We have previously synthesized a series of hybrid compounds by linking ferulic acid to tacrine as multifunctional agents based on the hypotheses that Alzheimer's disease (AD) generates cholinergic deficiency and oxidative stress. Interestingly, we found that they may have potential pharmacological activities for treating AD. Here we report for the first time that tacrine-6-ferulic acid (T6FA), one of these compounds, can prevent amyloid-β peptide (Aβ)-induced AD-associated pathological changes in vitro and in vivo. Our results showed that T6FA significantly inhibited auto- and acetylcholinesterase (AChE)-induced aggregation of Aβ1–40
in vitro and blocked the cell death induced by Aβ1–40 in PC12 cells. In an AD mouse model by the intracerebroventricular injection of Aβ1–40, T6FA significantly improved the cognitive ability along with increasing choline acetyltransferase and superoxide dismutase activity, decreasing AChE activity and malondialdehyde level. Based on our findings, we conclude that T6FA may be a promising multifunctional drug candidate for AD.
The deposition of amyloid β-protein (Aβ) fibrils into plaques within the brain parenchyma and along cerebral blood vessels is a hallmark of Alzheimer's disease (AD). Aβ42 oligomers and fibrils cause the breakdown of neural circuits, neuronal death and eventually dementia. Drugs that inhibit Aβ42 aggregation may be a novel direction in AD drug discovery. Cryptotanshinone (CTS), an active component of the medicinal herb Salvia miltiorrhiza, has been shown to improve learning and memory in several pharmacological models of AD. However, the effects of CTS on the Aβ aggregation and toxicity are unclear. The current work shows the effectiveness of CTS on the inhibition of Aβ42 aggregation and toxicity to human neuroblastoma cells. In this study, we demonstrated that CTS can inhibit Aβ42 spontaneous aggregation using thioflavin T fluorescence assay and transmission electron microscopy. Furthermore, we investigated the effects of CTS on Aβ-induced oxidative cell death in cultured SH-SY5Y cells. MTT and lactate dehydrogenase assays showed that CTS reduced the cytotoxicity induced by Aβ42. CTS also dramatically reduced Aβ42-induced cellular apoptosis and increased level of reactive oxygen species in these cells. Our study suggests that CTS may be useful in the inhibition or prevention of AD development and progression.
Excitotoxicity contributes to neuronal death and is involved in the pathogenesis of neurodegenerative disorders such as Alzheimer's disease (AD). In the present study, cryptotanshinone, an active ingredient from a Chinese plant, Salvia miltiorrhiza, was investigated to assess its neuroprotective effects against glutamate-induced toxicity in primary culture of rat cortical neurons. Cryptotanshinone reversed glutamate-induced neuronal toxicity, which was characterized by decreased cell viability, increased lactate dehydrogenase release, neuronal DNA condensation, and the alteration of the expression of Bcl-2 family proteins. The neuroprotective effects of cryptotanshinone could be blocked by LY294002 and wortmannin, two inhibitors of PI3K. The importance of the PI3K pathway was further confirmed by the activation of Akt and anti-apoptotic Bcl-2 by cryptotanshinone in a PI3K-dependent manner. These results suggest that cryptotanshinone protects primary cortical neurons from glutamate-induced neurotoxicity through the activation of PI3K/Akt pathway. Such neuroprotective effects may be of interest in AD and other neurodegenerative diseases.
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