NEUROIMUNOMODULACIJSKE I OKSIDACIJSKE PROMJENE U MOZGU ŠTAKORA NAKON ZDRUŽENOG IZLAGANJA ANESTETICIMA I TEŠKIM METALIMA

doctoral thesis

• Title (english): NEUROIMMUNOMODULATORY AND OXIDATIVE CHANGES IN THE RATS BRAIN AFTER COMBINED EXPOSURE TO ANESTHETICS AND HEAVY METALS
• Author: Nikola Lesar
• Mentor: Nada Oršolić (mentor)
• Mentor: Gordana Brozović (komentor)
• Committee member: Domagoj Đikić (predsjednik povjerenstva)
• Committee member: Romana Gračan (član povjerenstva)
• Committee member: Snježana Ramić (član povjerenstva)
• Granter: University of Zagreb; Faculty of Science; (Department of Biology); Zagreb
• Defense date and country: 2024-11-19, Croatia
• Scientific / art field, discipline and subdiscipline: NATURAL SCIENCES; Biology
• Universal decimal classification (UDC): 577 - Biochemistry. Molecular biology. Biophysics

Abstract

Cilj rada je bio istražiti učinak aluminij klorida ili željezo dekstrana uz prisutnost inhalacijskih anestetika (IA, sevoflurana i izoflurana) na nakupljanje metala u stanicama mozga, narušavanje esencijalnih elemenata te njihovu ulogu u promjeni redoks homeostaze, upale, aktivacije makrofaga i glija stanica, razine hepcidina, feritina i aktivnosti metaloproteinaza te nastanak posljedičnih strukturnih, funkcionalnih promjena koje vode razvoju neurodegenerativne bolesti. Rezultati ukazuju da subakutna, a posebice kronična primjena IA uz prekomjerni unos metala narušava stanični metabolizam, vodi poremećaju esencijalnih i nakupljanju visokotoksičnih i neesencijalnih metala, povećanju OS, upale, makrofagne polarizacije, imunosne supresije te manjih histopatoloških promjena u mozgu kroz nakupljanje amiloida. Izofluran u kombinaciji s metalima izaziva najveće promjene u mozgu kroz izrazito nakupljanje visokotoksičnih metala. Podaci ukazuju na poveznicu između visoke razine hepcidina, upale, polarizacije makrofaga prema M1 fenotipu, povećanja AChE, smanjenja BDNF i neurodegenerativnih oštećenja. Razina hepcidina usko je povezana s makrofagnom polarizacijom, OS, upalom i reorganizacijom oštećenog tkiva, dok su feritin i arginin te protuupalni citokini i BDNF zaštitne komponente mozga u prisutnosti metala i/ili IA. Nadalje, uvjeti mikrookoliša utječu na plastičnost makrofaga i odnos između fenotipova M1/M2 makrofaga; željezo regulira funkciju makrofaga kroz više putova, utječući na njihovu polarizaciju, enzimsku aktivnost i ukupnu ulogu u upali i imunosnom odgovoru. Metali tijekom kronične primjene potiskuju imunosni odgovor kroz mehanizam povezan s oksidacijskim stresom.

Abstract (english)

The aim of the work was to investigate the effect of aluminum chloride or iron dextran in the presence of inhalation anesthetics (IA, sevoflurane and isoflurane) on the accumulation of metals in brain cells, disruption of essential elements and their role in changing redox homeostasis, inflammation, activation of macrophages and glial cells, hepcidin level, ferritin and metalloproteinase activities and the resulting structural and functional changes that lead to the development of neurodegenerative diseases. The results indicate that subacute and especially chronic use of IA with excessive metal intake disrupts cellular metabolism, leads to disruption of essential and accumulation of highly toxic and non-essential metals, increased OS, inflammation, macrophage polarization, immune suppression and minor histopathological changes in the brain through amyloid accumulation. Isoflurane in combination with metals causes the greatest changes in the brain through the extreme accumulation of highly toxic metals. The data indicate a link between high hepcidin levels, inflammation, polarization of macrophages towards the M1 phenotype, increased AChE, decreased BDNF and neurodegenerative damage. The level of hepcidin is closely related to macrophage polarization, OS, inflammation and reorganization of damaged tissue, while ferritin and arginine and anti- inflammatory cytokines and BDNF are protective components of the brain in the presence of metals and/or IA. Furthermore, microenvironmental conditions affect macrophage plasticity and the relationship between M1/M2 macrophage phenotypes; iron regulates the function of macrophages through multiple pathways, affecting their polarization, enzymatic activity and overall role in inflammation and immune response. During chronic administration, metals suppress the immune response through a mechanism related to oxidative stress.

• Keywords: inhalacijski anestetici; sevofluran; izofluran; željezo dekstran; aluminijev klorid; Alzheimerova bolest; oksidacijski stres; neuroupala
• Keywords (english): inhalation anesthetics; sevoflurane; isoflurane; iron dextran; aluminum chloride; Alzheimer's disease; oxidative stress; neuroinflammation
• Language: croatian
• URN:NBN: urn:nbn:hr:217:322236
• Promotion: 2024
• Study programme: Title: Doctoral study; Study programme type: university; Study level: postgraduate; Academic / professional title: doktor/doktorica znanosti u području prirodnih znanosti (doktor/doktorica znanosti u području prirodnih znanosti)
• Type of resource: Text
• File origin: Born digital
• Access conditions: Open access
• Repository: Repository of the Faculty of Science
• Created on: 2024-12-02 18:22:23