Antidiarrheal mechanism of Carpolobia lutea leaf fractions in rats

Context: Carpolobia lutea G. Don (Polygalaceae) leaf is reputable as an antidiarrheal agent among the Efik and Ibibio tribe of Akwa Ibom State, Nigeria. The crude extract is reported to show antidiarrheal and antiulcer effects in rodents.

Objective: The isolation and characterization of drug molecules from the leaf fraction with antidiarrheal bioactivity and determination of mechanism of action are reported.

Material and methods: Gradient extraction by maceration yielding n-hexane, chloroform, ethyl acetate, and ethanol fractions (770?mg/kg) were used to establish the fractions suitable for drug discovery. The antidiarrheal effect of the leaf fractions of Carpolobia lutea was evaluated using castor oil–induced diarrhea, castor oil–induced intestinal transit, and enteropooling.

Results: Results indicate that all fractions produced a significant (p?<?0.01–0.001) decrease in castor oil–induced diarrhea in rats. This effect was not antagonized by isosorbide dinitrate (150?mg/kg, p.o), diphenoxylate (5?×?10^?3 mg/kg p.o) and yohimbine (1?mg/kg, s.c.) except for the chloroform fraction. The ethyl acetate fraction produced 100% inhibition of intestinal transit, an effect greater than pure drug. Phytochemical analysis of the ethyl acetate fraction yielded polyphenolic compounds.

Conclusion: The leaf fractions contain two types of antidiarrheal agents, one mediating its effect through α₁-presynaptic adrenoceptor while the other does not. Polyphenols isolated may in part lend credence for observed antidiarrheal activity.     

Design,synthesis, and biological activity evaluation of BACE1 inhibitors with antioxidant activity

The proteolytic enzyme β-secretase (BACE1) plays a central role in the synthesis of the pathogenic β-amyloid peptides (Aβ) in Alzheimer's disease (AD), antioxidants could attenuate the AD syndrome and prevent the disease progression. In this study, BACE1 inhibitors ( D1 – D18 ) with free radical-scavenging activities were synthesized by molecular hybridization of 2-aminopyridine with natural antioxidants. The biological activity evaluation showed that D1 had obvious inhibitory activity against BACE1, and strong antioxidant activity in 1,1-diphenyl-2-picrylhydrazyl (DPPH) and 2,2′-azinobis-(3-ethylbenzthiazoline-6-sulphonate) (ABTS^+•) assay, which could be used as a lead compound for further study.     

Protective effect of Basella alba and Carpolobia alba extracts against maneb-induced male infertility

Context: Male infertility is one of the leading causes of social frustration and marginalization, mainly in the developing world. It is attributed to many factors including exposure to agropesticides such as manganese ethylenebis (dithiocarbamate) (maneb), which is one of the most frequently used fungicides in Cameroon. Previous reports support efficiency of some medicinal plants commonly used in Cameroonian folk medicine for the treatment of this disorder.

Objective: The present study was aimed at assessing the protective effect of extracts from selected plant species, namely Basella alba L. (Basellaceae) (MEBa) and Carpolobia alba G. Don (Polygalaceae) (AECa), in alleviating the maneb-induced impairment of male reproductive function in Wistar albino rats.

Materials and methods: The rats were treated with vehicle, plant extract (MEBa or AECa), maneb and maneb plus plant extract, respectively, and their fertility was assessed. Animals were thereafter sacrificed and organs (liver, kidneys and reproductive organs) were dissected out and weighed. Serum androgens together with alanine aminotransferase, liver glutathione and thiobarbituric acid reactive species (TBARS) were also measured.

Results and discussion: From this study, both plant extracts stimulated testosterone and improved fertility. Administration of MEBa plus maneb prevented fertility reduction by maneb and minimized the inhibitory effect of maneb on testosterone levels. AECa also improved fertility of the maneb-exposed rats, though without restoring testosterone levels, and other investigated parameters remained unaffected by different treatments.

Conclusion: These findings emphasized the beneficial effects of B. alba and C. alba extracts on male fertility, and suggest their protective effect against maneb-induced toxicity in male reproductive function.     

Multifunctional properties of novel tacrine congeners: cholinesterase inhibition and cytotoxic activity

This review describes the synthesis of a wide range of novel tetrahydroacridine derivatives (tiocyanates, selenocyanates, ureas, selenoureas, thioureas, isothioureas, disulfides, diselenides and several tacrine homo‐ and hetro‐hybrids). These tacrine congeners exhibit significant anticholinesterase and cytotoxic properties and may therefore be of considerable potential for the development of new drugs for the treatment of Alzheimer's disease.     

Protective effect of Nelumbo nucifera extracts on beta amyloid protein induced apoptosis in PC12 cells,in vitro model of Alzheimer's disease

Alzheimer's disease (AD) is the most common cause of dementia in the elderly. β-Amyloid (Aβ) has been proposed to play a role in the pathogenesis of AD. Deposits of insoluble Aβ are found in the brains of patients with AD and are one of the pathological hallmarks of the disease, but the underlying signaling pathways are poorly understood. In order to develop antidementia agents with potential therapeutic value, we examined the inhibitory effect of the Nelumbo nucifera seed embryo extracts on to the aggregated amyloid β peptide (agg Aβ_1–40)-induced damage of differentiated PC-12 cells (dPC-12), a well-known cell model for AD. In the present study, seed embryos of N. nucifera were extracted with 70% methanol in water and then separated into hexane, ethyl acetate, n-butanol, and water layers. Among them, only the n-butanol layer showed strong activity and was therefore subjected to separation on Sephadex LH-20 chromatography. Two fractions showing potent activity were found to significantly inhibit Aβ_1–40 toxicity on dPC-12 cells in increasing order of concentration (10–50 μg/mL). Further purification and characterization of these active fractions identified them to be flavonoids such as rutin, orientin, isoorientin, isoquercetrin, and hyperoside. 2,2-Diphenyl-1-picrylhydrazyl hydrate scavenging activity of the extracts was also carried out to ascertain the possible mechanism of the activity.     

Neuropharmacological and pharmacokinetic properties of berberine: a review of recent research

Objectives This review summarizes recent research on the neuropharmacological and pharmacokinetic properties of berberine, an isoquinoline alkaloid extracted from Coptidis rhizoma. Key findings Berberine has multiple neuropharmacological properties, such as neuroprection, anti‐neuronal apoptosis, improvement of cerebral microcirculation and anti‐Alzheimer's disease, and so on. The pharmacokinetic characteristics of berberine are that it is not easily absorbed and it is not stable in the gastrointestinal tract of animals or humans. Summary Further studies need to be carried out to develop berberine as a drug for nervous system diseases, such as brain ischaemia and Alzheimer's disease, that has favorable pharmacokinetic properties.     

Synthesis and biological evaluation of genistein‐O‐alkylamine derivatives as potential multifunctional anti‐Alzheimer agents

A series of genistein derivatives were synthesized and evaluated as multifunctional anti‐Alzheimer agents. The results showed that these derivatives had significant acetylcholinesterase (AChE) inhibitory activity; compound 5a exhibited the strongest inhibition to AChE with an IC₅₀ value (0.034 μM) much lower than that of rivastigmine (6.53 μM). A Lineweaver–Burk plot and molecular modeling study showed that compound 5a targeted both the catalytic active site and the peripheral anionic site of AChE. These compounds also showed potent peroxy scavenging activity and metal‐chelating ability. The compounds did not show obvious effect on HepG2 and PC12 cell viability at the concentration of 100 μM. Therefore, these genistein derivatives can be utilized as multifunctional agents for the treatment of AD.     

沙蚕提取物的抗氧化活性研究

目的探讨沙蚕提取物的抗氧化活性。方法采用DPPH法观察沙蚕提取物的抗氧化活性，通过Sephadex LH-20凝胶过滤，对沙蚕提取物中的抗氧化物质进行了初步分离纯化。结果与结论沙蚕提取物具有较强的清除自由基（DPPH）的能力，通过定性分析方法确定该物质为一类小分子量的多肽类物质。     

Anti‐Alzheimer's multitarget‐directed ligands with serotonin 5‐HT6 antagonist,butyrylcholinesterase inhibitory,and antioxidant activity

Serotonin 5‐HT₆ receptors, butyrylcholinesterase (BuChE) and oxidative stress are related to the pathophysiology of Alzheimer's disease. Inhibition of BuChE provides symptomatic treatment of the disease and the same effect was demonstrated for 5‐HT ₆ antagonists in clinical trials. Oxidative stress is regarded as a major and primary factor contributing to the development of Alzheimer's disease; therefore, antioxidant agents may provide a disease‐modifying effect. Combining BuChE inhibition, 5‐HT ₆ antagonism, and antioxidant properties may result in multitarget‐directed ligands providing cognition‐enhancing properties with neuroprotective activity. On the basis of the screening of the library of 5‐HT ₆ antagonists against BuChE, we selected two compounds and designed their structural modifications that could lead to improved BuChE inhibitory activity. We synthesized two series of compounds and tested their affinity and functional activity at 5‐HT ₆ receptors, BuChE inhibitory activity and antioxidant properties. Compound 12 with K _i and K _b values against 5‐HT ₆ receptors of 41.8 and 74 nM, respectively, an IC ₅₀ value of 5 µM against BuChE and antioxidant properties exceeding the activity of ascorbic acid is a promising lead structure for further development of anti‐Alzheimer's agents.     

Synthesis of New Lipoic Acid Conjugates and Evaluation of Their Free Radical Scavenging and Neuroprotective Activities

A series of new lipoic acid derivatives were designed and synthesized as multitarget ligands against Alzheimer's disease. In particular, analogues combining both lipoic acid and cysteine core structures were synthesized. The antioxidant properties of these compounds were evaluated by 1,1‐diphenyl‐2‐picrylhydrazyl (DPPH), 2,2′‐azino‐bis(3‐ethylbenzothiazoline‐6‐sulfonic acid (ABTS^?+) radical cation scavenging assays and ferrous ion chelation. The antioxidant potential of the synthesized compounds was also evaluated in a cellular context and compared to α‐lipoic acid and its reduced form, dihydrolipoic acid. The antioxidant effects observed for these compounds in vitro confirmed the importance of free thiol functions for effective antioxidant capacities. However, these promising in vitro results were not mirrored by the antioxidant activity in T67 cell line. This suggests that multiple factors are at stake and warrant further investigations.     

Double-blind,placebo controlled study of acetyl-l-carnitine in patients with Alzheimer's dementia

Summary

A randomized, double-blind, placebo-controlled, parallel-group clinical trial was carried out to compare 24-week periods of treatment with I gacetyl-l-carnitine twice daily and placebo in the treatment of patients with dementia of the Alzheimer type. A total of 36 patients entered the trial, of whom 20 patients (7 active, 13 placebo) completed the full 24 weeks. Whilst several of the efficacy indices showed little change in either group during the trial, there was an apparent trend for more improvement in the acetyl-l-carnitine group in relation to the Names Learning Test and a computerized Digit Recall Test, both related to aspects of short-term memory. Similarly, there was a trend for reaction time in the computerized classification test to show less deterioration in the active treatment group. Changes within groups, and changes between groups, failed to reach statistical significance, at least partially because of the small number of patients available for analysis. Two indices of overall therapeutic benefit showed a trend for less deterioration in the active-treatment group than in the placebo group. Nausea and/or vomiting occurred in 5 patients in the acetyl-l-carnitine group. Laboratocy tests revealed no signs of drug toxicity. The results suggest that acetyl-l-carnitine may have a beneficial effect on some clinical features of Alzheimer-type dementia, particularly those related to short-term memory.     

Using Drosophila models of neurodegenerative diseases for drug discovery

Introduction: Neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease and Huntington's disease are increasing in prevalence as our aging population increases in size. Despite this, currently there are no disease-modifying drugs available for the treatment of these conditions. Drosophila melanogaster is a highly tractable model organism that has been successfully used to emulate various aspects of these diseases in vivo. These Drosophila models have not been fully exploited in drug discovery and design strategies.

Areas covered: This review explores how Drosophila models can be used to facilitate drug discovery. Specifically, we review their uses as a physiologically-relevant medium to high-throughput screening tool for the identification of therapeutic compounds and discuss how they can aid drug discovery by highlighting disease mechanisms that may serve as druggable targets in the future. The reader will appreciate how the various attributes of Drosophila make it an unsurpassed model organism and how Drosophila models of neurodegeneration can contribute to drug discovery in a variety of ways.

Expert opinion: Drosophila models of human neurodegenerative diseases can make a significant contribution to the unmet need of disease-modifying therapeutic intervention for the treatment of these increasingly common neurodegenerative conditions.     

Study of Nutraceuticals and Phytochemicals for the Management of Alzheimer's Disease: A Review

Background Alzheimer''s disease (AD) affects several people worldwide and has devastating impacts on society with a limited number of approaches for its pharmacological treatment. The main causes of AD are not clear yet. However, the formation of senile plaques, neurofibrillary tangles, hyper-phosphorylation of tau protein, and disruption of redox homeostasis may cause AD. These causes have a positive correlation with oxidative stress, producing reactive ions, which are responsible for altering the physiological condition of the body.Conclusion Ongoing research recommended the use of phytochemicals as acetylcholinesterase inhibitors to hinder the onset and progression of AD. The natural compound structures, including lignans, flavonoids, tannins, polyphenols, triterpenes, sterols, and alkaloids have anti-inflammatory, antioxidant, and anti-amyloidogenic properties. The purpose of this article is to provide a brief introduction to AD along with the use of natural compounds as new therapeutic approaches for its management.     

N-methylpiperazinyl and piperdinylalkyl-O-chalcone derivatives as potential polyfunctional agents against Alzheimer's disease: Design,synthesis and biological evaluation

The series of N-methylpiperazinyl and piperdinylalkyl-O-chalcone derivatives as potential polyfuctional agents against Alzheimer's disease that have been designed, synthesized and then evaluated biologically using in vitro assays for the inhibition of acetylcholinesterase (AChE) activity, AGEs, and free radical formation. The majority of synthesized compounds inhibited AChE & AGEs with additional free radical scavenging activities at nanomolar concentrations. Among these, compound 5k was found to have potent AChE inhibitory activity (IC₅₀ = 11.6 nM), superior than the reference compound donepezil (15.68 nM) along with the good anti-AGEs and free radical formation effect. Its potency was justified by docking studies that revealed its dual binding characteristic with both catalytic active site and peripheral anionic site of AChE, simultaneously. Furthermore, the in vivo evaluation of 5k against streptozotocin (STZ)-induced dementia in rats also showed improvement of memory functions (Morris water maze test) in animals. Also, 5k inhibited STZ-inudced brain AChE activity and oxidative stress which further strengthen the observed in vitro effects. The stability of the ligand-protein complex was then analyzed using a simulation-based interaction protocol. The results revealed that these N-methylpiperazinyl and piperdinylalkyl-O-chalcone derivatives could be considered for potential polyfunctional anti-Alzheimer's molecules.     

Safety and tolerability of transdermal and oral rivastigmine in Alzheimer's disease and Parkinson's disease dementia

Importance of the field: Cholinesterase inhibitors are the mainstay of symptomatic therapy for Alzheimer's disease (AD). Rivastigmine, an inhibitor of both acetylcholinesterase and butyrylcholinesterase, is available as a transdermal patch and in oral forms. It is also approved for the treatment of Parkinson's disease dementia (PDD) in many countries. The objective of this article is to review the safety and tolerability profile of transdermal and oral rivastigmine in AD and PDD patients.

Areas covered in this review: Articles were identified by searching MEDLINE in July 2009 using the terms rivastigmine, Exelon, ENA 713 and clinical trial. All double-blind, placebo-controlled randomized trials in which rivastigmine monotherapy was administered to AD or PDD patients for longer than 2 weeks were included.

What the reader will gain: This article provides a comprehensive summary of currently available safety data on rivastigmine.

Take home message: The main adverse events reported with rivastigmine therapy are gastrointestinal in nature. However, the transdermal patch appears to reduce these side effects, allowing more patients to access higher therapeutic doses. Overall, the safety profile of rivastigmine is favorable and the improved tolerability offered by the rivastigmine patch suggests that transdermal delivery may be the best way to deliver this drug in AD and PDD patients.     

Ameliorating effect of Celastrus paniculatus standardized extract and its fractions on 3-nitropropionic acid induced neuronal damage in rats: possible antioxidant mechanism

Context: Celastrus paniculatus Wild. (Celasteraceae) (CP) is a well-known Ayurvedic ‘Medhya Rasayana’ (nervine tonic), used extensively as a neuro-protective and memory enhancer, and in different central nervous system disorders.

Objective: To evaluate the effect of CP against 3-nitropropionic acid (3-NP) induced Huntington's disease (HD) like symptoms in Wistar male rats.

Materials and methods: The ethanol extract of CP seeds (CPEE), prepared by maceration, was standardized on the basis of linoleic acid content (6.42%) using thin layer chromatography densitometric analysis. Protective effect of CPEE (100 and 200?mg/kg) and its various fractions, viz., petroleum ether (40?mg/kg), ethyl acetate (2.5?mg/kg), n-butanol (7?mg/kg) and aqueous (18?mg/kg), administered orally for 20 days, against 3-NP (10?mg/kg, i.p. for 14 days) was assessed by their effect on body weight, locomotor activity, grip strength, gait pattern and cognitive dysfunction and biochemical parameters for oxidative damage in the striatum and cortex regions of the brain.

Results: CPEE (100 and 200?mg/kg) treated animals exhibited a significant (p?p?Conclusions: CPEE has a protective action against 3-NP induced HD like symptoms due to its strong antioxidant effect.     

An overview of investigational antiapoptotic drugs with potential application for the treatment of neurodegenerative disorders

Importance of the field: The increase in life expectancy in developed countries has given rise to several emerging social problems. Of particular note is the dramatic rise in the incidence of neurodegenerative diseases. Given this new social scenario, there is a need to identify therapeutic strategies to delay the advance of these pathologies, for which no effective treatment is currently available.

Areas covered in this review: The present review discusses some of the drugs that are now under development with antiapoptotic activity or currently on the market that may have a potential application for the treatment of neurodegenerative diseases. Moreover, we also comment on potential compounds such as resveratrol and melatonin. Despite the lack of information from clinical trials on these two compounds, they are attracting considerable attention because of their natural origin and antioxidant and antiapoptotic action. Furthermore, they do not show toxicity in humans. In addition, we discuss the potential application of several compounds, such as NMDA antagonists, JNK inhibitors and GSK-3 inhibitors, for the treatment of neurodegenerative disorders.

What the reader will gain: This article will review recent developments in the field of apoptosis inhibitors, which might provide future tools for the treatment of the neurodegenerative diseases.

Take home message: The treatment of neurodegenerative diseases is a major challenge in medicine. This is partly because the incidence of these disorders is expected to rise in the coming years. New developments in the field of apoptosis inhibitors may provide future tools for the treatment of the aforementioned neurodegenerative diseases.     

维吾尔药牛舌草提取物抗氧化活性研究

目的研究维吾尔药牛舌草提取物的抗自由基作用及体内抗氧化功能。方法采用体外分析法观察牛舌草提取物对DPPH·及超氧自由基的清除作用,并进一步针对牛舌草大孔树脂洗脱部位GZB-3及GZB-AB80的提取物,以小鼠血清SOD、GSH-Px的活性和MDA的含量变化,探讨牛舌草提取物在小鼠体内的抗氧化能力。结果牛舌草各提取物具有体外抗自由基功能,其中牛舌草GZB-3及GZB-AB80提取物有较好的清除DPPH·及超氧自由基的作用;牛舌草提取物可显著增强小鼠血清SOD、GSH-Px活性,降低MDA含量,其中GZB-AB80提取物有较好的体内抗氧化能力。结论体内外抗氧化实验表明,牛舌草提取物具有明显的抗自由基作用及抗氧化功能。