Dimeric Tacrine(10)-hupyridone as a Multitarget-Directed Ligand To Treat Alzheimer's Disease.

Alzheimer's disease (AD) is a neurodegenerative disorder with multiple pathological features. Therefore, a multitarget-directed ligands (MTDLs) strategy has been developed to treat AD. We have previously designed and synthesized dimeric tacrine(10)-hupyridone (A10E), a novel tacrine derivative with acetylcholinesterase (AChE) inhibition and brain-derived neurotrophic factor (BDNF) activation activity, by linking tacrine and a fragment of huperzine A. However, it was largely unknown whether A10E could act on other AD targets and produce cognitive-enhancing ability in AD animal models. In this study, A10E could prevent cognitive impairments in APP/PS1 transgenic mice and ß-amyloid (Aß) oligomers-treated mice, with higher potency than tacrine and huperzine A. Moreover, A10E could effectively inhibit Aß production and deposition, alleviate neuroinflammation, enhance BDNF expression, and elevate cholinergic neurotransmission in vivo. At nanomolar concentrations, A10E could inhibit Aß oligomers-induced neurotoxicity via the activation of tyrosine kinase receptor B (TrkB)/Akt pathway in SH-SY5Y cells. Furthermore, Aß oligomerization and fibrillization could be directly disrupted by A10E. Importantly, A10E at high concentrations did not produce obvious hepatotoxicity. Our results indicated that A10E could produce anti-AD neuroprotective effects via the inhibition of Aß aggregation, the activation of the BDNF/TrkB pathway, the alleviation of neuroinflammation, and the decrease of AChE activity. As MTDLs could produce additional benefits, such as overcoming the deficits of drug combination and enhancing the compliance of AD patients, our results also suggested that A10E might be developed as a promising MTDL lead for the treatment of AD.

A Chinese herbal decoction, reformulated from Kai-Xin-San, relieves the depression-like symptoms in stressed rats and induces neurogenesis in cultured neurons.

Kai-Xin-San (KXS), a Chinese herbal decoction for anti-depression, is a combination of paired-herbs, i.e. Ginseng Radix et Rhizoma (GR)-Polygalae Radix (PR) and Acori Tatarinowii Rhizoma (ATR)-Poria (PO). The make-up of the paired-herbs has been commonly revised according to syndrome differentiation and treatment variation of individual. Currently, an optimized KXS (KXS2012) was prepared by functional screening different combination of GR-PR and ATR-PO. The aim of this study was to verify the effect and underlying mechanism of KXS2012 against depression in chronic mild stress (CMS)-induced depressive rats and in primary cultures of neurons and astrocytes. In rat model, the CMS-induced depressive symptoms were markedly alleviated by the treatment with KXS2012. The CMS-suppressed neurotransmitter amounts were restored in the presence of KXS2012. And the expressions of neurotropic factors and its corresponding receptors were increased under KXS2012 administration. In cultured neurons, application of KXS2012 could promote neurogenesis by inducing the expression of synaptotagmin and dendritic spine density. Moreover, application of KXS2012 in cultured astrocytes, or in H2O2-stressed astrocytes, induced the expressions of neurotrophic factors: the increase might be associated with the modification of Erk1/2 and CREB phosphorylation. Our current results fully support the therapeutic efficacy of KXS2012 against depression in cell and animal models.