Diabetes Increases Polyol Pathway Activity in the Brain which is Blocked by Sorbinil.

We have reported that hyperglycemia is associated with reduction of neuronal size and reduced long-term spatial memory in the developing brain of streptozotocin diabetic (STZ-D) rats. We have also noted that recurrent hypoglycemia in age matched developing rat brains does not effect cell size or long-term memory. We have also shown that diabetes is associated with increased intracellular sorbitol and reduced taurine in the rat brain. Taurine is a cellular osmole regulator that counteracts the increased cellular osmoles associated with elevated sorbitol. Taurine is also a neurotrophic factor that stimulates neuronal growth. Objective: An aldose reductase inhibitor (sorbinil) was given to STZD rats to determine whether it would reduce polyol pathway activity and thereby increase intracellular taurine in the brain. Long-term spatial memory was also tested in these animals. Methods Male Wistar rats 4 weeks of age (100 g) were used. Control rats (10) were compared to STZ-D rats (10) and STZ-D rats receiving 65 mg/kg of oral sorbinil (STZ-D+S) (10) daily for 8 weeks. After 8 weeks of hyperglycemia each of the rats had long-term spatial memory tested using a radial-arm water maze. Brains were removed for measurement of sorbitol and taurine which were expressed as a function of tissue DNA. HbA1c was measured as an indicator of the degree of hyperglycemia. Results: The HbA1c levels of the STZ-D (8.2 ± 0.4), STZ-D+S (7.9 ± 0.3) rats were higher than controls (3.3 ± 0.0). Peripheral hyperglycemia was associated with increased brain sorbitol (0.14±0.02 vs 0.03±0.00lµg/ µg DNA) p<0.001, and reduced taurine (0.65±0.11 vs 1.3±0.09 mg/ µg DNA) p<0.001. Rats receiving Sorbinil had a reduction of cellular sorbitol (0.05 ± 0.001 vs 0.14 ± 0.02) p<0.01 and an increase in cellular taurine (1.26 ± 0.09 vs 0.65 ± 0.11) p<0.01. Long-term spatial memory following normal learning in the hyperglycemic animals was significantly impaired at 24 hours but was normal after receiving Sorbinil during 8 weeks of hyperglycemia. These animals also had normal cellular sorbitol and taurine. Conclusion: The reduced cognitive function associated with hyperglycemia in rats is corrected by inhibition of the polyol pathway and normalization of brain sorbitol and taurine without correcting the extracellular hyperglycemia. [ABSTRACT FROM AUTHOR]