventricular administration of streptozotocin. PLoS One. 2012;7(9):e46196. [Crossref] [PubMed] [PMC] 
  33. Liu P, Zou LB, Wang LH, Jiao Q, Chi TY, Ji XF, et al. Xanthoceraside attenuates tau hyperphosphorylation and cognitive deficits in intracerebroventricular-streptozotocin injected rats. Psychopharmacology (Berl). 2014;231(2):345-56. [Crossref] [PubMed] 
  34. Zhang H, Lin A, Gong P, Chen Y, Ye RD, Qian F, et al. The Chemokine-like Receptor 1 Deficiency Improves Cognitive Deficits of AD Mice and Attenuates Tau Hyperphosphorylation via Regulating Tau Seeding. J Neurosci. 2020;40(36):6991-7007. [Crossref] [PubMed] [PMC] 
  35. Nolan YM, Sullivan AM, Toulouse A. Parkinson's disease in the nuclear age of neuroinflammation. Trends Mol Med. 2013;19(3):187-96. [Crossref] [PubMed] 
  36. Vera E, Studer L. When rejuvenation is a problem: challenges of modeling late-onset neurodegenerative disease. Development. 2015;142(18):3085-9. [Crossref] [PubMed] [PMC] 
  37. Blandini F, Armentero MT. Animal models of Parkinson's disease. FEBS J. 2012;279(7): 1156-66. [Crossref] [PubMed] 
  38. Gubellini P, Kachidian P. Animal models of Parkinson's disease: An updated overview. Rev Neurol (Paris). 2015;171(11):750-61. [Crossref]  [PubMed] 
  39. Lee BD, Shin JH, VanKampen J, Petrucelli L, West AB, Ko HS, et al. Inhibitors of leucine-rich repeat kinase-2 protect against models of Parkinson's disease. Nat Med. 2010;16(9):998-1000. [Crossref] [PubMed] [PMC] 
  40. Dawson TM, Ko HS, Dawson VL. Genetic animal models of Parkinson's disease. Neuron. 2010;66(5):646-61. [Crossref] [PubMed] [PMC] 
  41. Haque ME, Mount MP, Safarpour F, Abdel-Messih E, Callaghan S, Mazerolle C, et al. Inactivation of Pink1 gene in vivo sensitizes dopamine-producing neurons to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and can be rescued by autosomal recessive Parkinson disease genes, Parkin or DJ-1. J Biol Chem. 2012;287(27):23162-70. [Crossref] [PubMed] [PMC] 
  42. Oliveras-Salvá M, Macchi F, Coessens V, Deleersnijder A, Gérard M, Van der Perren A, et al. Alpha-synuclein-induced neurodegeneration is exacerbated in PINK1 knockout mice. Neurobiol Aging. 2014;35(11):2625-36. [Crossref] [PubMed] 
  43. Pickrell AM, Pinto M, Moraes CT. Mouse models of Parkinson's disease associated with mitochondrial dysfunction. Mol Cell Neurosci. 2013;55:87-94. [Crossref] [PubMed] [PMC] 
  44. Bové J, Perier C. Neurotoxin-based models of Parkinson's disease. Neuroscience. 2012;211:51-76. [Crossref] [PubMed] 
  45. Langston JW. The MPTP Story. J Parkinsons Dis. 2017;7(s1):S11-S19. [Crossref] [PubMed] [PMC] 
  46. Costello S, Cockburn M, Bronstein J, Zhang X, Ritz B. Parkinson's disease and residential exposure to maneb and paraquat from agricultural applications in the central valley of California. Am J Epidemiol. 2009;169(8):919-26. [Crossref] [PubMed] [PMC] 
  47. Jackson-Lewis V, Przedborski S. Protocol for the MPTP mouse model of Parkinson's disease. Nat Protoc. 2007;2(1):141-51. [Crossref]  [PubMed] 
  48. Zhang QS, Heng Y, Mou Z, Huang JY, Yuan YH, Chen NH. Reassessment of subacute MPTP-treated mice as animal model of Parkinson's disease. Acta Pharmacol Sin. 2017;38(10):1317-1328. [Crossref] [PubMed] [PMC] 
  49. Kamel F. Epidemiology. Paths from pesticides to Parkinson's. Science. 2013;341(6147):722-3. [Crossref] [PubMed] 
  50. Cannon JR, Tapias V, Na HM, Honick AS, Drolet RE, Greenamyre JT. A highly reproducible rotenone model of Parkinson's disease. Neurobiol Dis. 2009;34(2):279-90. [Crossref] [PubMed] [PMC] 
  51. Uversky VN. Neurotoxicant-induced animal models of Parkinson's disease: understanding the role of rotenone, maneb and paraquat in neurodegeneration. Cell Tissue Res. 2004; 318(1):225-41. [Crossref] [PubMed] 
  52. Tinakoua A, Bouabid S, Faggiani E, De Deurwaerdère P, Lakhdar-Ghazal N, Benazzouz A. The impact of combined administration of paraquat and maneb on motor and non-motor functions in the rat. Neuroscience. 2015;311:118-29. [Crossref] [PubMed] 
  53. Ersoy N, Başak AN. Huntington hastalığı'nın moleküler biyolojisi [Molecular biology of Huntington's disease]. Turk J Neurol. 2005;11(1):27-44 [Link] 
  54. Menalled LB, Chesselet MF. Mouse models of Huntington's disease. Trends Pharmacol Sci. 2002;23(1):32-9. [Crossref] [PubMed] 
  55. Tang B, Seredenina T, Coppola G, Kuhn A, Geschwind DH, Luthi-Carter R, et al Gene expression profiling of R6/2 transgenic mice with different CAG repeat lengths reveals genes associated with disease onset and progression in Huntington's disease. Neurobiol Dis. 2011;42(3):459-67. [Crossref] [PubMed] [PMC] 
  56. Schilling G, Becher MW, Sharp AH, Jinnah HA, Duan K, Kotzuk JA, et al. Intranuclear inclusions and neuritic aggregates in transgenic mice expressing a mutant N-terminal fragment of huntingtin. Hum Mol Genet. 1999;8(3):397-407. Erratum in: Hum Mol Genet 1999;8(5):943. [Crossref] [PubMed] 
  57. Chang R, Liu X, Li S, Li XJ. Transgenic animal models for study of the pathogenesis of Huntington's disease and therapy. Drug Des Devel Ther. 2015;9:2179-88. [Crossref] [PubMed] [PMC] 
  58. Pouladi MA, Morton AJ, Hayden MR. Choosing an animal model for the study of Huntington's disease. Nat Rev Neurosci. 2013;14(10):708-21. [Crossref] [PubMed] 
  59. Tsunemi T, Ashe TD, Morrison BE, Soriano KR, Au J, Roque RA, et al. PGC-1α rescues Huntington's disease proteotoxicity by preventing oxidative stress and promoting TFEB function. Sci Transl Med. 2012;4(142): 142ra97. [Crossref] [PubMed] [PMC] 
  60. Al-Chalabi A, Hardiman O. The epidemiology of ALS: a conspiracy of genes, environment and time. Nat Rev Neurol. 2013;9(11):617-28. [Crossref] [PubMed] 
  61. Taylor JP, Brown RH Jr, Cleveland DW. Decoding ALS: from genes to mechanism. Nature. 2016;539(7628):197-206. [Crossref] [PubMed] [PMC] 
  62. Lutz C. Mouse models of ALS: Past, present and future. Brain Res. 2018;1693(Pt A):1-10. [Crossref] [PubMed] 
  63. Saberi S, Stauffer JE, Schulte DJ, Ravits J. Neuropathology of Amyotrophic Lateral Sclerosis and Its Variants. Neurol Clin. 2015;33(4): 855-76. [Crossref] [PubMed] [PMC] 
  64. Mackenzie IR, Frick P, Grässer FA, Gendron TF, Petrucelli L, Cashman NR, et al. Quantitative analysis and clinico-pathological correlations of different dipeptide repeat protein pathologies in C9ORF72 mutation carriers. Acta Neuropathol. 2015;130(6):845-61. [Crossref] [PubMed] 
  65. Liu Y, Pattamatta A, Zu T, Reid T, Bardhi O, Borchelt DR, et al. C9orf72 BAC Mouse Model with Motor Deficits and Neurodegenerative Features of ALS/FTD. Neuron. 2016;90(3): 521-34. [Crossref] [PubMed] 
  66. Philips T, Rothstein JD. Rodent Models of Amyotrophic Lateral Sclerosis. Curr Protoc Pharmacol. 2015;69:5.67.1-5.67.21. [Crossref]  [PubMed]  [PMC] 
  67. Joyce PI, Fratta P, Fisher EM, Acevedo-Arozena A. SOD1 and TDP-43 animal models of amyotrophic lateral sclerosis: recent advances in understanding disease toward the development of clinical treatments. Mamm Genome. 2011;22(7-8):420-48. [Crossref] [PubMed] 
  68. Morrice JR, Gregory-Evans CY, Shaw CA. Animal models of amyotrophic lateral sclerosis: A comparison of model validity. Neural Regen Res. 2018;13(12):2050-4. [Crossref] [PubMed] [PMC] 
  69. Tabata RC, Wilson JM, Ly P, Zwiegers P, Kwok D, Van Kampen JM, et al. Chronic exposure to dietary sterol glucosides is neurotoxic to motor neurons and induces an ALS-PDC phenotype. Neuromolecular Med. 2008;10(1):24-39. [Crossref] [PubMed] [PMC] 
  70. Dawson TM, Golde TE, Lagier-Tourenne C. Animal models of neurodegenerative diseases. Nat Neurosci. 2018;21(10):1370-9. [Crossref] [PubMed] [PMC] 

.: Up To Date

.: Process List

Login

 Forgot your password?

 New Registration  

Contact

Ortadoğu Reklam Tanıtım Yayıncılık Turizm Eğitim İnşaat Sanayi ve Ticaret A.Ş.

.: Address

Turkocagi Caddesi No:30 06520 Balgat / ANKARA
Phone: +90 312 286 56 56
Fax: +90 312 220 04 70
E-mail: info@turkiyeklinikleri.com

.: Manuscript Editing Department

Phone: +90 312 286 56 56/ 2
E-mail: yaziisleri@turkiyeklinikleri.com

.: English Language Redaction

Phone: +90 312 286 56 56/ 145
E-mail: tkyayindestek@turkiyeklinikleri.com

.: Marketing Sales-Project Department

Phone: +90 312 286 56 56/ 142
E-mail: reklam@turkiyeklinikleri.com

.: Subscription and Public Relations Department

Phone: +90 312 286 56 56/ 118
E-mail: abone@turkiyeklinikleri.com

.: Customer Services

Phone: +90 312 286 56 56/ 118
E-mail: satisdestek@turkiyeklinikleri.com

1. TERMS OF USE

1.1. To use the web pages with http://www.turkiyeklinikleri.com domain name or the websites reached through the sub domain names attached to the domain name (They will be collectively referred as "SITE"), please read the conditions below. If you do not accept these terms, please cease to use the "SITE." "SITE" owner reserves the right to change the information on the website, forms, contents, the "SITE," "SITE" terms of use anytime they want.

1.2. The owner of the "SITE" is Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. (From now on it is going to be referred as "Turkiye Klinikleri", shortly) and it resides at Turkocagi cad. No:30, 06520 Balgat Ankara. The services in the "SITE" are provided by "Turkiye Klinikleri."

1.3. Anyone accessing the "SITE" with or without a fee whether they are a natural person or a legal identity is considered to agree these terms of use. In this contract hereby, "Turkiye Klinikleri" may change the stated terms anytime. These changes will be published in the "SITE" periodically and they will be valid when they are published. Any natural person or legal identity benefiting from and reaching to the "SITE" are considered to be agreed to any change on hereby contract terms done by "Turkiye Klinikleri."

1.4. The "Terms of Use" hereby is published in the website with the last change on March 30th 2014 and the "SITE" is activated by enabling the access to everyone. The "Terms of Use" hereby is also a part of the any "USER Contract" was and/or will be done with the users using "Turkiye Klinikleri" services with or without a fee an inseparable.

2. DEFINITIONS

2.1. "SITE": A website offering different kind of services and context with a certain frame determined by "Turkiye Klinikleri" and it is accessible on-line on http://www.turkiyeklinikleri.com domain name and/or subdomains connected to the domain name.

2.2. USER: A natural person or a legal identity accessing to the "SITE" through online settings.

2.3. LINK: A link enabling to access to another website through the "SITE", the files, the context or through another website to the "SITE", the files and the context.

2.4. CONTEXT: Any visual, literary and auditory images published in the "Turkiye Klinikleri", "SITE" and/or any website or any accessible information, file, picture, number/figures, price, etc.

2.5. "USER CONTRACT": An electronically signed contract between a natural or a legal identity benefiting from special services "Turkiye Klinikleri" will provide and "Turkiye Klinikleri".

3. SCOPE OF THE SERVICES

3.1. "Turkiye Klinikleri" is completely free to determine the scope and quality of the services via the "SITE".

3.2. To benefit the services of "Turkiye Klinikleri" "SITE", the "USER" must deliver the features that will be specified by "Turkiye Klinikleri". "Turkiye Klinikleri" may change this necessity any time single-sided.

3.3. Not for a limited number, the services "Turkiye Klinikleri" will provide through the "SITE" for a certain price or for free are;

- Providing scientific articles, books and informative publications for health industry.

- Providing structural, statistical and editorial support to article preparation stage for scientific journals.

4. GENERAL PROVISIONS

4.1. "Turkiye Klinikleri" is completely free to determine which of the services and contents provided in the "SITE" will be charged.

4.2. People benefiting from the services provided by "Turkiye Klinikleri" and using the website can use the "SITE" only according to the law and only for personal reasons. Users have the criminal and civil liability for every process and action they take in the "SITE". Every USER agrees, declares and undertakes that they will not proceed by any function or action infringement of rights of "Turkiye Klinikleri"s and/or other third parties', they are the exclusive right holder on usage, processing, storage, made public and revealing any written, visual or auditory information reported to Turkiye Klinikleri" and/or "SITE" to the third parties. "USER" agrees and undertakes that s/he will not duplicate, copy, distribute, process, the pictures, text, visual and auditory images, video clips, files, databases, catalogs and lists within the "SITE", s/he will not be using these actions or with other ways to compete with "Turkiye Klinikleri", directly or indirectly.

4.3. The services provided and the context published within the "SITE" by third parties is not under the responsibility of "Turkiye Klinikleri", institutions collaborated with "Turkiye Klinikleri", "Turkiye Klinikleri" employee and directors, "Turkiye Klinikleri" authorized salespeople. Commitment to accuracy and legality of the published information, context, visual and auditory images provided by any third party are under the full responsibility of the third party. "Turkiye Klinikleri" does not promise and guarantee the safety, accuracy and legality of the services and context provided by a third party.

4.4. "USER"s cannot act against "Turkiye Klinikleri", other "USER"s and third parties by using the "SITE". "Turkiye Klinikleri" has no direct and/or indirect responsibility for any damage a third party suffered or will suffer regarding "USER"s actions on the "SITE" against the rules of the hereby "Terms of Use" and the law.

4.5. "USER"s accept and undertake that the information and context they provided to the "SITE" are accurate and legal. "Turkiye Klinikleri" is not liable and responsible for promising and guaranteeing the verification of the information and context transmitted to "Turkiye Klinikleri" by the "USER"s, or uploaded, changed and provided through the "SITE" by them and whether these information are safe, accurate and legal.

4.6. "USER"s agree and undertake that they will not perform any action leading to unfair competition, weakening the personal and commercial credit of "Turkiye Klinikleri" and a third party,  encroaching and attacking on personal rights within the "SITE" in accordance with the Turkish Commercial Code Law.

4.7. "Turkiye Klinikleri" reserves the right to change the services and the context within the "SITE"  anytime. "Turkiye Klinikleri" may use this right without any notification and timelessly. "USER"s have to make the changes and/or corrections "Turkiye Klinikleri" required immediately. Any changes and/or corrections that are required by "Turkiye Klinikleri", may be made by "Turkiye Klinikleri" when needed. Any harm, criminal and civil liability resulted or will result from changes and/or corrections required by "Turkiye Klinikleri" and were not made on time by the "USER"s belongs completely to the users.

4.8. "Turkiye Klinikleri" may give links through the "SITE" to other websites and/or "CONTEXT"s and/or folders that are outside of their control and owned and run by third parties. These links are provided for ease of reference only and do not hold qualification for support the respective web SITE or the admin or declaration or guarantee for the information inside. "Turkiye Klinikleri" does not hold any responsibility over the web-sites connected through the links on the "SITE", folders and context, the services or products on the websites provided through these links or their context.

4.9. "Turkiye Klinikleri" may use the information provided to them by the "USERS" through the "SITE" in line with the terms of the "PRIVACY POLICY" and "USER CONTRACT". It may process the information or classify and save them on a database. "Turkiye Klinikleri" may also use the USER's or visitor's identity, address, e-mail address, phone number, IP number, which sections of the "SITE" they visited, domain type, browser type, date and time information to provide statistical evaluation and customized services.

5. PROPRIETARY RIGHTS

5.1. The information accessed through this "SITE" or provided by the users legally and all the elements (including but not limited to design, text, image, html code and other codes) of the "SITE" (all of them will be called as studies tied to "Turkiye Klinikleri"s copyrights) belongs to "Turkiye Klinikleri". Users do not have the right to resell, process, share, distribute, display or give someone permission to access or to use the "Turkiye Klinikleri" services, "Turkiye Klinikleri" information and the products under copyright protection by "Turkiye Klinikleri". Within hereby "Terms of Use" unless explicitly permitted by "Turkiye Klinikleri" nobody can reproduce, process, distribute or produce or prepare any study from those under "Turkiye Klinikleri" copyright protection.

5.2. Within hereby "Terms of Use", "Turkiye Klinikleri" reserves the rights for "Turkiye Klinikleri" services, "Turkiye Klinikleri" information, the products associated with "Turkiye Klinikleri" copyrights, "Turkiye Klinikleri" trademarks, "Turkiye Klinikleri" trade looks or its all rights for other entity and information it has through this website unless it is explicitly authorized by "Turkiye Klinikleri".

6. CHANGES IN THE TERMS OF USE

"Turkiye Klinikleri" in its sole discretion may change the hereby "Terms of Use" anytime announcing within the "SITE". The changed terms of the hereby "Terms of Use" will become valid when they are announced. Hereby "Terms of Use" cannot be changed by unilateral declarations of users.

7. FORCE MAJEURE

"Turkiye Klinikleri" is not responsible for executing late or never of this hereby "Terms of Use", privacy policy and "USER Contract" in any situation legally taken into account as force majeure. Being late or failure of performance or non-defaulting of this and similar cases like this will not be the case from the viewpoint of "Turkiye Klinikleri", and "Turkiye Klinikleri" will not have any damage liability for these situations. "Force majeure" term will be regarded as outside of the concerned party's reasonable control and any situation that "Turkiye Klinikleri" cannot prevent even though it shows due diligence. Also, force majeure situations include but not limited to natural disasters, rebellion, war, strike, communication problems, infrastructure and internet failure, power cut and bad weather conditions.

8. LAW AND AUTHORISATION TO FOLLOW

Turkish Law will be applied in practicing, interpreting the hereby "Terms of Use" and managing the emerging legal relationships within this "Terms of Use" in case of finding element of foreignness, except for the rules of Turkish conflict of laws. Ankara Courts and Enforcement Offices are entitled in any controversy happened or may happen due to hereby contract.

9. CLOSING AND AGREEMENT

Hereby "Terms of Use" come into force when announced in the "SITE" by "Turkiye Klinikleri". The users are regarded to agree to hereby contract terms by using the "SITE". "Turkiye Klinikleri" may change the contract terms and the changes will be come into force by specifying the version number and the date of change on time it is published in the "SITE".

 

30.03.2014

Privacy Policy

We recommend you to read the terms of use below before you visit our website. In case you agree these terms, following our rules will be to your favor. Please read our Terms of Use thoroughly.

www.turkiyeklinikleri.com website belongs to Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. and is designed in order to inform physicians in the field of health

www.turkiyeklinikleri.com cannot reach to user’s identity, address, service providers or other information. The users may send this information to the website through forms if they would like to. However, www.turkiyeklinikleri.com may collect your hardware and software information. The information consists of your IP address, browser type, operating system, domain name, access time, and related websites. www.turkiyeklinikleri.com cannot sell the provided user information (your name, e-mail address, home and work address, phone number) to the third parties, publish it publicly, or keep it in the website. Gathered information has a directing feature to be a source for the website’s visitor profile, reporting and promotion of the services.

www.turkiyeklinikleri.com uses the taken information:

-To enhance, improve and maintain the quality of the website

-To generate visitor’s profile and statistical data

-To determine the tendency of the visitors on using our website

-To send print publications/correspondences

-To send press releases or notifications through e-mail

-To generate a list for an event or competition

By using www.turkiyeklinikleri.com you are considered to agree that;

-Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. cannot be hold responsible for any user’s illegal and immoral behavior,

-Terms of use may change from time to time,

-It is not responsible for other websites’ contents it cannot control or the harms they may cause although it uses the connection they provided.

Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. may block the website to users in the following events:

-Information with wrong, incomplete, deceiving or immoral expressions is recorded to the website,

-Proclamation, advertisement, announcement, libelous expressions are used against natural person or legal identity,

-During various attacks to the website,

-Disruption of the website because of a virus.

Written, visual and audible materials of the website, including the code and the software are under protection by legal legislation.

Without the written consent of Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. the information on the website cannot be downloaded, changed, reproduced, copied, republished, posted or distributed.

All rights of the software and the design of the website belong to Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc.

Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. will be pleased to hear your comments about our terms of use. Please share the subjects you think may enrich our website or if there is any problem regarding our website.

info@turkiyeklinikleri.com