Abstract

 
 
 
 Purpose: To determine the effect of ursolic acid (UA) on diabetes-induced cognitive defect, as well as its mechanism of action in streptozotocin (STZ)-induced diabetic rats.
 Methods: A rat model of diabetes was established by administration of STZ. The rats received UA via gastric perfusion for 56 successive days. Learning and memory functions were assessed using Morris water maze. Superoxide dismutase (SOD) activity and malondialdehyde (MDA) levels in hippocampus tissues were determined spectrophotometrically. Tumor necrosis factor-a (TNF-a), interleukin-1β (IL-1β) and interleukin-6 (IL-6) levels were assayed by quantitative real-time polymerase chain reaction (qRT- PCR) and enzyme-linked immunosorbent assay (ELISA). The protein expression levels of nuclear factor erythroid-2-related factor-2 (Nrf-2), heme oxygenase-1 (HO-1), Bcl-2 and Bax were evaluated by western blotting.
 Results: Learning and memory impairment in STZ-induced diabetic rats was mitigated by UA (p < 0.05). In hippocampus tissue, UA reduced oxidative stress by enhancing SOD activity and reducing MDA levels. Furthermore, UA reduced inflammatory response by downregulating TNF-α, IL-1β and IL-6 levels (p < 0.05). Concomitantly, the lower protein concentrations of Nrf-2 and HO-1 were elevated by administration of UA. Furthermore, UA suppressed Bax/Bcl-2 ratio to ameliorate apoptosis (p < 0.05).
 Conclusion: UA reduces diabetes-induced hippocampal oxidative stress, inflammation and apoptosis. Thus, it might be a potential drug candidate for delaying diabetes-associated cognitive decline (DACD).
 
 
 
Highlights
Long-term uncontrollable hyperglycemia has negative effects on multiple organs, resulting in diabetic complications [1]
Superoxide dismutase (SOD) activity was significantly reduced in DM group, while administration of ursolic acid (UA) markedly increased hippocampal SOD activity (p < 0.05; Figure 2 A)
Effect of UA on STZ-induced inflammatory response mRNA and protein expressions of TNF-α, IL-1β, and IL-6 were significantly enhanced in DM group
Summary
Long-term uncontrollable hyperglycemia has negative effects on multiple organs, resulting in diabetic complications [1]. Diabetes-associated cognitive dysfunction (DACD) is a neurogenic disease characterized by learning and memory impairments in patients with poorly controlled hyperglycemia. Streptozotocin (STZ) is widely used for establishment of animal model of diabetes [4]. It is involved in the development of brain disease, in cognitive decline [5]. Inflammatory responses and apoptosisinduced dysfunctions are essentially consequences of STZ-induced learning and memory impairments [6]. Consistent with these findings, anti-oxidation, anti-inflammation and anti-apoptosis may be effective approaches for prevention and therapy of DACD
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