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Molekularni mehanizmi regulacije antioksidativnih enzima u mozgu i jetri akutno i/ili hronično stresiranih pacova

Molecular mechanisms of regulation of antioxidant enzymes in the brain and liver of acutely and/or chronically stressed rats

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Disertacija.pdf (7.030Mb)
Author
Zlatković, Jelena M.
Mentor
Filipović, Dragana
Committee members
Nedeljković, Nadežda
Đurašević, Siniša
Pajović, Snežana
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Abstract
Aktivacija hipolamo-hipofizo-adrenalne (HHA) ose predstavlja jedan od odgovora organizma na izlaganje stresnim uslovima. Dok aktivacija HHA ose uzrokovana kratkotrajnim stresorima ima adaptivni karakter, hroničan stres može dovesti do brojnih patoloških promena među kojima su i poremećaji raspoloženja. Uzrok deregulacije HHA ose u stresnim uslovima još uvek nije u potpunosti utvrđen, a smatra se da može biti povezan sa i pojavom oksidativnog stresa. Stoga je ispitana i okarakterisana aktivnost HHA ose, merenjem koncentracije kortikosterona (CORT) kao markera stresnog odgovora, kao i mehanizmi regulacije antioksidativnih enzima CuZnSOD i MnSOD, kao biomarkera oksidativnog stresa, u uslovima akutnog, hroničnog i kombinovanog stresa u hipokampusu i prečeonoj kori mozga i jetri mužjaka pacova Wistar soja. Cilj ove teze je bio bolje razumevanje biohemijskih i molekularnih mehanizama delovanja antioksidativnih enzima u moždanim strukturama i jetri pacova nakon izlaganja 21-dnevnoj socijalnoj... izolaciji, koja predstavlja jedan od životinjskih modela depresije. Akutno izlaganje imobilizaciji ili niskoj temperaturi u trajanju od 2 sata korišćeno je kao pokazatelj “normalnog“ odgovora na stres, dok je kombinacija hroničnog i akutnog stresa služila kao potvrda maladaptivnog efekta hroničnog stresa. Rezultati istraživanja su pokazali povećanu koncentraciju CORT-a u serumu životinja izloženih akutnim stresorima, dok su kod životinja izlaganih hroničnoj socijalnoj izolaciji vrednosti ostale nepromenjene. Međutim, značajno niža koncentracija CORT-a između životinja koje su izlagane kombinovanom i odgovarajućem akutnom stresu ukazala je na poremećaj u regulaciji HHA ose koji je izazvana hroničnom socijalnom izolacijom, a što je rezultovalo u neadekvatnm odgovoru na nove stresne situacije. Akutni stres imobilizacije doveo je do povećanja ekspresije MnSOD proteina u mitohondrijama obe moždane strukture, dok je kod životinja akutno izlaganih niskoj temperaturi ili hroničnom stresu izolacije nivo ovog proteina ostao nepromenjen. Međutim, aktivnosti CuZnSOD i MnSOD-a u prečeonoj kori nisu pratile detektovanu proteinsku ekspresiju ukazujući time na moguće stanje oksidativnog stresa. Dodatni akutni stres doveo je do opadanja nivoa MnSOD proteina u mitohondrijama prečeone kore, što uz istovremeno povećanje u citosolnoj frakciji kao i oslobađanje citohroma c može ukazati na narušavanje integriteta mitohondrijske membrane...

The response of the organisms to stressors involves activation of hypothalamic-pituitary-adrenal (HPA) axis. HPA axis activation is adaptive in the short term, but chronic exposure to stressful stimuli may lead to pathological changes, such as mood disorders. Although precise cause of deregulation of HPA axis due to stress exposure is still unknown, it is thought that may be associated with increased oxidative stress. Therefore, we examined and characterized HPA axis activity, by measuring the concentration of serum corticosterone (CORT) as marker of stress response, and mechanisms of regulations of antioxidative enzymes CuZnSOD and MnSOD, as biomarkers of oxidative stress, in the prefrontal cortex, hippocampus and liver of male Wistar rats exposed to acute, chronic and combined stress. The aim of this thesis is better understanding the biochemical and molecular mechanisms of action of antioxidative enzymes in the brain structures and liver of rats subjected to 21-day social isolation,... that represent an animal model for depresion. Acute stressors of 2h immobilization or cold are used to indicate ’normal’ stress response, while combination of chronic and acute stress served as confirmation of maladaptive effect of chronic stress. Results showed increased concentration of serum CORT level in the animals exposed to acute immobilization or cold stress, while in animals expsosed to chronic isolation these values remain unchanged. However, significantly lower CORT level detected between animals exposed to combined and appropriate acute stress showed compromised HPA axis funcioning, caused by chronic social isolation, which has resulted in inadequate response to the novel stressful situations. Acute immobilization stress resulted in increased expression of MnSOD protein in mitochondria of both brain structures, while in animals acutely exposed to cold or chronic social isolation level of this protein remained unchanged. However, detected discrepancy between CuZnSOD and MnSOD activies and protein expression in the prefrontal cortex suggesting the possible state of oxidative stress. Additional acute stress decreased mitochondrial MnSOD protein level, which along with the increase in citosolnoj fraction and the release of cytochrome c indicate compromised integrity of the mitochondrial membrane in the prefrontal cortx...

Faculty:
Универзитет у Београду, Биолошки факултет
Date:
18-11-2013
Projects:
  • Effects of metabolic and nonmetabolic stressors on the expression and action of neuroendocrine regulators of energy homeostasis (RS-173023)
  • Molecular mechanisms of cellular responses on pathological changes in central neuronal system and peripheral organs of mammals (RS-173044)
Keywords:
hronična socijalna izolacija / chronic social isolation / oksidativni stres / nitrozativni stres / proapoptotska signalizacija / oxidative stress / nitrosative stress / proapoptotic signalization

DOI: 10.2298/bg20131118zlatkovic

[ Google Scholar ]
Handle
https://hdl.handle.net/21.15107/rcub_nardus_2124
URI
https://nardus.mpn.gov.rs/handle/123456789/2124
http://eteze.bg.ac.rs/application/showtheses?thesesId=871
https://fedorabg.bg.ac.rs/fedora/get/o:7264/bdef:Content/download
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