Učinak natriuretskih peptida na signalni put bradikinina nakon ishemijskog oštećenja mišjeg mozga

doctoral thesis

• Title (english): The effect of natriuretic peptide on the bradykinin signaling pathway after ischemic injury in the mouse brain
• Author: Marina Dobrivojević; MBZ: 333511
• Mentor: Srećko Gajović (mentor)
• Mentor: Aleksandra Sinđić (komentor)
• Committee member: nije dostupno (član povjerenstva)
• Granter: University of Zagreb; School of Medicine; Zagreb
• Defense date and country: 2013-07-05, Croatia
• Scientific / art field, discipline and subdiscipline: BIOMEDICINE AND HEALTHCARE; Basic Medical Sciences
• Universal decimal classification (UDC): 61 - Medical sciences

Abstract

Začepljenje moždanih arterija dovodi do moždanog udara te posljedično do moždanog edema
koji pridonosi povećanju ishemijske ozljede. Kako je bradikinin izravni uzročnik moždanog
edema te natriuretski peptidi smanjuju moždani edem nakon moždanog udara još uvijek
nepoznatim mehanizmom, cilj ovog istraživanja bio je razjasniti mogući mehanizam
djelovanja natriuretskih peptida na signalni sustav bradikinina te učinak njihovog
međudjelovanja na događaje koji slijede nakon ishemijske ozljede mozga. HEK-293 stanice
su korištene kao stanični model jer smo pokazali, koristeći RT-PCR, postojanje
bradikininskih receptora tipa 1 i 2, gvanilat ciklaze A i B te natriuretskog receptora tipa C.
Mjerenjem membranskih potencijala i unutarstanične koncentracije kalcija HEK-293 stanica
pokazali smo da natriuretski peptidi, agonisti gvanilat ciklaze-A (atrijski natriuretski peptid,
moždani natriuretski peptid, urodilatin), ali ne i gunailat ciklaze-B (C-tip natriuretski peptid)
inhibiraju bradikininski signalni put nakon aktivacije njegovog receptora tipa 2. U in vivo
pokusima na mišjem modelu moždanog udara pokazali smo da i.v. primjena urodilatina
sprječava nastanak ishemijske lezije mozga te posljedičnog moždanog edema koje smo
određivali mjerenjem stupnja neurološkog oštećenja, oslikavanjem mozgova
mikrokompjuteriziranom tomografijom, serijskim rezovima mozgova histološki bojenim po
Nisslu te određivanjem sadržaja vode u mozgu. Rezultati ovog istraživanja po prvi puta
pokazuju postojanje prirodnog antagonista bradikininskog receptora tipa 2 te moguću
primjenu natriuretskih peptida u liječenju moždanog udara.

Abstract (english)

Occlusion of the cerebral arteries leads to stroke and its consequence brain edema which
further increases the brain damage. The aim of this research was clarifying the possible
mechanisms of action of natriuretic peptides on bradykinin signaling, and their interactive
effects after ischemic brain injury, since bradykinin is involved in the formation of cerebral
edema and natriuretic peptides decrease brain edema via still unknown manner. HEK-293
cells were used as a model since using RT-PCR we proved the existence of bradykinin
receptors type 1 and 2, guanylyl cyclase A and B, and natriuretic receptor type C. Measuring
membrane potentials and intercellular calcium concentrations in HEK-293 cells we showed
that natriuretic peptides, guanylyl cyclase A agonists (atrial natriuretic peptide, brain
natriuretic peptide, urodilatin), excluding the guanylil cyclase B (C-type natriuretic peptide)
inhibited the bradykinin signaling pathway after activation of bradykinin receptor type 2. The
in vivo experiments on the animal model showed that urodilatin inhibited the formation of the
ischemic lesion and brain edema which was measured by neurological scoring, visualization
with microcomputerized tomography, serial Nissl stained sections and brain water content.
The results of this research show for the first time the existence of a natural antagonist of the
bradykinin type 2 receptor, and the possible use of natriuretic peptides in treatment of stroke.

• Keywords: medicina
• Keywords (english): medicine
• Language: croatian
• URN:NBN: urn:nbn:hr:105:845063
• Study programme: Title: Neuroscience; Study programme type: university; Study level: postgraduate; Academic / professional title: doktor/doktorica znanosti, područje biomedicine i zdravstva (doktor/doktorica znanosti, područje biomedicine i zdravstva)
• Type of resource: Text
• Extent: 115 str.
• File origin: Born digital
• Access conditions: Open access
• Created on: 2023-05-05 07:49:15