neurotoxicity and mechanisms of induced hyperexcitability

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ORIGINAL ARTICLE ORIGINALNI NAUČNI RAD ORIGINAL ARTICLE ORIGINALNI NAUČNI RADEXPERIMENTAL MODELS OFDIABETES MELLITUSJelena Pantic 1 , Vladislav Volarevic 1 , Aleksandar Djukic 11Faculty of Medicine, University of KragujevacEKSPERIMENTALNI MODELIDIJABETES MELITUSAJelena Pantić 1 , Vladislav Volarević 1 , Aleksandar Đukić 11Medicinski fakultet, Univerzitet u KragujevcuReceived / Primljen: 27. 07. 2010. Accepted / Prihvaćen: 03. 03. 2011.APSTRAKTEarly studies on pancreatectomised dogs confirmed thecentral role of the pancreas in the homeostasis of glycemia andresulted in the discovery of insulin. Today, hundreds of differentanimal models are used in experimental studies of diabetes. Theaim of this review is to present experimental models of type 1and type 2 diabetes. In preparing for this review, we searched theelectronic databases Medline, Highwire, and Hinari.The majority of the experiments are conducted on rodentmodels (mice and rats). Selective inbreeding resulted in the developmentof numerous models with pathogenic characteristics andthe manifestation of type 1 and 2 diabetes and the related phenotypesof obesity and insulin resistance. In addition to analyzingthe pathogenic mechanisms of the disease and its complications,these models are used to evaluate new treatment solutions as wellas the transplantation of beta cells and disease prevention. Newanimal models have been created using techniques based in molecularbiology and genetic engineering: transgenic, knockout andtissue-specific knockout models. These are very powerful methods,which may lead to exciting results in the future.Key words: animal models, experimental diabetes, mouse, ratSAŽETAKPrve studije rađene na psima kojima je prethodno uklonjenpankreas potvrdile su centralnu ulogu pankreasa uhomeostazi glikemije i doprineli otkriću insulina. Danas,veliki broj različitih eksperimentalnih modela se koristi uistraživanjima u oblasti dijabetesa. Cilj ovog revijskog radaje da predstavi neke od ovih modela, koristeći kao literaturuoriginalne i revijske radove elektronskih baza Medline,Highwire i Hinari.Većina laboratorija koristi selektivnim inbridingom dobijenemiševe i pacove, kao i transgene i nokaut životinje dobijenegenetskim inženjeringom, koje zbog svojih karakteristika(npr. gojaznost, rezistencija na insulin) predstavljaju idealneeksperimentalne modele za dijabetes tip 1 ili 2. Ovi eksperimentalnimodeli koriste se kako za ispitivanje patogenezedijabetesa tako i za ispitivanja novih terapijskih sredstava ulečenju šećerne bolesti.Ključne reči: animalni modeli, eksperimentalni dijabetes,miš, pacovUDK 616.379-008.64 / Ser J Exp Clin Res 2011; 12 (1): 29-35Correspondence to: Jelena Pantic, Address: Janka Veselinovica 3/3, 11000 BeogradTel: 064/1550001, 011/3861942, E-mail: panticjelena@open.telekom.rs29
INTRODUCTIONSince 1880, when von Mering and Minkowski removedthe pancreas from a dog displaying symptoms of diabetesmellitus (1), many experiments have been conducted onmice, rats, rabbits, and dogs, which were all used as experimentalmodels for this disease.The rodents (mice and rats) are most frequently usedin laboratory research of type 1 and type 2 diabetes becausethey are biologically and genetically similar to people,their reproductive potential is high, their life spanis short, and they are cheap and easy to handle (1). Themain drawback of these models is that sometimes theyare unable to successfully simulate pathological processesoccurring in humans; in those situations, the use of cats,dogs, pigs or primates is justifiable.Models of experimental diabetes are:1. induced (experimental)2. spontaneous (genetically induced) or3. transgenic and knock-out models (resulting from geneticengineering).Hyperglycemia is induced by:1. surgical method (partial or total pancreatectomy)2. non-surgical method (using a diabetogenic toxin in experimentalanimals) (Table 1) (2).MATERIALS AND METHODSWe searched the electronic databases Medline, Highwire,and Hinari. Selected papers, both original and review,have been summarized and cited with regard to theirscientific relevance for this research field.EXPERIMENTAL MODELS OFTYPE 1 DIABETES MELLITUSA) Induced modelsMultiple low-dose streptozotocin-induced diabetesStreptozotocin (STZ) is a derivative of nitrosoureathat has been isolated from Streptomyces achromogenes.It is a strong alkylating agent that affects glucose trans-ToxinDiabetogenic effectStreptozotocin Hyperglycemia, glucose intoleranceAlloxanHyperglycemia, glucose intoleranceChlorozotocin Hyperglycemia, glucose intoleranceDithizone Hyperglycemia, glucose intoleranceVacorHyperglycemiaOxineHyperglycemiaMethylnitrosurea Glucose intoleranceCyproheptadine Glucose intoleranceTable 1. Toxins with diabetogenic effectport (the role of glucokinase) and induces numerous lesionsin the beta-cell DNA chain (3-5). It can selectivelybind to glucose-transport protein 2 (GLUT2), which ispredominantly expressed on the membranes of pancreaticbeta-cells (3).Toxicity of the streptozotocin on beta-cells is complexand includes genetic and non-genetic mechanisms (6). Nitricoxide (NO) and other free radicals influenced by streptozotocinresult in spontaneous lesions of the DNA chain(7). Damaged DNA chains activate poly-(ADP-ribose)polymerase (PARP) as a reparatory mechanism, which incase of over-activation may have proapoptotic effects (8).PARP knockout mice were shown to be resistant for streptozotocin-induceddiabetes (8).In addition, the toxicity of streptozotocin is associatedwith a drastic decrease of insulin reserves within beta cells,resulting from the fast catabolism of nicotinamide-adenine-dinucleotide+(NAD+), a substrate for PARP activation(9). Decrease of NAD+ and ATP+ provokes significantdepletion of insulin secretion as well as other basic processesinside the cell. While excessive activation of PARPrepresents a proapoptotic stimulus, the reduction of necessarycell energy results in cellular necrotic death.A single high dose of streptozotocin provokes diabetesin rodents, possibly as a result of the direct toxic effect.Multiple low-dose streptozotocin-induced diabetes (whenstreptozotocin is administered in lower doses (40 mg/kg)during five consecutive days) is an experimental modelof type 1 diabetes and immune-mediated insulitis and iswidely used for studying the immunological backgroundof this disease (10).Partial pancreatectomyThe partially pancreatectomised rat was one of the firstexperimental models of diabetes (11). The surgical removalof 90% of the pancreatic tissue resulted in a slow developmentof hyperglycemia over the course of 12 weeks to 20months (12). The period of post-surgical euglycemia is followedby the development of chronic hyperglycemia as aconsequence of a further failure of the remaining beta cells.The first stage of disease refers to glucose intolerancefollowed by a compensatory hyper-function of beta-cells,the exhaustion of the remaining beta cells and their furtherbreakdown 14 weeks after surgery (12). Altered beta cellgene expression is associated with a decreased productionof islet amylin polypeptide (IAPP), transcription factors,ionic canals and pumps, including GLUT2, glucokinase,mitochondrial glycerophosphate dehydrogenase (mGPD)and pyruvate carboxylase (13). A reduction of insulin secretionfollows even in conditions of high concentrationsof glucose and even after application of insulin secretagogues(14).Histopathological findings demonstrate hypertrophyand fibrosis of pancreatic islets related to the level of hyperglycemia(13). Insulitis, demonstrated as the infiltrationof inflammatory cells, may be depressed, thus slowingdown the process of cell degeneration (15).30
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