Naslov
Therapeutic strategies in the rat model of sporadic Alzheimer's disease

Autori
Šalković-Petrišić, Melita ; Osmanović-Barilar, Jelena ; Knezović, Ana ; Mandel, Silvia ; Youdim, Moussa ; Riederer, Peter

Vrsta, podvrsta i kategorija rada
Sažeci sa skupova, sažetak, znanstveni

Izvornik
Periodicum biologorum / - , 2010

Skup
6th Croatian Congress of Pharmacology with International Participation

Mjesto i datum
Opatija, Hrvatska, 15.09.2010. - 18.09.2010

Vrsta sudjelovanja
Pozvano predavanje

Vrsta recenzije
Domaća recenzija

Ključne riječi
streptozotocin; learning and memory; M30; HLA-20; glycogen synthase kinase

Sažetak
Introduction: Considering the diverse etiological nature of sporadic Alzheimer’s disease (sAD), novel therapeutic strategies are currently focused on the implementation of cocktail of drugs, directed to various neuronal targets. Iron accumulation and brain insulin system dysfunction are both involved in the sAD pathophysiology. Novel multifunctional, brain permeable, neuroprotective drugs, M-30 and HLA-20, exert iron chelating potency, radical scavenging and neurorescue activities in several models of neurodegenerative diseases. We have investigated their therapeutic potential in experimental sAD- like model, streptozotocin- intracerebroventricularly treated (STZ-icv) rats known to develop both cognitive deficits and insulin resistant brain state. Methods: Adult male Wistar rats were pretreated for 5 days with M-30 and HLA-20 (5 or 10 mg/kg per os) followed by a vehicle or STZ single icv injection (1.5 mg/kg ; preventive paradigm). In the other set of experiments, M30 per os treatment (same doses, given for 10-19 days) has been initiated after STZ-icv administration (neurorescue paradigm). Cognitive deficits were measured in Morris Water Maze Swimming Test (MWM) and Passive Avoidance Test (PA). Protein expression of tau protein and glycogen synthase kinase 3 β (GSK3β) was measured in hippocampus by SDS PAGE electrophoresis followed by Western blot analysis. Data were analysed by Kruskal-Wallis ANOVA Median test followed b Mann-Whitney U test (p<0.05). Results: STZ-icv treated rats demonstrated significant cognitive deficit in learning and memory functions 4 weeks after STZ-icv treatment ; in average, 40% in platform searching time and 80% in number of mistakes in MWM ; and 59% in PA. However, significant prevention of cognitive deficits was observed in rats pretreated with both M-30 (10 mg/kg) and HLA-20 (5 mg/kg). A similar action on cognitive deficits was obtained when M30 treatment was initiated after sAD-like development. M30 also improved STZ-icv induced increase in hippocampal total tau protein expression (from +29.59% to +6% in comparison to the controls), independently of its effect on the GSK3β activity. Conclusion: M30 and HLA20 demonstrate promising therapeutic potential for both prevention and restoration of cognitive deficits in non- transgenic animal sAD- like model. Further research will clarified the mechanism of cognitive improvement induced by M30 and HLA20 in relation to their effect on the insulin receptor signalling pathway in the brain. Acknowledgement: Supported by Croatian MZOS (108- 1080003-0020) and German DAAD projects.

Izvorni jezik
Engleski

Znanstvena područja
Temeljne medicinske znanosti

POVEZANOST RADA