Expression changes of growth-associated protein-43 (GAP-43) and mitogen-activated protein kinase phosphatase-1 (MKP-1) and in hippocampus of streptozotocin-induced diabetic cognitive impairment rats
Introduction
Diabetes mellitus (DM) in adults is a global health problem and its incidence has generally increased worldwide (Ott et al., 1999). DM impairs tissues and organs causing serious diseases such as diabetic retinopathy, diabetic nephropathy, and peripheral neuropathy (Bailes, 2002, Bansal et al., 2006). These have already been studied widely, but there have been relatively few studies on the effects of DM on the central nervous system. DM increases the risk of dementia in general (Biessels et al., 2006) and vascular dementia (Roman, 2005) in particular. A recent study has shown that cognitive decline is more marked in diabetic patients (Alvarez and Ruarte, 2002). Cognition involves learning ability, memory and problem-solving ability etc. Some reports indicate that synaptic plasticity is an important factor in cognition, particularly in Hippocampal dentate gyrus (DG) and frontal cortex (Oestreicher et al., 1997).
The neuronal growth-associated protein-43 (GAP-43) is a presynaptic membrane phosphoprotein involved in guiding the growth of axons and modulating the formation of new connections (Farina et al., 2004). Other events, such as axonal regeneration following nerve injury and long term potentiation (LTP) also increase GAP-43 expression (Chirwa et al., 2005). Mitogen-activated protein kinase phosphatase-1 (MKP-1) is a dual serine/threonine, tyrosine phosphatase and specifically inactivates MAPK family members (Brunet et al., 1995). It was reported that the mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) signaling cascade contributes to synaptic plasticity and to long-term memory formation that was the foundation of learning ability and memory (Kelleher et al., 2004).
In order to provide some laboratory explanations for why DM could increase the risk of dementia, we employed streptozotocin (STZ)-induced diabetic rats and test their capacity for learning and memory by three-arm radial maze and used transmission electron microscopy (TEM) to investigate their neuronal ultrastructure changes in the Hippocampal area. We also carried out a quantitative evaluation on the alteration of MKP-1 mRNA levels in the Hippocampal area 4 weeks after the induction of diabetes.
Section snippets
Animal model induction
Thirty Sprague–Dawley (SD) female rats (Experiment animal center of Zhejiang University) weighing 150–200 g were divided into two groups at random (diabetes and control respectively). The rats were weighed, urine was collected, and blood samples were taken from caudal vein after anaesthetization. Plasma glucose level was measured by Glucose Electrode Calibrator (MediSense QA2583-3364, USA), and urine glucose level by Test Strips for Urine Glucose (Anjian GZZJ 1-2002, China). Fifteen rats were
Diabetes induction
The weight, blood glucose and urine glucose showed no significant differences between both groups of rats before STZ injection (P > 0.05). The differences between diabetes and control groups were statistically significant 4 weeks after STZ injection (P < 0.01) (Table 1).
Three-arm radial maze test
Table 2 shows that the control group made significantly fewer error number in session 4 than session 1 (P < 0.01) while in the diabetic group the error number was relatively similar for the two sessions. Therefore the control group
Discussion
DM is often accompanied with severe complications, such as cardiovascular disease, renal failure, retinopathy, peripheral and autonomic neuropathy (Bailes, 2002, Bansal et al., 2006). Although proper metabolic control reduces the incidences of these complications, it is not sufficient to prevent them completely. In this study, we focused on cognitive decline of DM which has an increasing prevalence worldwide (Alvarez and Ruarte, 2002). Among diabetic patients, the most prominent mental
Acknowledgments
The authors would like to thank Dr. Shu Han for their excellent assistant and helpful comments on this manuscript. This research was supported by Zhejiang Natural Science Foundation (No. Y204036) and Fund of Health Bureau of Zhejiang Province (No. 2006A083).
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