Increased amyloid beta-peptide (1-40) level in brain of streptozotocin-induced diabetic rats.
The aims of the study were to investigate whether the level of amyloid beta-peptide (Abeta) (1-40) was increased in brain of diabetic rats and whether the increase was associated with dysfunction of P-glycoprotein at the blood-brain barrier. A diabetes-like condition was induced by single administration of 65 mg/kg streptozotocin via i.p. injection. Abeta (1-40) levels in brain of the diabetic rats were measured using an enzyme linked immunosorbent assay (ELISA) kit. The in vivo brain-to-blood efflux and blood-to-brain influx transport of [(125)I]-labeled human amyloid-beta-peptide (hAbeta) (1-40) were measured using the brain efflux index and brain permeability coefficient-surface area product, respectively. [(14)C]inulin served as a reference compound. The results showed that Abeta (1-40) levels significantly increased in temporal cortex and hippocampus of the diabetic rats. The brain remaining percentage of [(125)I]hAbeta (1-40) in diabetic rats significantly increased at 30 min after intracerebral microinjection, accompanied by decrease of the brain efflux index. Pretreatment of P-glycoprotein inhibitors verapamil or cyclosporin A significantly increased the brain remaining percentage of [(125)I]hAbeta (1-40). The brain permeability coefficient-surface area product of [(125)I]hAbeta (1-40) was increased in diabetic rats, accompanied by increased Abeta (1-40) levels in plasma. The present study demonstrated that a diabetic state could increase Abeta (1-40) levels in brain, which might be explained, at least in part, by the decline in brain-to-blood efflux of Abeta (1-40) due to deficient cerebral P-glycoprotein function in diabetic rats.
Liu
Y
Y
Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China.
Liu
H
H
Yang
J
J
Liu
X
X
Lu
S
S
Wen
T
T
Xie
L
L
Wang
G
G
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism / Q000503:physiopathology; D001921:Brain / Q000378:metabolism* / Q000503:physiopathology; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism* / Q000503:physiopathology; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D016229:Amyloid beta-Peptides