lignans and Dementia

Multi-target drugs, such as the cocktail therapy used for treating AIDS, often show stronger efficacy than single-target drugs in treating complicated diseases. This review will focus on clausenamide (clau), a small molecule compound originally isolated from the traditional Chinese herbal medicine, Clausenalansium. The finding of four chiral centers in clau molecules predicted the presence of 16 clau enantiomers, including (-)-clau and (+)-clau. All of the predicted enantiomers have been successfully synthesized via innovative chemical approaches, and pharmacological studies have demonstrated (-)-clau as a eutomer and (+)-clau as a distomer in improving cognitive function in both normal physiological and pathological conditions. Mechanistically, the nootropic effect of (-)-clau is mediated by its multi-target actions, which include mild elevation of intracellular Ca(2+) concentrations, modulation of the cholinergic system, regulation of synaptic plasticity, and activation of cellular and molecular signaling pathways involved in learning and memory. Furthermore, (-)-clau suppresses the pathogenesis of Alzheimer's disease by inhibiting multiple etiological processes: (1) beta amyloid protein-induced intracellular Ca(2+) overload and apoptosis and (2) tau hyperphosphorylation and neurodegeneration. In conclusion, the nature of the multi-target actions of (-)-clau substantiates it as a promising chiral drug candidate for enhancing human cognition in normal conditions and treating memory impairment in neurodegenerative diseases.

Topics: Animals; Dementia; Humans; Lactams; Lignans; Medicine, Chinese Traditional; Memory Disorders

Alzheimer's Dementia (AD) and Vascular Dementia (VaD) are two main types of dementias for which no specific treatment is available. Chronic Cerebral Hypoperfusion (CCH) is a pathogenesis underlying AD and VaD that promotes neuroinflammatory responses and oxidative stress. Honokiol (HNK) is a natural compound isolated from magnolia leaves that can easily cross blood brain barrier and has anti-inflammatory and antioxidant effects. In the present study, the effects of HNK on astrocyte polarization and neurological damage in in vivo and in vitro models of chronic cerebral hypoperfusion were explored. We found that HNK was able to inhibit the phosphorylation and nuclear translocation of STAT3, A1 polarization, and reduce conditioned medium's neuronal toxicity of astrocyte under chronic hypoxia induced by cobalt chloride; STAT3 phosphorylation inhibitor C188-9 was able to mimic the above effects of HNK, suggesting that HNK may inhibit chronic hypoxia-induced A1 polarization in astrocytes via STAT3. SIRT3 inhibitor 3-TYP reversed, while Sirt3 overexpression mimicked the inhibitory effects of HNK on oxidative stress, STAT3 phosphorylation and nuclear translocation, A1 polarization and neuronal toxicity of astrocyte under chronic hypoxic conditions. For in vivo research, continuous intraperitoneal injection of HNK (1 mg/kg) for 21 days ameliorated the decrease in SIRT3 activity and oxidative stress, inhibited astrocytic STAT3 nuclear translocation and A1 polarization, and prevented neuron and synaptic loss in the hippocampal of CCH rats. Besides, HNK application improved the spatial memory impairment of CCH rats, as assessed with Morris Water Maze. In conclusion, these results suggest that the phytochemical HNK can inhibit astrocyte A1 polarization via regulating SIRT3-STAT3 axis, thus improving CCH-induced neurological damage. These results highlight HNK as novel treatment for dementia with underlying vascular mechanisms.

Topics: Animals; Astrocytes; Brain Ischemia; Dementia; Lignans; Rats; Sirtuin 3

Dementia is a category of brain diseases that cause a decrease in cognitive functions. Alzheimer's disease (AD) is the most frequently mentioned neurodegenerative disease showing dementia. Although many useful drugs for dementia were developed, we still need better and safer drugs. Here, we tested pinoresinol, a lignan found in sesame seed and olive oil, whether it could be a candidate for this purpose. Pinoresinol (25 mg/kg, p.o.) ameliorated memory impairment in dementia model induced by cholinergic blockade in the passive avoidance test in a dose-dependent manner. Moreover, pinoresinol (50 μM) facilitated induction of hippocampal long-term potentiation, a cellular model of learning and memory. Pinoresinol blocked acetylcholinesterase (AchE), an acetylcholine-degrading enzyme, activity in a concentration-dependent manner. Moreover, pinoresinol (50 μM) facilitated calcium influx into neuro2a cell. These results suggest that pinoresinol improves memory impairment and facilitates hippocampal LTP induction and these results might be related to the effect of pinoresinol on AChE and calcium influx.

Topics: Acetylcholinesterase; Animals; Calcium; Cell Line; Cholinesterase Inhibitors; Cyclic AMP Response Element-Binding Protein; Dementia; Extracellular Signal-Regulated MAP Kinases; Furans; Hippocampus; Lignans; Long-Term Potentiation; Male; Memory Disorders; Mice, Inbred ICR; Neuronal Plasticity; Proto-Oncogene Proteins c-akt; Scopolamine