Efekat kratkotrajne moždane ishemije/reperfuzije i tretmana dehidroepiandrosteronom na komponente signalnog puta NMDA receptora u hipokampusu i prečeonoj kori pacova
Effects of brief cerebral ischemia/reperfusion and dehydroepoandrosterone treatment on components of NMDA receptor-mediated signalling in rat hippocampus and prefrontal cortex
Doktorand
Zarić, Marina M.Mentor
Martinović, JelenaČlanovi komisije
Nedeljković, NadeždaDrakulić, Dunja
Metapodaci
Prikaz svih podataka o disertacijiSažetak
Stanje moţdane ishemije/reperfuzije (I/R) karakteristično je za cerebrovaskularna
oboljenja kao što su moţdani udar i tranzitorni ishemijski atak
(TIA). Promena signalizacije posredovana N-metil-D-aspartat (NMDA)
receptorom ima značajnu ulogu u I/R-uzrokovanom oštećenju, dok je
dehidroepiandrosteron (DHEA), pozitvni alosterični modulator NMDA
receptora, najčešće okarakterisan kao neuroprotektivan u tretmanu ishemičnih
stanja.
U ovoj disertaciji ispitivana je proteinska ekspresija komponenti
kompleksa NMDA receptora i njegove nishodne signalizacije u hipokampusu i
prečeonoj kori muţjaka pacova Wistar soja 24 sata nakon podvezivanja obe
zajedničke karotidne arterije u trajanju od 15 min i/ili efekat tretmana DHEA
primenjenog 4 sata od hirurške procedure. Praćenje senzo-motorne funkcije i
prisustvo infarktnih lezija na presecima celog mozga korišćeno je za validaciju
I/R modela za proučavanje blaţih ishemičnih stanja poput TIA. Takođe,
izvršeno je ispitivanje efekata I/R i tretmana na his...to/morfološkom nivou.
Odsustvo senzo-motornih deficita i infarktnih lezija kao i očuvana
struktura tkiva i morfologija neurona u hipokampusu i prečeonoj kori nakon
I/R ukazuju na potencijalnu primenu modela u ispitivanju umerenih
ishemičnih stanja. Region-specifične promene signalnog puta NMDA
receptor/neuralna azot oksid sintaza/azot oksid nakon kratkotrajne I/R govore
u prilog većoj osetljivosti hipokampusa u odnosu na prečeonu koru. Efekat
DHEA uočen je isključivo nakon I/R, vraćajući u prečeonoj kori parametare na
kontrolnu vrednost, dok u hipokampusu promene Bax/Bcl -2 odnosa i
potencijala mitohondrijske membrane ukazuju na pokretanje pro-apoptotskih
dešavanja. Stoga, prethodno okarakterisani neuroprotektivni efekat DHEA
treba dodatno istraţiti.
Cerebral ischemia/reperfusion (I/R) is characteristic of cerebro-vascular
diseases such as stroke and transient ischemic attack (TIA). Alterations of Nmethyl-
D-aspartate (NMDA) receptor-mediated signalling pathway are well
recognized features of I/R-governed damage, while dehydroepiandrosterone
(DHEA), its positive allosteric modulator, has been previously described as
neuroprotective and potentially promising for therapy of ischemic conditions.
In this doctoral dissertation changes of components of the NMDA
receptor complex and downstream signalling in hippocampus and prefrontal
cortex were examined in male Wistar rats 24 h following 15 min bilateral
common carotid artery occlusion. In addition, effects of 4 h post-surgical DHEA
treatment were investigated. Sensory-motor function and presence of infarct
lesions were used to validate suitability of I/R model for studying mild
ischemic conditions such as TIA. Additionally, effects of I/R and treatment
were evaluated on histo/morphologi...cal level.
Absence of sensory-motor deficits and infarct lesions, as well as
preserved tissue structure and overall neuronal morphology in hippocampus
and prefrontal cortex following I/R and treatment were detected indicating
suitability of used I/R model for investigation of mild ischemic states. Regionspecific
postischemic changes of NMDA receptor/neuronal nitric oxide
synthase/nitric oxide following short-term I/R indicate higher sensitivity of
hippocampus compared to prefrontal cortex. DHEA effect was detected
exclusively following I/R, returning the parameters in prefrontal cortex to the
control value, while hippocampal Bax/Bcl-2 ratio and mitochondrial membrane
potential changes indicate the initiation of pro-apoptotic events. Therefore,
previously reported neuroprotective effect of DHEA should be considered with
caution and further investigated.