Terapijski učinak multifunkcionalnog kelatora željeza M30 u štakorskom modelu sporadične Alzheimerove bolesti

master's thesis

• Title (english): Therapeutic effects of multifunctional iron-chelating agent M30 in a rat model of sporadic Alzheimer's disease
• Author: Una Smailović
• Mentor: Melita Šalković-Petrišić (mentor)
• Committee member: VLADIMIR TRKULJA (predsjednik povjerenstva)
• Committee member: Jasenka Markeljević (član povjerenstva)
• Committee member: Melita Šalković-Petrišić (član povjerenstva)
• Granter: University of Zagreb; School of Medicine; (Department of Pharmacology); Zagreb
• Defense date and country: 2015-07-15, Croatia
• Scientific / art field, discipline and subdiscipline: BIOMEDICINE AND HEALTHCARE; Basic Medical Sciences; Pharmacology

Abstract

Štakori s intracerebroventrikularnom primjenom streptozotocina (STZ-icv) predloženi su kao model sporadične Alzheimerove bolesti (sAD). Rad je imao za cilj ispitati terapijski potencijal multifunkcionalnog kelatora željeza M30 u STZ-icv štakorskom modelu sAD-a. Odraslim Wistar štakorima je icv injiciran STZ (3 mg/kg) ili citratni pufer (kontrola). Počevši od 8. dana od icv primjene, polovica STZ-icv skupine tretirana je oralno vodom (STZ), druga polovica s M30 (10 mg/kg 3x tjedno) (STZ+M30), te su sve životinje žrtvovane 2 tjedna nakon icv primjene. Ekspresija fosfo tau PHF13 i AT8 proteina te fosfo i ukupne glikogen sintaze kinaze 3β (GSK3β) i ciklin ovisne kinaze 5 (CDK5) mjerena je u hipokampusu pomoću SDS-PAGE. Nakupljanje željeza u mozgu detektirano je histološki bojanjem Berlinskim modrilom. Primjena M30 smanjila je povećanu ekspresiju p-tau-PHF13 (p<0,05) u STZ-icv štakorskom modelu, u usporedbi sa STZ-icv tretiranim štakorima koji su primali samo vodu. Ekspresija/aktivnost AT8 i GSK3β ostala je nepromijenjena u svim grupama. Ekspresija CDK5 bila je značajno niža u STZ i STZ+M30 skupinama, u usporedbi s kontrolom (p<0,05). Primjena M30 značajno je smanjila pozitivan signal patološki nakupljenog željeza u mozgu STZ-icv štakora. Naši rezultati podupiru neuroprotektivnu ulogu multifunkcionalnog kelatora željeza M30 i pružaju dokaze molekularnih mehanizama terapijskog djelovanja M30 u STZ-icv modelu sAD-a.

Abstract (english)

Rats treated intracerebroventricularly with streptozotocin (STZ-icv) have been proposed as a model of sporadic Alzheimer’s disease (sAD). We aimed to assess the therapeutic potential of a novel multifunctional iron-chelating compound M30 in STZ-icv rat model. Adult male Wistar rats were injected icv with STZ (3 mg/kg) or vehicle (control). STZ-icv injected rats were treated orally with water (STZ) or M30 (10 mg/kg 3x a week) starting 8 days after icv treatment (STZ+M30), respectively, and sacrificed 2 weeks after icv treatment. Protein expression of phospho tau protein PHF13 and AT8, phospho and total glycogen synthase kinase 3β (GSK3β) and cyclin-dependent kinase 5 (CDK5) in hippocampus was measured by SDS-PAGE. Brain iron levels were detected by Prussian blue iron staining. M30 treatment decreased STZ-icv-induced increment in p-tau PHF13 expression (p<0.05), compared to STZ-icv treatment alone. AT8 and GSK3β expression/activity remained unchanged in all groups. CDK5 expression was found significantly decreased both in STZ and STZ+M30 compared to the control (p<0.05). M30 treatment reduced positive signal of pathological iron accumulation in the STZ-icv rat brain. The results further support the neuroprotective role of multifunctional iron-chelator M30 and provide evidence on the molecular mechanisms of the therapeutic potential of M30 in STZ-icv model of sAD.

• Keywords: sporadična Alzheimerova bolest; streptozotocin; M30
• Keywords (english): sporadic Alzheimer’s disease; streptozotocin; M30
• Language: croatian
• URN:NBN: urn:nbn:hr:105:818987
• Project: Number: MZOŠ 108-1080003-0020; Title: Mozak, eksperimentalni i cerebralni dijabetes i kognitivni i drugi poremećaji; Leader: Melita Šalković-Petrišić; Jurisdiction: Croatia; Funder: MZOŠ
• Study programme: Title: Medicine; Study programme type: university; Study level: integrated undergraduate and graduate; Academic / professional title: doktor/doktorica medicine (doktor/doktorica medicine)
• Type of resource: Text
• File origin: Born digital
• Access conditions: Open access
• Created on: 2016-08-10 08:49:17