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.
Highlights
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by dysfunction of synapses and loss of neurons in the cerebral cortex and hippocampus of the brain
The effect of SF on p-Glycogen synthase kinase-3β (GSK-3β) (S9) was blocked by LY294002 (p < 0:01). These results indicate that the effects of SF on BV-2 cells depend on the PI3K/Akt/GSK-3β pathway
We reported for the first time that SF ameliorated cognitive deficits induced by STZ in rats through inhibition of neuroinflammation and tau protein hyperphosphorylation via regulating the PI3K/Akt/GSK-3β pathway
Summary
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by dysfunction of synapses and loss of neurons in the cerebral cortex and hippocampus of the brain. AD usually causes cognitive deficits and memory loss. Despite the complex pathogenesis of AD, the two major neuropathological hallmarks of AD brain are the formation of extracellular senile plaques from beta amyloids (Aβ) and intracellular neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau [1]. Oxidative Medicine and Cellular Longevity pathogenesis such as amyloid deposition, neuronal damage, tangle formation, and neuronal death. Neuroinflammation occurs at a very early stage of AD, even before the formation of Aβ plaques and tangles. Activated microglia and neuroinflammation could cause oxidative stress and neuronal damage, leading to amyloid plaque and tangle formation in the brain of AD patients [2]. The identification of therapeutic agents that can regulate neuroinflammation would be a plausible way in AD prevention and treatment
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