Terapijski potencijal peroralno primijenjene galaktoze za kognitivne i metaboličke promjene u dvama eksperimentalnim modelima Alzheimerove bolesti

doctoral thesis

• Title (english): Therapeutic potential of orally administered galactose on cognitive and metabolic changes in two experimental models of Alzheimer's disease
• Author: Ana Babić Perhoč
• Mentor: Melita Šalković-Petrišić (mentor)
• Committee member: Goran Šimić (predsjednik povjerenstva)
• Committee member: Fran Borovečki (član povjerenstva)
• Committee member: Ninoslav Mimica (član povjerenstva)
• Granter: University of Zagreb; School of Medicine; Zagreb
• Defense date and country: 2021-12-22, Croatia
• Scientific / art field, discipline and subdiscipline: BIOMEDICINE AND HEALTHCARE; Basic Medical Sciences; Pharmacology
• Universal decimal classification (UDC): 615 - Pharmacology. Therapeutics. Toxicology

Abstract

Alzheimerova bolest (AB) je neurodegenerativna bolest povezana s inzulinskom rezistencijom i hipometabolizmom glukoze u mozgu. Za razliku od štetnog učinka parenteralne, peroralno primijenjena galaktoza, uspješno sprječava nastanak kognitivnog deficita u modelu sporadičnog AB-a (sAB) dobivenog intracerebroventrikularnom primjenom streptozotocina (STZ-icv). Temeljem tih rezultata, u ovom istraživanju ispitan je utjecaj oralne galaktoze u dvije faze dvaju eksperimentalnih modela AB-a; ranoj i uznapredovaloj fazi STZ-icv-induciranog štakorskog modela sAB-a te predsimptomatskom i blagom stadiju Tg2576 mišjeg modela familijarnog AB-a (fAB). Rezultati istraživanja pokazali su da dvomjesečna primjena oralne galaktoze uspješno normalizira kognitivni deficit u ranom stadiju sAB-a, posredovano poboljšanjem metabolizma glukoze u mozgu i stimulacijom učinaka posredovanih glukagonu sličnim peptidom 1 (GLP-1). Usprkos normalizaciji metabolizma glukoze u mozgu i pojedinih drugih mjerenih parametara, oralna galaktoza nije imala blagotvoran učinak na kogniciju i homeostazu sistemskog GLP-1 u modelu uznapredovalog sAB-a, kao ni u predsimptomatskom i blagom fAB-u. Dobiveni rezultati daju nove smjernice potencijalnom terapijskom učinku oralne galaktoze upućujući da bi on mogao biti ograničen na sporadični oblik AB-a (nasuprot neučinkovitosti u fAB-u) i to samo u njegovom ranom stadiju (nasuprot uznapredovalom stadiju s ireverzibilnim promjenama). Ove spoznaje također govore u prilog postojanja metaboličkih razlika u patofiziologiji eksperimentalnog sAB i fAB te potvrđuju značaj odabira modela i stadija AB-a u interpretaciji rezultata nekliničkih ispitivanja novih terapijskih strategija u liječenju AB-a.

Abstract (english)

Alzheimer's disease (AD) is a neurodegenerative disorder associated with brain insulin resistance and glucose hypometabolism. Unlike its deleterious parenteral effect, chronic oral administration of galactose prevents cognitive impairment in a streptozotocin-induced model (STZ-icv) of sporadic AD (sAD). Based on this result, the present research investigated the effect of chronic oral galactose administration in two stages of two experimental models of AD; early and moderate STZ-icv-induced sAD in rats, and presymptomatic and mild familial AD (fAD) in Tg2576-transgenic mice. The research results showed that 2-month oral galactose treatment normalised previously developed cognitive deficits in early-stage sAD, associated with galactose-induced improvements in brain glucose metabolism and stimulation of glucagon-like peptide-1 (GLP-1)-mediated effects. Despite normalising brain glucose metabolism and other parameters in moderate sAD, presymptomatic and mild fAD, oral galactose did not improve cognition or systemic GLP-1 homeostasis. These results provide new insights into the therapeutic potential of oral galactose and indicate that the observed effect might be confined to sAD (compared to its ineffectiveness in fAD), and only in its early stage (in contrast to moderate sAD irreversible changes). These findings advocate the importance of metabolic differences in sAD/fAD pathophysiology and confirm the significance of the choice of the model and stage of AD when interpreting results from preclinical studies of new therapeutic strategies in AD.

• Keywords: Alzheimerova bolest; Streptozocin; Galaktoza; Inzulinska rezistencija; Mozak; Kognitivna disfunkcija; Glukoza; Homeostaza; Kognicija
• Keywords (english): Alzheimer Disease; Streptozocin; Galactose; Insulin Resistance; Brain; Cognitive Dysfunction; Glucose; Homeostasis; Cognition
• Language: croatian
• URN:NBN: urn:nbn:hr:105:566097
• Study programme: Title: Biomedicine and Health Sciences; Study programme type: university; Study level: postgraduate; Academic / professional title: doktor/doktorica znanosti, područje biomedicine i zdravstvo (doktor/doktorica znanosti, područje biomedicine i zdravstvo)
• Type of resource: Text
• Extent: 185 str.
• File origin: Born digital
• Access conditions: Open access
• Created on: 2022-01-27 08:51:03