Gastrodin Improves Cognitive Dysfunction in REM Sleep-Deprived Rats by Regulating TLR4/NF-κB and Wnt/β-Catenin Signaling Pathways

Abstract

Gastrodin is the active ingredient in Gastrodia elata. Our previous studies demonstrated that gastrodin ameliorated cerebral ischemia-reperfusion and hypoperfusion injury and improved cognitive deficit in Alzheimer's disease. This study aims to examine the effects of gastrodin on REM sleep deprivation in rats. Gastrodin (100 and 150 mg/kg) was orally administered for 7 consecutive days before REM sleep deprivation. Seventy-two hours later, pentobarbital-induced sleep tests and a Morris water maze were performed to measure REM sleep quality and learning and memory ability. Histopathology was observed with hematoxylin-eosin staining, and the expression of the NF-κB and Wnt/β-catenin signaling pathways was examined using Western blot. After REM sleep deprivation, sleep latency increased and sleep duration decreased, and the ability of learning and memory was impaired. Neurons in the hippocampal CA1 region and the cortex were damaged. Gastrodin treatment significantly improved REM sleep-deprivation-induced sleep disturbance, cognitive deficits and neuron damage in the hippocampus CA1 region and cerebral cortex. A mechanism analysis revealed that the NF-κB pathway was activated and the Wnt/β-catenin pathway was inhibited after REM sleep deprivation, and gastrodin ameliorated these aberrant changes. Gastrodin improves REM sleep-deprivation-induced sleep disturbance and cognitive dysfunction by regulating the TLR4/NF-κB and Wnt/β-catenin signaling pathways and can be considered a potential candidate for the treatment of REM sleep deprivation.

Keywords: Gastrodin (GAS); REM sleep-deprived rats; TLR4/NF-κB signaling pathways; Wnt/β-catenin signaling pathways; cognitive dysfunction.

Figure 1

Effects of GAS on REM sleep-deprivation-induced sleep latency and sleep duration in rats: (A) the experiment design; (B) sleep latency; (C) sleep duration. Control + NS group: SD rats were lavaged with normal saline; Model + NS group: REM sleep-deprived rats were lavaged with normal saline; Model + GAS100, GSA150 groups: REM sleep-deprived rats were lavaged with gastrodin (100 or 150 mg/kg). ^# p < 0.05, versus control group; * p < 0.05, versus model group; (mean ± SD, n = 5).

Figure 2

Effects of GAS on cognitive deficits in REM sleep-deprived rats: (A) the escape latency for 4 continuous days; (B) time spent in the target quadrant. ^# p < 0.05, versus control group; * p < 0.05, versus model group; (mean ± SD, n = 7–10).

Figure 3

Effects of GAS on the pathological damage of neurons in the hippocampal CA1 region and cerebral cortex in REM sleep-deprived rats: (A) representative HE staining in hippocampus CA1 region; (B) representative HE staining in the cerebral cortex. The top row of pictures has a magnification of 400, bar = 50 μm; the bottom row of pictures has a magnification of 200, bar = 20 μm; n = 4.

Figure 4

Effects of GAS on TLR4/NF-κB signaling pathway in REM sleep-deprived rats: (A,B) expression of TLR4, p-p65, p65, p-IκBα, IκBα proteins in the hippocampus; (B–D) quantitation of TLR4, p-p65 and p-IκBα levels. ^# p < 0.05, versus control group; * p < 0.05, versus model group; (mean ± SD, n = 3).

Figure 5

Effects of GAS on Wnt/β-catenin signaling pathway in REM sleep-deprived rats: (A) expression of Wnt3a and β-catenin proteins in the hippocampus; (B,C) quantitation of Wnt3a and β-catenin levels. ^# p < 0.05, versus control group; * p < 0.05, versus model group; (mean ± SD, n = 3).