Sulforaphene Ameliorates Neuroinflammation and Hyperphosphorylated Tau Protein via Regulating the PI3K/Akt/GSK-3βPathway in Experimental Models of Alzheimer’s Disease

Abstract

Alzheimer’s disease (AD) is the most common form of dementia characterized by progressive loss of cognitive functions due to neuronal death mainly in the hippocampal and cortical brain. Sulforaphene (SF) is one of the main isothiocyanates isolated from a Chinese herb Raphani Semen. In this study, we aimed to investigate the neuroprotective effects of SF using in vitro and in vivo models of AD. Streptozotocin (STZ) was intracranially injected into the rats; then, SF (25 and 50 mg/kg) was given orally once a day for 6 consecutive weeks. After drug treatment, the cognitive functions were assessed using the Morris Water Maze Test (MWMT). After the MWMT, the rats were euthanized and brain tissues were collected. In the in vitro test, BV-2 microglia were pretreated with SF (1 and 2 μM) for 1 h and then stimulated with lipopolysaccharide (LPS) for another 23 h. Both molecular and histological methods were used to unravel the action mechanisms and elucidate the signaling pathway. The MWMT results showed that SF treatment significantly improved the STZ-induced cognitive deficits in rats. SF treatment markedly suppressed the production of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) but increased the release of IL-10 in the STZ-treated rats. In addition, SF significantly inhibited the phosphorylation of tau protein at Thr205, Ser396, and Ser404 sites, while enhancing the ratios of p-Akt (Ser473)/Akt and p-GSK-3β (Ser9)/GSK-3β in the hippocampus of the STZ-treated rats. On the other hand, SF (1 and 2 μM) treatment also markedly attenuated the cytotoxicity induced by LPS in BV-2 cells. In addition, SF treatment obviously suppressed the releases of nitric oxide (NO), TNF-α, and IL-6 in the LPS-stimulated BV-2 cells. Moreover, SF treatment significantly mitigated the nuclear translocation of p-NF-κB p65 and the ratio of p-GSK-3β (Ser9)/GSK-3β in LPS-stimulated BV-2 cells. Taken together, SF possessed neuroprotective effects against the STZ-induced cognitive deficits in rats and LPS-induced neuroinflammation in BV-2 cells via modulation of the PI3K/Akt/GSK-3β pathway and inhibition of the NF-κB activation, suggesting that SF is a promising neuroprotective agent worthy of further development into AD treatment.

Tau Cleavage Contributes to Cognitive Dysfunction in Strepto-Zotocin-Induced Sporadic Alzheimer’s Disease (sAD) Mouse Model

“…GSK3 facilitates the production of amyloid β in brains of APP transgenic mice [101] and its inhibition reduces the amyloid β production [102]. Pharmacological modulation of (PI3K-AKT-GSK3-β) pathway improves the hippocampus-dependent memory impairment in STZ-lesioned rodents and in transgenic AD animal models undergoing tau pathology [46,103]. Our in vivo experiments on the neuroprotective action of 12A12mAb, including the down-regulation of the amyloidogenic pathway (i.e., APP and BACE-1 expression levels) and of the ptau/total tau ratio and the improvement in cognitive performance, involving the modulation of Ser9 phosphorylation of GSK3-β in brains of ICV-STZ mice, are consistent with these findings.…”

Dexmedetomidine Alleviates Hypoxia‐Induced Synaptic Loss and Cognitive Impairment via Inhibition of Microglial NOX2 Activation in the Hippocampus of Neonatal Rats

“…Four weeks after treatment (P31), the MWM test was used to examine the spatial learning and memory ability of rats as previously described [ 33 ]. The MWM test was performed for 6 days; it included a 5-day place navigation test and a probe trial on the sixth day.…”

Comparison of the chemical constituents and anti-Alzheimer’s disease effects of Uncaria rhynchophylla and Uncaria tomentosa

“…AD model was induced by intracerebroventricular (ICV) injection of STZ as previously described [14] with minor modifications. Briefly, rats were fixed on the stereotaxic apparatus (Stoelting, Wood Dale, IL, USA) under anesthesia with an intraperitoneal injection of ketamine (75 mg/kg) and xylazine (10 mg/kg).…”

“…Uncariae Ramulus Cum Uncis (also known as Gou-teng in Chinese) is derived from the stem with hook of Uncaria rhynchophylla (Uncaria). This herb is one of the most commonly prescribed herbs in Asia, and has been extensively used in Chinese medicine practice to treat a variety of cerebral diseases, such as epilepsy, convulsion, headache and hypertension [14]. It is also incorporated into a number of herbal formulae which are prescribed for the treatment of AD, such as Chotosan (Gouteng-San in Chinese) and Yokukansan (Yigan-San in Chinese) [15,16].…”