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Ugotavljanje protektivnosti fulerenola in vivo v akutni in kronični kardiomiopatiji pri terapiji malignih neoplazem z doksorubicinom pri podganah : doktorska disertacija
Injac, Rade (Author), Štrukelj, Borut (Mentor) More about this mentor... This link opens in a new window

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Abstract
Fulereni so posebna oblika ogljika, ki so jih odkrili sredi osemdesetih let devetnajstega stoletja. Najbolj poznan med njimi je buckyball, ki predstavlja zaprto sferično strukture v obliki nogometne žoge. Trenutno se odvijajo številne raziskave, v katerih poskušajo odkriti tisto farmacevtsko obliko, ki bi kar najbolje izkoristila biološke lastnosti fulerenov in njihovih derivatov. Danes že izkoriščajo nekatere lastnosti fulerena, kot sta sposobnost odstranjevanja radikalov ter posebna molekulska zgradba. V raziskavah so pokazali, da je fulerenol učinkovit pri zaviranju metastaziranja, zdravljenju cerebralnih sprememb, kot sta Alzheimerjeva in Parkinsonova bolezen, zdravljenju hepatitisa C in aidsa. Fulerenole C60(OH)n, polihidroksi derivate fulerena, intenzivno proučujejo zaradi dobrih antioksidativnih lastnosti. Domnevajo, da delujejo kot lovilci radikalov v bioloških sistemih, pri oksidativnem stresu, ki ga povzroči radioaktivno obsevanje. Za fulerenol C60(OH)24 so dokazali, da ima zaščitne učinke pred z doksorubicinom povzročeno toksičnostjo v živalskih modelih. Potencialno zaščitno vlogo pred kardio-, hepato-, nefro- in pulmotoksičnostjo, povzročeno z doksorubicinom, so proučevali na modelih podgan s kemijsko povzročenim rakom. Naša raziskovalna skupina je na podlagi rezultatov preliminarnih raziskav na zdravih odraslih podganah vrste Wistar potrdila, da ima fulerenol v odmerku 100 mg/kg intraperitonealno, injiciran 30 minut pred doksorubicinom, zaščitni učinek na srčno in jetrno tkivo. V nadaljnjih raziskavah smo določili, da je tak odmerek učinkovit za zaščito pred z doksorubicinom povzročenima akutno in kronično toksičnostjo. Izvedli smo tudi in vivo ter in vitro raziskavo, s katero smo potrdili potencialno zaščitno vlogo fulerenola C60(OH)24 na z doksorubicinom povzročeno hepatotoksičnost. In vivo rezultati (na podganah vrste Sprague-Dawley) so pokazali, da pride pod vplivom doksorubicina do značilnih sprememb v serumskih koncentracijah alanin-aminotransferaze (ALT), aspartat-aminotransferaze (AST), laktat-dehidrogenaze (LDH) in alfa-hidroksibutirat-dehidrogenaze (α-HBDH) kot tudi sprememb v koncentracijah malondialdehida (MDA), glutationa (GSH), glutation-peroksidaze (GSH-Px), glutation-reduktaze (GR), katalaze (CAT) in superoksid-dizmutaze (SOD) ter spremembe celotnega antioksidativnega statusa (TAS) v jetrnem tkivu. Omenjeni učinki so se izrazito zmanjšali po predhodnem injiciranju fulerenola, in sicer pri vseh preiskovanih dejavnikih, razen pri koncentracijah MDA in GSH. V drugem sklopu poskusov smo celično linijo hepatocelularnega karcinoma (HepG2) izpostavili fulerenolu v koncentracijah 10 ali 44 mg/ml za 12, 24, 48 ali 96 ur. Z namenom, da bi ovrednotili modulirajočo aktivnost fulerenola na z doksorubicinom povzročeno hepatotoksičnost, smo celično linijo istočasno izpostavili doksorubicinu (1 μM; 5 μM) in fulerenolu (10 μg/ml; 44 μg/ml) v različnih kombinacijah. Kadar smo celice izpostavili 5 μM doksorubicinu in fulerenolu, smo ohranili celično aktivnost v celotnem času trajanja poskusa. Na osnovi rezultatov lahko zaključimo, da je že sam fulerenol citotoksičen za HepG2, kadar pa je oksidativni stres prevelik, prevladajo nadcitotoksičnimi učinki fulerenola njegove močne zaščitne antioksidativne lastnosti. Poškodbe srčne mišice po vnosu doksorubicina smo potrdili na podlagi ultrastrukturnih patološksprememb, sprememb v koncentracijah SOD, MDA, CAT, GSSG (oksidirani glutation) in GR tsprememb TAS, enako kot protektivni vpliv fulerenola apliciranega pred doksorubicinom v akutfaz. Sam fulerenol v odmerku 100 mg/kg ni imel vliva na poškodbo srca v podganah z rakom dojk. Trezultati nakazujejo, da bi fulerenol lahko uporabili kot potencialni kardioprotektiv pri bolnikih, ji zdravimo z doksorubicinom.V časovnem obdobju treh tednov smo proučevali učinke fulerenola C60(OH)24 v treh odmerkih (250 in 100 mg/kg/teden) na z doksorubicinom povzročeno kardio- in hepatotoksičnost pri podganas kolorektalnim rakom. Uporabili smo in vivo model na podganah samcih vrste Wistar, pri čemsmo ugotavljali, ali je fulerenol sposoben preprečiti z doksorubicinom (1,5 mg/kg/teden v obdobtreh tednov) povzročeni kronični kardio- in hepatotoksičnost. Učinke smo primerjali z učinki dobpoznanega antioksidanta, vitamina C (100 mg/kg/teden v obdobju treh tednov). Na podlagrezultatov makroskopskih, mikroskopskih, hematoloških, biokemijskih, fizioloških, farmakološkin farmakokinetičnih raziskav smo potrdili, da ima fulerenol v vseh preiskovanih odmerkih zaščitnučinke na srčno in jetrno tkivo pred kronično toksičnostjo, inducirano z doksorubicinom.Ključna prednost fulerenola pred ostalimi znanimi antioksidanti je njegovo dvojno delovanje – ščpred učinki sevanja in ščiti pred poškodbami tkiv (srca, jeter, ledvic in pljuč) med protirakavizdravljenjem (radio- in kemo- terapijo). Potrebne pa bodo še nadaljnje raziskave, in sicer raziskavakutnih in kroničnih učinkov na prašičih in nato klinične raziskave na ljudeh.

Language:Slovenian
Keywords:protektivnost fulerenola, Alzheimerjeva bolezen, Parkinsonova bolezen, toksičnost, doksorubicin
Work type:Dissertation (m)
Tipology:2.08 - Doctoral Dissertation
Organization:FFA - Faculty of Pharmacy
Year:2008
Publisher:[R. Injac]
Number of pages:203 str.
Place:Ljubljana
UDC:542
COBISS.SI-ID:2473073 This link opens in a new window
Views:95
Downloads:20
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Secondary language

Language:English
Title:Investigation of protective effects of fullerenol in vivo in acute and chronic cardiomyopathy during doxorubicine therapy of malign neoplasma in rats
Abstract:
Fullerenes are a type of carbon molecules first discovered in the mid-1980s. The most well-known of these is the buckyball, which is a closed spherical molecule, shaped like a soccer ball. Many studies are presently in progress to search for pharmaceutical products that can capitalize on the excellent bioactivity of fullerenes and their derivatives. Thus far, different fullerene properties have been put to use, such as its ability to eliminate radicals as well as its particular molecular structure. Studies have found it to be efficient in suppression of metastases, treatment of cerebral conditions such as Alzheimer's and Parkinson's diseases, type-C hepatitis therapy, and HIV treatment. A polyhydroxilated derivative of fullerene, named fullerenols C60(OH)n, is being extensively studied due to its great potential as an antioxidant. It is proposed that fullerenols may act as free radical scavengers in biological systems, in xenobiotics, as well as radioactive irradiation-induced oxidative stress. It has demonstrated protective effects against cytotoxicity of doxorubicin (Dox) in animal models, especially by fullerenol C60(OH)24. Different rat models with chemically induced cancer were used to investigate a potential protective role of fullerenol against cardio-, hepato-, nephro- and pulmotoxicity induced by Dox. According to preliminary studies on healthy adult Wistar rats, our research group confirmed that 100 mg/kg (i.p.) of fullerenol administered 30 min before Dox has a protective influence on heart and liver tissue. Therefore, that dose was chosen as effective against acute and chronic Dox-induced toxicity in further examinations. An in vivo – in vitro study was examined to confirm the potential protective role of fullerenol C60(OH)24 on Dox-induced liver toxicity. The in vivo results (Sprague-Dawley rats) showed that treatment with Dox alone caused significant changes in serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), and alpha-hydroxybutyrate dehydrogenase (α-HBDH), as well as in levels of malondialdehyde (MDA), glutathione (GSH), glutathione peroxidase (GSH-Px), total antioxidant status (TAS), glutathione reductase (GR), catalase (CAT), and superoxide dismutase (SOD) in the liver tissue. These effects were drastically reduced for all investigated parameters by pretreatment with fullerenol, although not for the MDA and GSH level. On the other hand, the human hepatocellular carcinoma (HepG2) cell line was continuously treated with fullerenol for 12, 24, 48 and 96 h, at concentrations of 10 and 44 μg/mL. With the aim of evaluating the modulating activity of fullerenol on Dox-induced hepatotoxicity, the cell line was concurrently treated with Dox (1 μM; 5 μM) and fullerenol (10 μg/mL; 44 μg/mL) in different combinations. When the cells are treated with 5 μM Dox along with the fullerenol, a significant development of cell capability during the entire timeline can be seen. It was concluded that fullerenol has cytotoxic effects on HepG2 by itself, but when the oxidative stress is too high, the cytotoxic effects of fullerenol are overcome bits protective role as a strong antioxidant compound. Damage to the heart muscle after Dox administration was also confirmed by changes in the ultstructural pathology results and SOD, MDA, CAT, GSSG (oxidized GSH), GR, and TAS levels, well as potential cardioprotective influence of fullerenol as a pretreatment agent for Dox therapy the acute phase. Fullerenol itself, in a dose of 100 mg/kg, did not affect heart injury in rats witbreast cancer. The presented results suggested that fullerenol might be a potential cardioprotector Dox-treated individuals.Effects of fullerenol C60(OH)24 at three different doses (25, 50, and 100 mg/kg/week) on heart anliver tissue after Dox-induced toxicity in rats with colorectal cancer were investigated durig a timspan of three weeks. An in vivo Wistar male rat model was used to explore whether fullerenocould protect against Dox-induced (1.5 mg/kg/week for three weeks) chronic cardio- andhepatotoxicity, and the effect was compared with a well-known antioxidant, vitamin C (10mg/kg/week for three weeks). According to macroscopic, microscopic, hematological, biochemicaphysiological, pharmacological, and pharmacokinetic results, we confirmed that, at all examinedoses, fullerenol exhibits a protective influence on the heart and liver tissue against chronic toxiciinduced by Dox. The key benefit of fullerenol, in contrast to other known antioxidants, is its dual function as radprotector and organo-protector (heart, liver, kidney, and lung) during the anticancer therapy (radiand chemo-). However, there is a need to carry out further studies, including an acute and chroninvestigation in small pigs, and then after human trials.


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