title: Antidiabetic drugs restore abnormal transport of amyloid-β across the blood-brain barrier and memory impairment in db/db mice.
abstract: Previous studies have shown significant changes in amyloid-β (Aβ) transport across the blood-brain barrier (BBB) under diabetic conditions with hypoinsulinemia, which is involved in diabetes-associated cognitive impairment. Present study employed db/db mice with hyperinsulinemia to investigate changes in Aβ transport across the BBB, hippocampal synaptic plasticity, and restorative effects of antidiabetic drugs. Our results showed that db/db mice exhibited similar changes in Aβ transport across the BBB to that of insulin-deficient mice. Chronic treatment of db/db mice with antidiabetic drugs such as metformin, glibenclamide and insulin glargine significantly decreased Aβ influx across the BBB determined by intra-arterial infusion of (125)I-Aβ(1-40), and expression of the receptor for advanced glycation end products (RAGE) participating in Aβ influx. Insulin glargine, but not, metformin or glibenclamide increased Aβ efflux across the BBB determined by stereotaxic intra-cerebral infusion of (125)I-Aβ(1-40), and expression of the low-density lipoprotein receptor related protein 1 (LRP1) participating in Aβ efflux. Moreover, treatment with these drugs significantly decreased hippocampal Aβ(1-40) or Aβ(1-42) and inhibited neuronal apoptosis. The drugs also ameliorated memory impairment confirmed by improved performance on behavioral tasks. However, insulin glargine or glibenclamide, but not metformin, restored hippocampal synaptic plasticity characterized by enhancing in vivo long-term potentiation (LTP). Further study found that these three drugs significantly restrained NF-κB, but only insulin glargine enhanced peroxisome proliferator-activated receptor γ (PPARγ) activity at the BBB in db/db mice. Our data indicate that the antidiabetic drugs can partially restore abnormal Aβ transport across the BBB and memory impairment under diabetic context.
authors.affiliation: Department of Pharmacology, and Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Chen
authors.affiliation: Department of Pharmacology, and Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Rong Rong
authors.initials: RR
authors.lastname: Dong
authors.affiliation: Department of Pharmacology, and Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Kai Long
authors.initials: KL
authors.lastname: Zhong
authors.affiliation: Department of Pharmacology, and Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Arijit
authors.initials: A
authors.lastname: Ghosh
authors.affiliation: Department of Pharmacology, and Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Su Su
authors.initials: SS
authors.lastname: Tang
authors.affiliation: Department of Pharmacology, and Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Long
authors.affiliation: Department of Pharmacology, and Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Mei
authors.initials: M
authors.lastname: Hu
authors.affiliation: Department of Pharmacology, and Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Ming Xing
authors.initials: MX
authors.lastname: Miao
authors.affiliation: Department of Pharmacology, and Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Jian Min
authors.initials: JM
authors.lastname: Liao
authors.affiliation: Department of Pharmacology, and Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Hong Bing
authors.initials: HB
authors.lastname: Sun
authors.affiliation: Department of Pharmacology, and Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Ling Yi
authors.initials: LY
authors.lastname: Kong
authors.affiliation: Department of Pharmacology, and Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University, Nanjing 210009, China. Electronic address: honghao@cpu.edu.cn.
authors.forename: Hao
authors.initials: H
authors.lastname: Hong
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000235:genetics; D004195:Disease Models, Animal; D005106:Exploratory Behavior / Q000187:drug effects; D005215:Fasting / Q000097:blood; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D007328:Insulin / Q000097:blood; D007456:Iodine Isotopes / Q000493:pharmacokinetics; D017774:Long-Term Potentiation / Q000187:drug effects / Q000235:genetics; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008569:Memory Disorders / Q000188:drug therapy* / Q000209:etiology; D051379:Mice; D008817:Mice, Mutant Strains; D000067759:Receptor for Advanced Glycation End Products / Q000378:metabolism; D054411:Receptors, Leptin / Q000235:genetics
chemical_list: D016229:Amyloid beta-Peptides; D007004:Hypoglycemic Agents; D007328:Insulin; D007456:Iodine Isotopes; D000067759:Receptor for Advanced Glycation End Products; D054411:Receptors, Leptin; C515447:leptin receptor, mouse
keywords: Advanced glycation end products; Amyloid-β; Antidiabetic drugs; Blood–brain barrier; Hippocampal synaptic plasticity; Low-density lipoprotein receptor related protein 1