title: Diabetes augments cognitive dysfunction in chronic cerebral hypoperfusion by increasing neuronal cell death: implication of cilostazol for diabetes mellitus-induced dementia.
abstract: Many patients with diabetes are at increased risk of cognitive dysfunction and dementia. Diabetes mellitus is a vascular risk factor that may increase the risk of dementia through its associations with vascular dementia. We tested whether cognitive impairment could be exacerbated in combined injury using a rat model of chronic cerebral hypoperfusion with diabetes. We also determined whether a potent inhibitor of type III phosphodiesterase could prevent the cognitive decline caused by this combined injury. We used Otsuka Long-Evans Tokushima Fatty (OLETF) rats as a model of type II diabetes (T2DM) and Long-Evans Tokushima Otsuka (LETO) rats as a control. Chronic cerebral hypoperfusion was modeled by permanent bilateral common carotid artery occlusion (BCCAO). At 24weeks, the non-diabetic and T2DM rats were randomly assigned into groups for the following experiments: analysis I (1) sham non-diabetic rats (n=8); (2) hypoperfused non-diabetic rats (n=9); (3) sham T2DM rats (n=8); (4) hypoperfused T2DM rats (n=9); analysis II- (1) sham T2DM rats without treatment (n=8); (2) cilostazol-treated T2DM rats (n=8); (3) hypoperfused T2DM rats (n=9); and (4) hypoperfused T2DM rats and cilostazol treatment (n=9). The rats were orally administered cilostazol (50mg/kg) or vehicle once a day for 2weeks after 24weeks. Rats performed Morris water maze tasks, and neuronal cell death and neuroinflammation were investigated via Western blots and histological investigation. Spatial memory impairment was exacerbated synergistically in the hypoperfused T2DM group compared with the hypoperfused non-diabetic group and sham T2DBM group (P<0.05). Compared with the control group, neuronal cell death was increased in the hippocampus of the hypoperfused T2DM group. Cilostazol, a PDE-3 inhibitor, improved the memory impairments through inhibition of neuronal cell death, activation of CREB phosphorylation and BDNF expression in the hypoperfused T2DM group. Our experimental results support the hypothesis that there are deleterious interactions between chronic cerebral hypoperfusion and T2DM. That is, metabolic diseases such as diabetes may exacerbate cognitive impairment in a rat model of vascular dementia. We also suggest that surprisingly, the phosphodiesterase III inhibitor, cilostazol may be useful for the treatment of cognitive impairment in diabetes mellitus-induced dementia. In conclusion, diabetes can aggravate cognitive dysfunction in vascular dementia, and PDE-3 inhibitors, such as cilostazol, may form the basis of a novel therapeutic strategy for diabetes-associated cognitive impairment or vascular dementia.
authors.affiliation: Department of Neuroscience, Center for Neuroscience Research, Institute of Biomedical Science and Technology, Konkuk University School of Medicine, Republic of Korea.
authors.forename: Kyoung Ja
authors.initials: KJ
authors.lastname: Kwon
authors.affiliation: Department of Neuroscience, Center for Neuroscience Research, Institute of Biomedical Science and Technology, Konkuk University School of Medicine, Republic of Korea.
authors.forename: Eun Joo
authors.initials: EJ
authors.lastname: Lee
authors.affiliation: Department of Pharmacology, Center for Neuroscience Research, Institute of Biomedical Science and Technology, Konkuk University School of Medicine, Republic of Korea.
authors.forename: Min Kyeong
authors.initials: MK
authors.lastname: Kim
authors.affiliation: Department of Pharmacology, Center for Neuroscience Research, Institute of Biomedical Science and Technology, Konkuk University School of Medicine, Republic of Korea.
authors.forename: Soo Young
authors.initials: SY
authors.lastname: Kim
authors.affiliation: Department of Pharmacology, Center for Neuroscience Research, Institute of Biomedical Science and Technology, Konkuk University School of Medicine, Republic of Korea.
authors.forename: Jung Nam
authors.initials: JN
authors.lastname: Kim
authors.affiliation: Department of Neuroscience, Center for Neuroscience Research, Institute of Biomedical Science and Technology, Konkuk University School of Medicine, Republic of Korea; Department of Neurology, Konkuk University Medical Center, 120-1 Neungdong-ro, Gwangjin-gu, Seoul 143-701, Republic of Korea.
authors.forename: Jin Ok
authors.initials: JO
authors.lastname: Kim
authors.affiliation: Department of Neurology, College of Medicine, Hanyang University, 17 Heangdang-dong, Seongdong-gu, Seoul, Republic of Korea.
authors.forename: Hee-Jin
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: Department of Neuroscience, Center for Neuroscience Research, Institute of Biomedical Science and Technology, Konkuk University School of Medicine, Republic of Korea; Department of Neurology, Konkuk University Medical Center, 120-1 Neungdong-ro, Gwangjin-gu, Seoul 143-701, Republic of Korea.
authors.forename: Hahn Young
authors.initials: HY
authors.lastname: Kim
authors.affiliation: Department of Biological Sciences, Center for Neuroscience Research, Institute of Biomedical Science and Technology, Konkuk University School of Medicine, Republic of Korea.
authors.forename: Jung-Soo
authors.initials: JS
authors.lastname: Han
authors.affiliation: Department of Pharmacology, Center for Neuroscience Research, Institute of Biomedical Science and Technology, Konkuk University School of Medicine, Republic of Korea.
authors.forename: Chan Young
authors.initials: CY
authors.lastname: Shin
authors.affiliation: Department of Neuroscience, Center for Neuroscience Research, Institute of Biomedical Science and Technology, Konkuk University School of Medicine, Republic of Korea; Department of Neurology, Konkuk University Medical Center, 120-1 Neungdong-ro, Gwangjin-gu, Seoul 143-701, Republic of Korea. Electronic address: alzdoc@naver.com.
authors.forename: Seol-Heui
authors.initials: SH
authors.lastname: Han
mesh_terms: D000818:Animals; D001921:Brain / Q000473:pathology; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D050882:CREB-Binding Protein / Q000378:metabolism; D002340:Carotid Artery Diseases / Q000150:complications*; D053148:Caspase 3 / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D000077407:Cilostazol; D003072:Cognition Disorders / Q000188:drug therapy* / Q000209:etiology*; D003924:Diabetes Mellitus, Type 2 / Q000150:complications*; D004195:Disease Models, Animal; D005500:Follow-Up Studies; D020287:In Situ Nick-End Labeling; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D051381:Rats; D011919:Rats, Inbred Strains; D020318:Rats, Long-Evans; D011930:Reaction Time / Q000187:drug effects; D013777:Tetrazoles / Q000627:therapeutic use*
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D018696:Neuroprotective Agents; D013777:Tetrazoles; D050882:CREB-Binding Protein; D053148:Caspase 3; D000077407:Cilostazol
keywords: Diabetes mellitus; Learning and memory; Neuroprotection; Phosphodiesterase III inhibitor; Vascular dementia