Susceptibility to beta-amyloid-induced toxicity is decreased in Goto-Kakizaki diabetic rats: Involvement of oxidative stress

The response of synaptosomes isolated from Wistar non-diabetic rats and Got o-Kakizaki (GK) diabetic rats to the -beta-amyloid fragment A beta 25-35 wa s compared. The synaptosomal redox activity, evaluated by the MTT [3-(4,5-d imethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay, was shown to b e decreased in GK rats (72.8 +/- 7.45% of MTT reduction). However, the redu ction of MTT was decreased in synaptosomes of Wistar rats upon A beta 25-35 treatment (84.47 +/- 3.73%), while in GK rats it was not affected. A beta 25-35 induced lipid peroxidation in synaptosomes of Wistar rats, but not in that of GK rats, leading to an 1.5-fold increase in thiobarbituric acid re active substances (TBARS) levels. In the absence of A beta 25-35, basal TEA RS levels were 1.6-fold higher in GK rats. In the former preparations, the content in vitamin E was also higher (a-fold). A decrease in ATP levels, of about a-fold, was observed in synaptosomes of Wistar rats treated with A b eta 25-35, while no significant changes were observed in synaptosomes of GK rats. No significant differences between the two groups were detected in t he basal ATP levels. The extrasynaptosomal accumulation of aspartate and gl utamate increased upon A beta 25-35 treatment, only in synaptosomes of Wist ar rats (aspartate and glutamate accumulation increased by 1.1-fold and 1.5 -fold, respectively), while the accumulation of glycine increased in both W istar (by 1.8-fold) and GK (by 2.2-fold) rats. No statistical differences i n the basal accumulation of aminoacids were observed. These results show th at synaptosomes of GK diabetic rats have a lower redox activity, but are le ss susceptible to the AP25-35-induced toxicity. Data also suggest that oxid ative stress occurs in this hyperglycemia animal model and that an increase in the antioxidant defense systems may exert protection against toxic insu lts. This mechanism, occuring in the early phases of diabetes, may correspo nd to an adaptive response. (C) 2000 Academic Press.