Zaščitni in škodljivi učinki aripiprazola in olanzapina v celičnih modelih jeter

Aripiprazol (ARI) in olanzapin (OLA) sta pogosto uporabljena atipična antipsihotika s številnimi prednostmi pri zdravljenju shizofrenije in bipolarne motnje. Oba antipsihotika izkazujeta zaščitno delovanje, vendar so ob dolgotrajni terapiji zlasti problematične metabolne komplikacije, katerih vzroki so slabo poznani in bi jih potencialno lahko povezali z nepravilnim delovanjem jeter. Jetra so namreč osrednji organ presnove in detoksikacije obeh antipsihotikov, zato bi lahko motene celične funkcije bistveno pripomogle k razvoju opaženih učinkov. Namen dela je bil raziskati morebitne škodljive in zaščitne učinke ARI in OLA v celičnih modelih jeter. Proučili smo odziv celic na kratkotrajne in dolgotrajne tretmaje z izbranima antipsihotikoma ter vpliv zunanjega vira oksidativnega stresa. ARI je za jetrne celice bolj citotoksičen v primerjavi z OLA. OLA namreč ne izkazuje neposrednega citotoksičnega vpliva na jetrne celice niti po večtedenski izpostavitvi, medtem ko je učinek ARI takojšen, in sicer v obliki mitohondrijske hiperpolarizacije. Mitohondrijska hiperpolarizacija znatno upočasni celični metabolizem in delitev celic ter vodi v trajno povečan oksidativni stres. Prav ta pa bi lahko hkrati imel znaten prispevek k zaščitnemu delovanju ARI proti zunanjemu viru oksidativnega stresa, saj morajo celice vseskozi vzdrževati visok nivo antioksidativne obrambe. Zaščitni učinek ARI vsaj deloma poteka preko antioksidativnih encimov po dolgotrajni izpostavitvi in ni neposredno povezan z uravnavanjem apoptoze, avtofagije in proteasoma. ARI ščiti celice Fao in primarne hepatocite, medtem ko smo zaščitni učinek OLA opazili zgolj v kratkotrajnih poskusih na primarnih hepatocitih. Dolgotrajna izpostavitev celic antipsihotikoma je bistveno pripomogla k relevantnosti raziskave, saj je razkrila učinke, ki jih zgolj s kratkotrajnimi tretmaji ne bi uspeli zaznati. Predstavljen celični model kronične izpostavitve antipsihotikom torej bolje odraža delovanje učinkovin v ravnotežnem stanju in je potencialno uporaben tudi pri proučevanju drugih zdravil s predvidenimi dolgotrajnimi terapijami. Aripiprazole (ARI) and olanzapine (OLA) are commonly used atypical antipsychotics with many benefits in the treatment of schizophrenia and bipolar disorder. Despite of protective effects of both antipsychotics, there are metabolic complications, particularly during long-term therapy. The causes are poorly understood and could potentially be associated with liver dysfunction. The liver is the central organ of metabolism and detoxification of both antipsychotics. Impaired cellular functions could significantly contribute to the development of the observed effects. The purpose of this study was to investigate the potential adverse and protective effects of ARI and OLA in liver cell models. We studied the cellular response to short-term and long-term antipsychotic treatments exposed to acute oxidative stress. ARI is more cytotoxic to liver cells compared to OLA. OLA does not have a direct cytotoxic effect on liver cells even after several weeks of exposure, while the effect of ARI is immediate, in the form of mitochondrial hyperpolarization. Mitochondrial hyperpolarization significantly slows down cellular metabolism as well as cell division and leads to permanently elevated oxidative stress. The latter could be also linked with the protective role of ARI against external sources of oxidative stress, as cells must permanently maintain the high level of antioxidant defense. The protective effect of ARI is at least partially mediated by endogenous antioxidant enzymes after prolonged ARI exposure and it is not directly linked with the regulation of apoptosis, autophagy or proteasome activity. ARI protected Fao cells and primary hepatocytes, while the protective effect of OLA was observed only on primary hepatocytes during acute treatment. Long-term exposure to antipsychotics revealed effects that could not be detected with short-term treatments alone. Therefore, the proposed cellular model of chronic exposure to antipsychotics better reflects the action of drugs in the equilibrium and is also potentially useful to study the effects of other drugs used in long-term therapies.