engleski

Neuroprotective potential of novel multifunctional, lipophylic iron-chelators M-30 and HLA-20 in rat model of sporadic Alzheimer's disease

Background Iron accumulation and brain insulin system dysfunction are involved in the pathophysiology of sporadic Alzheimer's disease (sAD). 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 effect on cognitive deficits and brain insulin system in experimental sAD model, streptozotocin-intracerebroventricularly treated (STZ-icv) rats. 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). Cognitive deficits were measured in Morris Water Maze Swimming Test (MWM) and Passive Avoidance Test (PA). Insulin receptor (IR) and insulin degrading enzyme (IDE) protein expression was measured in parietal cortex (PC) and hippocampus (HPC) by Western blot analysis. Data were analysed by 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 ; 59% in PA. However, significant behavioural improvements were observed in rats pretreated with both M-30 (10 mg/kg) and HLA-20 (5 mg/kg). Preliminary immunobloting analysis demonstrated that STZ-icv induced a significant decrement of IR (46%) and IDE (34%) protein expression in PC which were prevented by M-30 (10 mg/kg) pretreatment. Conclusion M-30 and HLA-20 prevent cognitive impairments and region-specific alterations of brain insulin system in STZ-icv rat model of sAD. Supported by Croatian MZOS (108-1080003-0020) and DAAD

streptozotocin; sporadic Alzheimer disease; insulin; brain; neuroprotective drugs; M-30 and HLA-20;

DOI:10.1159/000318232