Abstract
Diabetic encephalopathy is a type of central diabetic neuropathy resulting from diabetes mainly manifested as cognitive impairments. However, its underlying pathogenesis and effective treatment strategies remain unclear. In the present study, we investigated the effect of Lipin1, a phosphatidic acid phosphatase enzyme, on the pathogenesis of diabetic encephalopathy. We found that in vitro, Lipin1 exerts protective effects on high glucose-induced reductions of PC12 cell viability, while in vivo, Lipin1 is downregulated within the CA1 hippocampal region in a type I diabetes rat model. Increased levels of Lipin1 within the CA1 region are accompanied with protective effects including amelioration of dendritic spine and synaptic deficiencies, phosphorylation of the synaptic plasticity-related proteins, LIM kinase 1 (p-limk1) and cofilin, as well as increases in the synthesis of diacylglycerol (DAG), and the expression of phosphorylated protein kinase D (p-PKD). These effects are associated with the rescue of cognitive disorders as shown in this rat model of diabetes. In contrast, knockdown of Lipin1 within the CA1 region enhanced neuronal abnormalities and the genesis of cognitive impairment in rats. These results suggest that Lipin1 may exert neuroprotective effects involving the PKD/Limk/Cofilin signaling pathway and may serve as a potential therapeutic target for diabetic encephalopathy.
Highlights
Diabetes can result in chronic complications involving multiple systems
PC12 cells were cultured for either 24 or 48 h under different concentrations of glucose and mannitol (25-150 mM, with 25 mM serving as the control concentration), and cell viability was assessed using the CCK-8 assay
As decreases in cell viability with 100 mM/48 h (P < 0:01) were more evident than that obtained with 75 mM/48 h (P < 0:05), the 100 mM/48 h condition was chosen for use as the high glucose (HG) condition in subsequent experiments
Summary
In some diabetic patients, varying degrees of cognitive deficits and even dementia may be present. The term “diabetic encephalopathy (DE)” was first proposed in 1950 to describe the cognitive impairments related to diabetes [1]. Such impairments in cognitive function, which can be revealed as declines in learning, attention, and spatial memory, comprise an important basis for the disability and death of these patients. The exact pathogenesis of DE is quite complex and remains unclear [2]. A more detailed understanding of DE pathogenesis will be required in order to identify new approaches for the prevention and treatment of this condition
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