Hyperglycemia-induced alterations in synaptosomal membrane fluidity and activity of membrane bound enzymes: beneficial effect of N-acetylcysteine supplementation

Diabetic encephalopathy is characterized by impaired cognitive functions that appear to underlie neuronal damage triggered by glucose driven oxidative stress. Hyperglycemia-induced oxidative stress in diabetic brain may initiate structural and functional changes in synaptosomal membranes. The objective of the present study was to examine the neuroprotective role of N-acetylcysteine (NAC) in hyperglycemia-induced alterations in lipid composition and activity of membrane bound enzymes (Na+,K+-ATPase and Ca2+-ATPase) in the rodent model of type 1 diabetes. Male Wistar rats weighing between 180 and 200 g were rendered diabetic by a single injection of streptozotocin (50 mg/kg body weight, i.p.). The diabetic animals were administered NAC (1.4–1.5 g/kg body weight) for eight weeks and lipid composition along with membrane fluidity were determined. A significant increase in lipid peroxidation was observed in cerebral cortex of diabetic rats. NAC administration on the other hand lowered the hyperglycemia-induced lipid peroxidation to near control levels. The increased lipid peroxidation following chronic hyperglycemia was accompanied by a significant increase in the total lipids which can be attributed to increase in the levels of cholesterol, triglycerides and glycolipids. On the contrary phospholipid and ganglioside levels were decreased. Hyperglycemia-induced increase in cholesterol to phospholipid ratio reflected decrease in membrane fluidity. Fluorescence polarization (p) with DPH also confirmed decrease in synaptosomal membrane fluidity that influenced the activity of membrane bound enzymes. An inverse correlation was found between fluorescence polarization with the activities of Na+,K+-ATPase (r2=0.416, P<0.05) and Ca2+ ATPase (r2=0.604, P<0.05). NAC was found to significantly improve lipid composition, restore membrane fluidity and activity of membrane bound enzymes. Our results clearly suggest perturbations in lipid composition and membrane fluidity as a major factor in the development of diabetic encephalopathy. Furthermore, NAC administration ameliorated the effect of hyperglycemia on oxidative stress and alterations in lipid composition thereby restoring membrane fluidity and activity of membrane bound enzymes.