Glucose Fluctuation Inhibits Nrf2 Signaling Pathway in Hippocampal Tissues and Exacerbates Cognitive Impairment in Streptozotocin-Induced Diabetic Rats.

BACKGROUND: This research investigated whether glucose fluctuation (GF) can exacerbate cognitive impairment in streptozotocin-induced diabetic rats and explored the related mechanism.

METHODS: After 4 weeks of feeding with diets containing high fats plus sugar, the rat model of diabetes mellitus (DM) was established by intraperitoneal injection of streptozotocin (STZ). Then, GF was triggered by means of alternating satiety and starvation for 24 h. The weight, blood glucose level, and water intake of the rats were recorded. The Morris water maze (MWM) test was carried out to appraise the cognitive function at the end of week 12. Moreover, the morphological structure of hippocampal neurons was viewed through HE and Nissl staining, and transmission electron microscopy (TEM) was performed for ultrastructure observation. The protein expression levels of Nrf2, HO-1, NQO-1, Bax, Bcl-2, and Caspase-3 in the hippocampal tissues of rats were measured via Western blotting, and the mRNA expressions of Nrf2, HO-1, and NQO-1 were examined using qRT-PCR. Finally, Western blotting and immunohistochemistry were conducted to detect BDNF levels.

RESULTS: It was manifested that GF not only aggravated the impairment of spatial memory in rats with STZ-induced type 2 DM but also stimulated the loss, shrinkage, and apoptosis of hippocampal neurons. Regarding the expressions in murine hippocampal tissues, GF depressed Nrf2, HO-1, NQO-1, Bcl-2, and BDNF but boosted Caspase-3 and Bax.

CONCLUSIONS: GF aggravates cognitive impairment by inhibiting the Nrf2 signaling pathway and inducing oxidative stress and apoptosis in the hippocampal tissues.