аЯрЁБс>ўџ 57ўџџџ4џџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџьЅС @№ПŒ%bjbjqфqф .&ŽŽd џџџџџџˆrrrrrrr†ъъъъ, †ІЖ.....   ѕїїїїїї$\RЎ hEr     rr..л`ччч –r.r.ѕч ѕччrrч." `Е•њАШъŸчб$v0Іч Џ. ч††rrrrчB r)Ј  ч     ††dън ††ъALTERED EXPRESSION OF INSULIN RECEPTOR IN HIPPOCAMPUS OF STREPTOZOTOCIN INTRACEREBROVENTRICULLARY TREATED RATS J. Osmanovi, M. `alkovi-Petriai, P. Riederer Introduction: Ethiopathogenesis of sporadic Alzheimer disease (SAD) is associated whit changes in brain glucose metabolism particularly in the brain regions connected with cognition and memory. Glucose metabolism in the brain is partly controlled by insulin in the brain which binds to the neuronal insulin receptor (IR) demonstrating signal transduction mechanism similar to the one at the periphery. Following insulin binding, IR becomes autophosphorylated and binds insulin receptor substrate which transduces the signal downstream the phosphatidylinositol-3 kinase pathway inactivating glycogen synthase kinase (GSK-3). GSK-3Б isoform is involved in the regulation of metabolism of amyloid-В peptides and GSK-3В isoform is involved in tau-protein phosphorylation. Therefore, changes in the phosphorylation/dephosphorylation homeostasis of IR signal cascade are capable of causing alterations in amyloid precursor protein metabolism and tau hyperphosphorylation, both known as the major hallmarks of SAD. In the human post mortem brain tissue of SAD patients IR density was found increased while IR mRNA and protein expression as well as IR tyrosine kinase were found decreased. Brain insulin system has also been investigated in experimental AD model, rats treated intracerebroventricularly (icv) with a betacytotoxic drug streptozotocin (STZ). STZ-icv rat model demonstrates brain glucose metabolism changes and deficit in learning and memory that resemble those found in AD patients. We have recently reported altered expression of enzymes downstream the IR signaling pathway; decreased phosphorylated GSK-3/non-phosphorylated GSK-3 (p-GSK-3/ GSK-3) ratio and increased level of p-tau protein in the hippocampus of STZ-icv treated rats, three months following the drug (1 mg/kg) icv treatment. In these rats increased expression of IR protein was found in hippocampus. We were investigated the changes of IR protein expression in the hippocampus of rats treated with a higher STZ-icv dose three month after the drug icv treatment. Material and Methods: Three-month-old male Wistar rats (Department of Pharmacology, School of Medicine, University of Zagreb) were given general anaesthesia (chloralhydrate 300 mg/kg, ip), followed by STZ (3 mg/kg), dissolved in 0.05M citrate buffer pH 4.5 injection bilaterally into the lateral ventricle (2 (L/ventricle). Control animals were given vehicle icv. Cognitive functions were tested by Morrris Water Maze Swimming Test. Animals were sacrificed three months after the drug treatment. IR protein expression was measured by SDS electrophoresis followed by a Western blot analysis. Data were analysed by Mann-Whitney U test (p<0.05). Results: Cognitive deficits in learning and memory were found 3 months following the STZ-icv treatment (p<0.05). These cognitive deficits were followed by decreased levels (-23%) of IR ,0<NTrВФмоі0 2 > @ D ` Œ Ь W b e l v w „ Ѓ Є Б З Л М Р Ф Х ј№хнх№хнехЭХОЗОАЉЁ™Ž†~Ё~v™~Ёn™Ёn™n™fh‹W<mH sH h‹W<mH sH ht~,mH sH hmH sH hP*mH sH hP*hP*mH sH h96#mH sH hŽ&ГmH sH  hЋ\{hŽ&Г hЋ\{hѓ%! hЋ\{hЋ\{ hЋ\{h!AоhЋ\{h!Aо>*h%YmH sH h)DFmH sH h!AоmH sH hРchРcmH sH hРcmH sH hЋ\{mH sH $о> @ —v$?%‰%Š%‹%Œ%яяяппЯЛЛЎЎЎ „А„А]„А^„Аgdњf"$ Ц,„А„А]„А^„Аa$gdЋ\{$„А„А]„А^„Аa$gd!Aо$„А„А]„А^„Аa$gdŽ&Г$„А„А]„А^„Аa$gdРc Œ%ўХ Э у № ё     2 4 Y Z g ˆ ‘ ˜ Н к № ё $ . 2 „ ˜   Ф Ю к D Z p x ь $>ƒŽ‘’ШѕэхнѕнѕнхѕнэеэЭнХКХѕХѕЎЅѕЭ‘ѕ‘ѕ‘‰ѕХѕѕѕХѕ‰Хh„wЪmH sH h)DFmH sH h‹W<h‹W<\mH sH hФJ_mH sH hФJ_\mH sH h‹W<hФJ_\mH sH h h mH sH hѓ%!mH sH h!AоmH sH h mH sH h96#mH sH hŽ&ГmH sH h‹W<mH sH h‹W<h‹W<mH sH /Шцэ*5?&Cgrsu|…ЄНбч№  ELXw~ˆ›ЈЉЊі /26ABE`ј№шрјрјреЭеЭеУИАИЈАИАИАИ ИАИА ˜АИˆ№€xp№p€№ˆhФJ_mH sH hћvхmH sH hšgLmH sH h­%mH sH h­ žmH sH h­%mH sH hšgLmH sH hŽ&ГmH sH h RmH sH hS3бh RmH sH h RCJmH sH h„wЪmH sH h56h RmH sH h„wЪmH sH h#TвmH sH hŽ&ГmH sH hRH$mH sH ,`h•–ЏFfghnoz™šЄЮЯлнJ‰шј&(1ј№шјнеЭТЗЭЌЄœен’œ‡€‡Ќ‡€Ќx‡Ќga[QhОHKaJmH sH  hОHKaJ h!AоaJ hОHKhОHKaJmH nHsH tHh)*хmH sH  hj'phmkhОHKhmkmH sH  jm№hj'phmkhОHKmH sH hЕmH sH hОHKhОHKmH sH hЕhОHKmH sH hЕh­%mH sH h­%mH sH hŽ&ГmH sH hŽ&ГhmkmH sH hОHKmH sH h­%mH sH hŽ&ГmH sH 19:R]КЫви$P$V$W$e$f$i$k$o$r$s$t$u$v$x$‚$ƒ$„$>%‰%Š%‹%Œ%іьіьітиьижьЬПЬПЬьиЕиЋиЂь˜ьтŽ„ynchj'phP*mH sH hj'pht~,mH sH hj'phmkmH sH hЋ\{aJmH sH h#TвaJmH sH hj'paJmH sH h!AоhРcaJh^RaJmH sH hšgLaJmH sH hЕhЕaJmH sH hЕaJmH sH UhТAaJmH sH h­%aJmH sH hОHKaJmH sH hњf"aJmH sH  found in hippocampus of STZ-icv treated rats in comparison to the control ones (135.67Б5.4 vs. 175.33Б5.5) (p<0.05). Conclusion: Decreased IR expression in hippocampus of rats treated with a higher STZ-icv dose is in line with SAD human data suggesting that STZ-icv treated rats are useful tool in modelling of SAD. Acknowledgement: Suported by DAAD and Croatian MZOS (108-1080003-0020). ,1hА‚. 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