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 24 weeks, 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 12DM rats (n = 9); analysis II- (1) sham T2DM rats without treatment (n = 8); (2) cilostazol-treated T2DM rats (n = 8); (3) hypoperfused 12DM rats (n = 9); and (4) hypoperfused T2DM rats and cilostazol treatment (n = 9). The rats were orally administered cilostazol (50 mg/kg) or vehicle once a day for 2 weeks after 24 weeks. 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 12DM 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 C) 2015 Elsevier Inc All rights reserved.