Shogaol-huprine hybrids: Dual antioxidant and anticholinesterase agents with beta-amyloid and tau anti-aggregating properties

Multitarget compounds are increasingly being pursued for the effective treatment of complex diseases. Herein, we describe the design and synthesis of a novel class of shogaolhuprine hybrids, purported to hit several key targets involved in Alzheimer"s disease. The hybrids have been tested in vitro for their inhibitory activity against human acetylcholinesterase and butyrylcholinesterase and antioxidant activity (ABTS.+, DPPH and Folin-Ciocalteu assays), and in intact Escherichia coli cells for their Aβ42 and tau anti-aggregating activity. Also, their brain penetration has been assessed (PAMPA-BBB assay). Even though the hybrids are not as potent AChE inhibitors or antioxidant agents as the parent huprine Y and [4]-shogaol, respectively, they still exhibit very potent anticholinesterase and antioxidant activities and are much more potent Aβ42 and tau anti-aggregating agents than the parent compounds. Overall, the shogaolhuprine hybrids emerge as interesting brain permeable multitarget anti-Alzheimer leads.

Amyloid Beta Precursor Protein: Proper Credit for the Basic Biochemical Properties of the Most Studied Protein in the 21st Century

The amyloid precursor protein (APP) is mainly known for being the precursor of the ß-amyloid peptide, which accumulates in plaques found in the brain of Alzheimer's disease patients. Expression in different tissues and the degree of sequence identity among mammals indicate an essential and non-tissue specific physiological function. APP is anchored to the membrane and displays a single C-terminal intracellular domain and a longer N-terminal extracellular domain. The basic biochemical properties and the scattered data on research, not related to production of beta-amyloid peptide, suggest that the protein and the molecules resulting from APP proteolytic cleavage may act as adhesion factors, enzymes, hormones/neurotransmitters and/or protease inhibitors. APP deserves to be known for its quite notable properties and its physiological role(s).

Hipertensión arterial y enfermedad de Alzheimer

Hypertension (HT) is the most prevalent cardiovascular risk factor associated with dementia and Alzheimer disease (AD). The evidence about the association within hight blood pressure (BP) level in the middle age and dementia and Alzheimer’s disease incidence in the advanced age has increased. Longitudinal studies show that in the previous years of onset AD, BP is similar or lower in the patients who develop AD with regard to those who not develop. When patients has developed AD the case is the same that the previous one. Most studies show that BP reduction is beneficious to prevent cognitive impairment, dementia and AD. Is spite of some discordant studies, health authorities recommend to treat isolated systolic HT with an ‘A’ evidence degree, level 1, to prevent AD. Animal experimentation prove different ways to act of antihypertensive drugs in the AD prevention and has established the pathophysiological bases in this relation, until now only showed through various clinical studies

Health-related quality-of-life instruments for Alzheimer's disease and mixed dementia

BACKGROUND: Over the last 20 years, a number of instruments developed for the assessment of health-related quality of life (HRQL) in dementia have been introduced. The aim of this review is to synthesize evidence from published reviews on HRQL measures in dementia and any new literature in order to identify dementia specific HRQL instruments, the domains they measure, and their operationalization. METHODS: An electronic search of PsycINFO and PubMed was conducted, from inception to December 2011 using a combination of key words that included quality of life and dementia. RESULTS: Fifteen dementia-specific HRQL instruments were identified. Instruments varied depending on their country of development/validation, dementia severity, data collection method, operationalization of HRQL in dementia, psychometric properties, and the scoring. The most common domains assessed include mood, self-esteem, social interaction, and enjoyment of activities. CONCLUSIONS: A number of HRQL instruments for dementia are available. The suitability of the scales for different contexts is discussed. Many studies do not specifically set out to measure dementia-specific HRQL but do include related items. Determining how best to operationalize the many HRQL domains will be helpful for mapping measures of HRQL in such studies maximizing the value of existing resources.

Health-related quality of life in the Cambridge City over-75s Cohort (CC75C): development of a dementia-specific scale and descriptive analyses.

BACKGROUND: The assessment of Health Related Quality of Life (HRQL) is important in people with dementia as it could influence their care and support plan. Many studies on dementia do not specifically set out to measure dementia-specific HRQL but do include related items. The aim of this study is to explore the distribution of HRQL by functional and socio-demographic variables in a population-based setting. METHODS: Domains of DEMQOL's conceptual framework were mapped in the Cambridge City over 75's Cohort (CC75C) Study. HRQL was estimated in 110 participants aged 80+ years with a confirmed diagnosis of dementia with mild/moderate severity. Acceptability (missing values and normality of the total score), internal consistency (Cronbach's alpha), convergent, discriminant and known group differences validity (Spearman correlations, Wilcoxon Mann-Whitney and Kruskal-Wallis tests) were assessed. The distribution of HRQL by socio-demographic and functional descriptors was explored. RESULTS: The HRQL score ranged from 0 to 16 and showed an internal consistency Alpha of 0.74. Validity of the instrument was found to be acceptable. Men had higher HRQL than women. Marital status had a greater effect on HRQL for men than it did for women. The HRQL of those with good self-reported health was higher than those with fair/poor self-reported health. HRQL was not associated with dementia severity. CONCLUSIONS: To our knowledge this is the first study to examine the distribution of dementia-specific HRQL in a population sample of the very old. We have mapped an existing conceptual framework of dementia specific HRQL onto an existing study and demonstrated the feasibility of this approach. Findings in this study suggest that whereas there is big emphasis in dementia severity, characteristics such as gender should be taken into account when assessing and implementing programmes to improve HRQL.

El virus de la por

La grip és una malaltia vírica que ens visita cada any. Per això és habitual que se'n parli quan s'acosta la tardor. Aquest any, però, ja fa temps que se'n parla. A la premsa hi ha notícies pràcticament cada dia, sovint de portada. I la resposta científica ha estat excepcional. Des de gener s'han publicat 700 articles i 5.000 seqüències del seu genoma. Tot això fa que hom es pregunti què té d'especial [...].

Efficacy of methotrexate to prevent postoperative recurrence of Crohn's disease

BACKGROUND: endoscopic postoperative recurrence (POR) of Crohn’s disease (CD) is the presence of lesions in previously unaffected intestinal segments and occurs in up to 85% of patients one year after bowel resection. Patients at low risk for POR can either remain untreated until lesions recur or receive immediate prevention after surgery with mesalazine, azathioprine (AZA) and/or metronidazole, although with moderate benefit. Out of the postoperative setting, methotrexate (MTX) has been shown to be efficacious for induction and maintenance of remission and has been established as the second-line immunosuppressant for patients with CD unresponsive or intolerant to AZA.AIMS: to determine the efficacy and safety of MTX to prevent endoscopic and clinical POR at 24 weeks after surgery in low risk patientsMETHODS: the study consists on a multicenter, randomized, double-blind and placebo-controlled clinical trial that will enroll 132 patients at low risk for POR (non-smokers, first intestinal resection, non-penetrating behavior). Patients will be randomized to receive subcutaneous MTX at doses of 25 mg/week or an identical placebo, for 24 weeks. Endoscopic and clinical assessment of POR will be performed after 24 weeks (6 months) of treatment. The main outcome is endoscopic POR, defined as a Rutgeerts score of >i2, and secondary outcomes include clinical POR, defined as >i2 lesions plus a Crohn’s Disease Activity Index (CDAI) >150, and description of adverse events

Thioflavin-S staining of bacterial inclusion bodies for the fast, simple, and inexpensive screening of amyloid aggregation inhibitors

Amyloid aggregation is linked to a large number of human disorders, from neurodegenerative diseases as Alzheimer"s disease (AD) or spongiform encephalopathies to non-neuropathic localized diseases as type II diabetes and cataracts. Because the formation of insoluble inclusion bodies (IBs) during recombinant protein production in bacteria has been recently shown to share mechanistic features with amyloid self-assembly, bacteria have emerged as a tool to study amyloid aggregation. Herein we present a fast, simple, inexpensive and quantitative method for the screening of potential anti-aggregating drugs. This method is based on monitoring the changes in the binding of thioflavin-S to intracellular IBs in intact Eschericchia coli cells in the presence of small chemical compounds. This in vivo technique fairly recapitulates previous in vitro data. Here we mainly use the Alzheimer"s related beta-amyloid peptide as a model system, but the technique can be easily implemented for screening inhibitors relevant for other conformational diseases simply by changing the recombinant amyloid protein target. Indeed, we show that this methodology can be also applied to the evaluation of inhibitors of the aggregation of tau protein, another amyloidogenic protein with a key role in AD.

1,2,3,4-Tetrahydrobenzo[h][1,6]naphthyridines as a new family of potent peripheral-to-midgorge-site inhibitors of acetylcholinesterase: synthesis, pharmacological evaluation and mechanistic studies

A series of 1,2,3,4-tetrahydrobenzo[h][1,6]naphthyridines differently substituted at positions 1, 5, and 9 have been designed from the pyrano[3,2-c]quinoline derivative 1, a weak inhibitor of acetylcholinesterase (AChE) with predicted ability to bind to the AChE peripheral anionic site (PAS), at the entrance of the catalytic gorge. Fourteen novel benzonaphthyridines have been synthesized through synthetic sequences involving as the key step a multicomponent Povarov reaction between an aldehyde, an aniline and an enamine or an enamide as the activated alkene. The novel compounds have been tested against Electrophorus electricus AChE (EeAChE), human recombinant AChE (hAChE), and human serum butyrylcholinesterase (hBChE), and their brain penetration has been assessed using the PAMPA-BBB assay. Also, the mechanism of AChE inhibition of the most potent compounds has been thoroughly studied by kinetic studies, a propidium displacement assay, and molecular modelling. We have found that a seemingly small structural change such as a double O → NH bioisosteric replacement from the hit 1 to 16a results in a dramatic increase of EeAChE and hAChE inhibitory activities (>217- and >154-fold, respectively), and in a notable increase in hBChE inhibitory activity (> 11-fold), as well. An optimized binding at the PAS besides additional interactions with AChE midgorge residues seem to account for the high hAChE inhibitory potency of 16a (IC50 = 65 nM), which emerges as an interesting anti-Alzheimer lead compound with potent dual AChE and BChE inhibitory activities.

Synthesis and multi-target biological profiling of a novel family of rhein derivatives as disease-modifying anti-Alzheimer agents

We have synthesized a family of rhein-huprine hybrids to hit several key targets for Alzheimer"s disease. Biological screening performed in vitro and in Escherichia coli cells has shown that these hybrids exhibit potent inhibitory activities against human acetylcholinesterase butyrylcholinesterase, and BACE-1, dual Aβ42 and tau anti-aggregating activity, and brain permeability. Ex vivo studies with the leads (+)- and (-)-7e in brain slices of C57bl6 mice have revealed that they efficiently protect against the Aβ-induced synaptic dysfunction , preventing the loss of synaptic proteins and/or have a positive effect on the induction of long term potentiation. In vivo studies in APP-PS1 transgenic mice treated i.p. for 4 weeks with (+)- and (-)-7e have shown a central soluble Aβ lowering effect, accompanied by an increase in the levels of mature amyloid precursor protein (APP). Thus, (+)- and (-)-7e emerge as very promising disease-modifying anti-Alzheimer drug candidates.

Shogaol-huprine hybrids: Dual antioxidant and anticholinesterase agents with beta-amyloid and tau anti-aggregating properties

Multitarget compounds are increasingly being pursued for the effective treatment of complex diseases. Herein, we describe the design and synthesis of a novel class of shogaolhuprine hybrids, purported to hit several key targets involved in Alzheimer"s disease. The hybrids have been tested in vitro for their inhibitory activity against human acetylcholinesterase and butyrylcholinesterase and antioxidant activity (ABTS.+, DPPH and Folin-Ciocalteu assays), and in intact Escherichia coli cells for their Aβ42 and tau anti-aggregating activity. Also, their brain penetration has been assessed (PAMPA-BBB assay). Even though the hybrids are not as potent AChE inhibitors or antioxidant agents as the parent huprine Y and [4]-shogaol, respectively, they still exhibit very potent anticholinesterase and antioxidant activities and are much more potent Aβ42 and tau anti-aggregating agents than the parent compounds. Overall, the shogaolhuprine hybrids emerge as interesting brain permeable multitarget anti-Alzheimer leads.

1,2,3,4-Tetrahydrobenzo[h][1,6]naphthyridines as a new family of potent peripheral-to-midgorge-site inhibitors of acetylcholinesterase: synthesis, pharmacological evaluation and mechanistic studies

A series of 1,2,3,4-tetrahydrobenzo[h][1,6]naphthyridines differently substituted at positions 1, 5, and 9 have been designed from the pyrano[3,2-c]quinoline derivative 1, a weak inhibitor of acetylcholinesterase (AChE) with predicted ability to bind to the AChE peripheral anionic site (PAS), at the entrance of the catalytic gorge. Fourteen novel benzonaphthyridines have been synthesized through synthetic sequences involving as the key step a multicomponent Povarov reaction between an aldehyde, an aniline and an enamine or an enamide as the activated alkene. The novel compounds have been tested against Electrophorus electricus AChE (EeAChE), human recombinant AChE (hAChE), and human serum butyrylcholinesterase (hBChE), and their brain penetration has been assessed using the PAMPA-BBB assay. Also, the mechanism of AChE inhibition of the most potent compounds has been thoroughly studied by kinetic studies, a propidium displacement assay, and molecular modelling. We have found that a seemingly small structural change such as a double O → NH bioisosteric replacement from the hit 1 to 16a results in a dramatic increase of EeAChE and hAChE inhibitory activities (>217- and >154-fold, respectively), and in a notable increase in hBChE inhibitory activity (> 11-fold), as well. An optimized binding at the PAS besides additional interactions with AChE midgorge residues seem to account for the high hAChE inhibitory potency of 16a (IC50 = 65 nM), which emerges as an interesting anti-Alzheimer lead compound with potent dual AChE and BChE inhibitory activities.

Synthesis and multi-target biological profiling of a novel family of rhein derivatives as disease-modifying anti-Alzheimer agents

We have synthesized a family of rhein-huprine hybrids to hit several key targets for Alzheimer"s disease. Biological screening performed in vitro and in Escherichia coli cells has shown that these hybrids exhibit potent inhibitory activities against human acetylcholinesterase butyrylcholinesterase, and BACE-1, dual Aβ42 and tau anti-aggregating activity, and brain permeability. Ex vivo studies with the leads (+)- and (-)-7e in brain slices of C57bl6 mice have revealed that they efficiently protect against the Aβ-induced synaptic dysfunction , preventing the loss of synaptic proteins and/or have a positive effect on the induction of long term potentiation. In vivo studies in APP-PS1 transgenic mice treated i.p. for 4 weeks with (+)- and (-)-7e have shown a central soluble Aβ lowering effect, accompanied by an increase in the levels of mature amyloid precursor protein (APP). Thus, (+)- and (-)-7e emerge as very promising disease-modifying anti-Alzheimer drug candidates.

Shogaol-huprine hybrids: Dual antioxidant and anticholinesterase agents with beta-amyloid and tau anti-aggregating properties

Multitarget compounds are increasingly being pursued for the effective treatment of complex diseases. Herein, we describe the design and synthesis of a novel class of shogaolhuprine hybrids, purported to hit several key targets involved in Alzheimer"s disease. The hybrids have been tested in vitro for their inhibitory activity against human acetylcholinesterase and butyrylcholinesterase and antioxidant activity (ABTS.+, DPPH and Folin-Ciocalteu assays), and in intact Escherichia coli cells for their Aβ42 and tau anti-aggregating activity. Also, their brain penetration has been assessed (PAMPA-BBB assay). Even though the hybrids are not as potent AChE inhibitors or antioxidant agents as the parent huprine Y and [4]-shogaol, respectively, they still exhibit very potent anticholinesterase and antioxidant activities and are much more potent Aβ42 and tau anti-aggregating agents than the parent compounds. Overall, the shogaolhuprine hybrids emerge as interesting brain permeable multitarget anti-Alzheimer leads.

Dual inhibitors of beta-amyloid aggregation and acetylcholinesterase as multi-target anti-Alzheimer drug candidates

Notwithstanding the functional role that the aggregates of some amyloidogenic proteins can play in different organisms, protein aggregation plays a pivotal role in the pathogenesis of a large number of human diseases. One of such diseases is Alzheimer"s disease (AD), where the overproduction and aggregation of the β-amyloid peptide (Aβ) are regarded as early critical factors. Another protein that seems to occupy a prominent position within the complex pathological network of AD is the enzyme acetylcholinesterase (AChE), with classical and non-classical activities involved at the late (cholinergic deficit) and early (Aβ aggregation) phases of the disease. Dual inhibitors of Aβ aggregation and AChE are thus emerging as promising multi-target agents with potential to efficiently modify the natural course of AD. In the initial phases of the drug discovery process of such compounds, in vitro evaluation of the inhibition of Aβ aggregation is rather troublesome, as it is very sensitive to experimental assay conditions, and requires expensive synthetic Aβ peptides, which makes cost-prohibitive the screening of large compound libraries. Herein, we review recently developed multi-target anti-Alzheimer compounds that exhibit both Aβ aggregation and AChE inhibitory activities, and, in some cases also additional valuable activities such as BACE-1 inhibition or antioxidant properties. We also discuss the development of simplified in vivo methods for the rapid, simple, reliable, unexpensive, and high-throughput amenable screening of Aβ aggregation inhibitors that rely on the overexpression of Aβ42 alone or fused with reporter proteins in Escherichia coli.