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Background/Objective: We previously reported that chronic hyperglycemia, but not hypoglycemia, was associated with the reduction of neuronal size in the rat brain. We hypothesized that hyperglycemia-induced changes in neuronal structure would have negative consequences, such as impaired learning and memory. We therefore assessed the effects of hyperglycemia and hypoglycemia on neuronal dendritic structure and cognitive functioning in young rats. Design/Methods: Experimental manipulations were conducted on male Wistar rats for 8 wk, beginning at 4 wk of age. At the completion of the treatments, all rats were trained in the radial-arm water maze, a spatial (hippocampus-dependent) learning and memory task. Three groups of rats were tested: an untreated control group, a streptozotocin-induced diabetic (STZ-D) group, and an intermittent hypoglycemic group. Following behavioral training, the brains of all animals were examined with histologic and biochemical measurements. Results: Peripheral hyperglycemia was associated with significant increases in brain sorbitol (7.5 ± 1.6 vs. 5.84 ± 1.0 μM/mg) and inositol (9.6 ± 1.4 vs. 7.1 ± 1.1 μM/mg) and reduced taurine (0.65 ± 0.1 vs. 1.3 ± 0.1 mg/mg). Histologic evaluation revealed neurons with reduced dendritic branching and spine density in STZ-D rats but not in control or hypoglycemic animals. In addition, the STZ-D group exhibited impaired performance on the water maze memory test. Conclusions: Hyperglycemia, but not hypoglycemia, was associated with adverse effects on the brain polyol pathway activity, neuronal structural changes, and impaired long-term spatial memory. This finding suggests that the hyperglycemic component of diabetes mellitus has a greater adverse effect on brain functioning than does intermittent hypoglycemia. [ABSTRACT FROM AUTHOR]

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]