Xiaojuan Chao

Tacrine-6-Ferulic Acid, a Novel Multifunctional Dimer, Inhibits Amyloid-β-Mediated Alzheimer's Disease-Associated Pathogenesis In Vitro and In Vivo

We have previously synthesized a series of hybrid compounds by linking ferulic acid to tacrine as multifunctional agents based on the hypotheses that Alzheimers 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.

Design, synthesis and pharmacological evaluation of novel tacrine-caffeic acid hybrids as multi-targeted compounds against Alzheimer's disease.

A novel series of tacrine-caffeic acid hybrids (5a-f) were designed and synthesized by combining caffeic acid (CA) with tacrine. The antioxidant study revealed that all the hybrids have much more antioxidant capacities compared to CA. Among these compounds, 5e showed the highest selectivity in inhibiting acetylcholinesterase (AChE) over butyrylcholinesterase (BuChE). Enzyme kinetic study had suggested that 5e binds to both catalytic (CAS) and peripheral anionic sites (PAS) of AChE. Moreover, compound 5e also inhibited self- or AChE-induced β-amyloid(1-40) aggregation, as well as had potent neuroprotective effects against H(2)O(2)- and glutamate- induced cell death with low toxicity in HT22 cells.

Fasudil and its analogs: a new powerful weapon in the long war against central nervous system disorders?

Introduction: Rho kinase (ROCK) plays a critical role in actin cytoskeleton organization and is involved in diverse fundamental cellular functions such as contraction and gene expression. Fasudil, a ROCK inhibitor, has been clinically applied since 1995 for the treatment of subarachnoid hemorrhage (SAH) in Japan. Increasing evidences indicate that fasudil could exhibit markedly therapeutic effect on central nervous system (CNS) disorders, such as Alzheimers disease. Areas covered: This article summarizes results from supporting evidence for the potential therapy for fasudil against a variety of CNS diseases. And the properties of its analogs are also summarized. Expert opinion: Current therapies against CNS disorders are only able to attenuate the symptoms and fail in delaying or preventing disease progression and new approaches with disease-modifying activity are desperately needed. The dramatic effects of fasudil in animal models and/or clinical applications of CNS disorders make it a promising strategy to overcome CNS disorders in human beings. Given the complex pathology of CNS disorders, further efforts are necessary to develop multifunctional fasudil derivatives or combination strategies with other drugs in order to exert more powerful effects with minimized adverse effects in the combat of CNS disorders.

Protective effects of caffeic acid and caffeic acid phenethyl ester against acrolein-induced neurotoxicity in HT22 mouse hippocampal cells

Acrolein-induced oxidative stress is hypothesized to involve in the etiology of Alzheimers disease (AD). Caffeic acid (CA) and caffeic acid phenethyl ester (CAPE) have antioxidative and neuroprotective properties. The present study investigated the protective effects of CA/CAPE on acrolein-induced oxidative neuronal toxicity. HT22 mouse hippocampal cells were pretreated with CA/CAPE and then exposed to acrolein. Cell viability, intracellular reactive oxygen species (ROS), and glutathione (GSH) level were measured. MAPKs and Akt/GSK3β signaling proteins as well as α/β-secretase of amyloid protein precursor were assayed by Western blotting. Pretreatment with CA/CAPE significantly attenuated acrolein-induced neurotoxicity, ROS accumulation, and GSH depletion. Further study suggested that CA/CAPE showed protective effects against acrolein by modulating MAPKs and Akt/GSK3β signaling pathways. Moreover, CA/CAPE restored the changes of β-secretase (BACE-1) and/or activation of α-secretase (ADAM-10) induced by acrolein. These findings suggest that CA/CAPE may provide a promising approach for the treatment of acrolein-related neurodegenerative diseases, such as AD.

Fenofibrate ameliorates cardiac hypertrophy by activation of peroxisome proliferator-activated receptor-α partly via preventing p65-NFκB binding to NFATc4.

Fenofibrate, a specific peroxisome proliferator-activated receptor alpha (PPAR-α) agonist, was reported to inhibit cardiac hypertrophy. However, the detailed molecular mechanisms and particularly the transcriptional components that are decisive in this process remain to be elucidated. Here we found that fenofibrate ameliorated cardiac hypertrophy in vitro and in vivo. Fenofibrate prevented nuclear translocation of nuclear factor of activated T-cells c4 (NFATc4) and p65 subunit of nuclear factor-kappa B (p65-NFκB) induced by pressure overload or angiotensinII (AngII). Moreover, fenofibrate increased the association of PPAR-α with NFATc4 in nucleus, which inhibited the interaction of NFATc4 with p65-NFκB. Our results suggested that the anti-hypertrophic effect of fenofibrate may be partially attributed to activation of PPAR-α, which decreases the binding of p65-NFκB to NFATc4 and thereby inhibits transactivation of NFATc4.

Effect of tacrine-3-caffeic acid, a novel multifunctional anti-Alzheimer's dimer, against oxidative-stress-induced cell death in HT22 hippocampal neurons: Involvement of Nrf2/HO-1 pathway

Oxidative stress (OS) plays an important role in the pathogenesis of neurodegenerative diseases, including Alzheimers disease (AD). This study was designed to uncover the cellular and biochemical mechanisms underlying the neuroprotective effects of tacrine‐3‐caffeic acid (T3CA), a novel promising multifunctional anti‐Alzheimers dimer, against OS‐induced neuronal death.

Tacrine-6-Ferulic Acid, a Novel Multifunctional Dimer Against Alzheimer's Disease, Prevents Oxidative Stress-Induced Neuronal Death Through Activating Nrf2/ARE/HO-1 Pathway in HT22 Cells

1 State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China 2 Laboratory of Neurodegenerative Diseases and Aging, Department of Pharmacology & Toxicology, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, China 3 Departments of Pediatrics, Nuerosury & Neurodegenerative Diseases and Aging, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangdong, China 4 Department of Traditional Chinese Medicine Chemistry, College of Chinese Materia Madica, Guangzhou University of Chinese Medicine, Guangzhou, China 5 School of Pharmaceutical Sciences, Peking University, Beijing, China 6 Dipartimento di Scienze Farmaceutiche, Università di Pisa, Pisa, Italy

The effects of chronic copper exposure on the amyloid protein metabolisim associated genes’ expression in chronic cerebral hypoperfused rats

The pathogens of Alzheimers disease (AD) are still unclear, while accumulating evidences have indicated that both genetic and environmental factors are involved in the pathogenesis of AD. Recent studies suggest that AD is primarily a vascular disorder and copper (Cu) may play an important role in AD pathology. However, the consequences of chronic Cu exposure at the presence of other AD risk factors remain to be clarified. To investigate the effects of chronic Cu intake on cerebral hypoperfusion-induced AD pathology, Sprague-Dawley rats suffered bilateral common carotid artery occlusion (2VO) were administrated with 250 ppm copper-containing water or not. Morris water maze test showed that Cu exposure for 3 months exacerbated cognitive impairment induced by 2VO. Elevated amyloid precursor protein (APP) and beta-site APP-cleaving enzyme 1 (BACE1) expression in mRNA and protein levels were also observed in brain of Cu-exposed rats suffered 2VO. In contrast, these Cu-exacerbated changes were ameliorated after Cu was withdrawn from drinking water. In summary, our findings demonstrate that chronic Cu exposure might exacerbate AD pathology in 2VO rats.

Downregulation of Nrf2/HO-1 pathway and activation of JNK/c-Jun pathway are involved in homocysteic acid-induced cytotoxicity in HT-22 cells

Previous studies have suggested that elevated blood homocysteic acid (HCA) levels increased the risk of Alzheimers disease (AD), but the underlying mechanisms are unclear. Herein, we studied the neuronal toxicity of HCA and the underlying mechanisms in HT-22 cells. Results showed that HCA induced cell death in concentration- and time-dependent manners, but did not activate Caspase-3. Additionally, HCA increased ROS production, depleted GSH, inactivated the Nrf2/HO-1 pathway, decreased mitochondrial membrane potential and increased the ratio of Bax/Bcl-2, two apoptosis-related proteins. Furthermore, HCA significantly increased the levels of p-JNK and p-c-Jun and its toxicity dramatically attenuated by SP600125, a specific JNK pathway inhibitor. Taken together, our results provide evidence that HCA induced cytotoxicity in HT-22 cells through down-regulating of Nrf2/HO-1 pathway and activating JNK/c-Jun pathway, supporting that HCA might be a therapeutic target for AD.

Berberine protects homocysteic acid-induced HT-22 cell death: involvement of Akt pathway

Berberine (BBR), one of the major constituents of Chinese herb Rhizoma coptidis, has been reported to exert beneficial effects to various diseases, including Alzheimer’s disease (AD). In the present work, we aimed to investigate the effects of BBR on neuronal cell death induced by homocysteic acid (HCA), which was considered as a risk of AD. BBR significantly reduced HCA-induced reactive oxygen species (ROS) generation, lactate dehydrogenase release and subsequent cell death. LY294002, the PI3K inhibitor, blocked the protection as well as the up-regulation of Akt phosphorylation of BBR. Taken together, our results indicate that BBR protects HCA-induced HT-22 cell death partly via modulating Akt pathway, suggesting BBR may be a promising therapeutic agent for the treatment of HCA-related diseases, including AD.