Inhibition behavior of fructus psoraleae’s ingredients towards human carboxylesterase 1 (hCES1)

1.?Fructus psoraleae (FP) is the dried ripe seeds of Psoralea corylifolia L. (Fabaceae) widely used in Asia, and has been reported to exert important biochemical and pharmacological activities. The adverse effects of FP remain unclear. The present study aims to determine the inhibition of human carboxylesterase 1 (CES1) by FP’s major ingredients, including neobavaisoflavone, corylifolinin, coryfolin, psoralidin, corylin and bavachinin.

2.?The probe substrate of CES1 2-(2-benzoyl-3-methoxyphenyl) benzothiazole (BMBT) was derived from 2-(2-hydroxy-3-methoxyphenyl) benzothiazole (HMBT), and human liver microsomes (HLMs)-catalyzed BMBT metabolism was used to phenotype the activity of CES1. In silico docking method was employed to explain the inhibition mechanism.

3.?All the tested compounds exerted strong inhibition towards the activity of CES1 in a concentration-dependent behavior. Furthermore, the inhibition kinetics was determined for the inhibition of neobavaisoflavone, corylifolinin, coryfolin, corylin and bavachinin towards CES1. Both Dixon and Lineweaver–Burk plots showed that neobavaisoflavone, corylifolinin, coryfolin and corylin noncompetitively inhibited the activity of CES1, and bavachinin competitively inhibited the activity of CES1. The inhibition kinetic parameters (K_i) were calculated to be 5.3, 9.4, 1.9, 0.7 and 0.5 μM for neobavaisoflavone, corylifolinin, coryfolin, corylin and bavachinin, respectively. In conclusion, the inhibition behavior of CES1 by the FP’s constituents was given in this article, indicating the possible adverse effects of FP through the disrupting CES1-catalyzed metabolism of endogenous substances and xenobiotics.     

GSK-3 inhibitors and their potential in the treatment of Alzheimer’s disease

Glycogen synthase kinase-3 (GSK-3) is a ubiquitously expressed kinase that has emerged as a promising drug target for several diseases, including various neurological conditions, Type 2 diabetes and cancer. For this reason, a number of drug candidates are being developed to achieve very different goals, any of which could have therapeutic value in the treatment of Alzheimer’s disease (AD). The importance of GSK-3 in so many processes, however, also suggests that issues of side effects will need to be addressed before GSK-3 inhibitors can be used in the clinic. This review discusses the role of GSK-3 in the development of AD, the various approaches that have been used to inhibit GSK-3 activity and the patents describing the use of GSK-3 inhibitors in the treatment of AD.     

Inhibition of tau phosphorylation: a new therapeutic strategy for the treatment of Alzheimer’s disease and other neurodegenerative disorders

There is some evidence to suggest that hyperphosphorylation of tau protein is an early event in the development of neurofibrillary pathology and appears to compromise the ability of tau to bind to and stabilise microtubules. Thus, the blockade of this hyperphosphorylation step may be a prime target at which to interrupt the pathogenic cascade. Efforts to discover rational targets (mainly tau kinases) and inhibitors of tau hyperphosphorylation (protein kinase inhibitors) are discussed in this paper. Patenting activity from 1997 to date has focused on two major areas: development of methods for screening new compounds and discovery of tau protein kinases inhibitors. Some mention is also made regarding Alzheimer’s disease (AD) diagnosis methods based on tau hyperphosphorylation.     

The role of inflammatory processes in Alzheimer’s disease

It has become increasingly clear that inflammatory processes play a significant role in the pathophysiology of Alzheimer's disease (AD). Neuroinflammation is characterized by the activation of astrocytes and microglia and the release of proinflammatory cytokines and chemokines. Vascular inflammation, mediated largely by the products of endothelial activation, is accompanied by the production and the release of a host of inflammatory factors which contribute to vascular, immune, and neuronal dysfunction. The complex interaction of these processes is still only imperfectly understood, yet as the mechanisms continue to be elucidated, targets for intervention are revealed. Although many of the studies to date on therapeutic or preventative strategies for AD have been narrowly focused on single target therapies, there is accumulating evidence to suggest that the most successful treatment strategy will likely incorporate a sequential, multifactorial approach, addressing direct neuronal support, general cardiovascular health, and interruption of deleterious inflammatory pathways.     

Possible role of DPP4 inhibitors to promote hippocampal neurogenesis in Alzheimer’s disease

As well-known to the scientific community, Alzheimer’s disease (AD) is an irreversible neurodegenerative disease that ends up with impairment of memory and cognition. Patient quality of life can be enhanced by targeting neurogenesis as a therapeutic paradigm. Preserving functional activity of SDF-1α and GLP-1 by DPPIV inhibition will enhance the homing of stem cells and modulate cell signalling pathways. The non-invasive approach presented in this article is a major advantage for managing AD, as regular/conventional stem-cell therapy necessarily relies on the application of regenerative stem cells exogenously. Using DPP-4 inhibitors to achieve the SDF-1α/CXCR4 axis stabilisation and augmenting GLP-1 levels, will enhance the homing/recruitment of brain resident and non-resident circulating stem cells/progenitor cells towards the sites of lesion to increase synaptic plasticity, a promising approach and also a novel one as well.     

Knowledge and pharmacological management of Alzheimer’s disease by managing community pharmacists: a nationwide study

Background Managing community pharmacists can play a leading role in supporting community dwelling individuals with Alzheimer’s disease and their caregivers. Objective The main purpose of this study was to assess knowledge of managing community pharmacists towards Alzheimer’s disease and its pharmacological management. Setting Community pharmacies in the Maltese islands. Method A nationwide survey was conducted with full-time managing community pharmacists in possession of a tertiary education degree in pharmacy studies. The level of knowledge was investigated using the Alzheimer’s Disease Knowledge Scale and the Alzheimer’s Disease Pharmacotherapy Measure. Participants were also asked to rate a number of statements related to disease management. Results Maltese managing community pharmacists (57 % response rate) had inadequate knowledge on risk factors, caregiving issues and pharmacological management of Alzheimer’s disease. Age and number of years working in a community pharmacy setting were found to be negatively correlated with increased knowledge. Conclusion The findings highlight the need of providing training and continued educational support to managing community pharmacists in order to provide quality advice to individuals with dementia and their caregivers in the community.     

Advancements in the treatment of agitation in Alzheimer’s disease

Introduction: Neuropsychiatric symptoms (NPS) in Alzheimer’s disease (AD) are associated with significant negative outcomes for patients and their caregivers. Agitation, one of the most distressing NPS, lacks well-established long-term interventions that are both effective and safe. While non-pharmacological interventions are the suggested first-line treatment, it isn’t effective in managing symptoms for every patient. In such cases, clinicians turn to the use of pharmacological interventions. Traditionally, these interventions consist of off-label use of antipsychotics, sedative/hypnotics, anxiolytics, acetylcholinesterase inhibitors, memantine and antidepressants, where the efficacy doesn’t necessarily outweigh the associated risks.

Areas covered: Gains made in understanding the neurobiological mechanisms underlying agitation have fueled several recent clinical trials. A comprehensive literature search for published articles evaluating pharmacologic interventions for agitation in AD was done. A review of some of these clinical trials was completed: dextromethorphan/quinidine, scyllo-inositol, brexpiprazole, prazosin, cannabinoids, dronabinol and citalopram show promise in treating agitation.

Expert opinion: Neurobiological findings and enhanced trial designs have re-ignited the area of pharmacological treatment of NPS. Although further research is needed to fully determine the safety, tolerability and efficacy of these treatments, the mission to finding effective treatments for NPS such as agitation in patients with dementia is well underway.     

Endothelial LRP1 – A Potential Target for the Treatment of Alzheimer’s Disease

The accumulation of the neurotoxin beta-amyloid (Aβ) is a major hallmark in Alzheimer’s disease (AD). Aβ homeostasis in the brain is governed by its production and various clearance mechanisms. Both pathways are influenced by the ubiquitously expressed low-density lipoprotein receptor-related protein 1 (LRP1). In cerebral blood vessels, LRP1 is an important mediator for the rapid removal of Aβ from brain via transport across the blood-brain barrier (BBB). Here, we summarize recent findings on LRP1 function and discuss the targeting of LRP1 as a modulator for AD pathology and drug delivery into the brain.     

TGF-β1 Neuroprotection via Inhibition of Microglial Activation in a Rat Model of Parkinson’s Disease

Transforming growth factor (TGF)-β1 is a pleiotropic cytokine with immunosuppressive and anti-inflammatory properties. Recently we have shown that TGF-β1 pretreatment in vitro protects against 1-methyl-4-phenylpyridinium (MPP⁺)-induced dopaminergic neuronal loss that characterizes in Parkinson’s disease (PD). Herein, we aimed to demonstrate that TGF-β1 administration in vivo after MPP⁺ toxicity has neuroprotection that is achieved by a mediation of microglia. A rat model of PD was prepared by injecting MPP⁺ unilaterally in the striatum. At 14 days after MPP⁺ injection, TGF-β1 was administrated in the right lateral cerebral ventricle. Primary ventral mesencephalic (VM) neurons and cerebral cortical microglia were treated by MPP⁺, respectively, and TGF-β1 was applied to neuronal or microglial cultures at 1 h after MPP⁺ treatment. As expected, MPP⁺ resulted in decrease in TGF-β1 production in the substantia nigra and in primary VM neurons and microglia. TGF-β1 intracerebroventricular administration alleviated MPP⁺-induced PD-like changes in pathology, motor coordination and behavior. Meanwhile, TGF-β1 ameliorated MPP⁺-induced microglial activation and inflammatory cytokine production in vivo. Interestingly, TGF-β1 treatment was not able to ameliorate MPP⁺-induced dopaminergic neuronal loss and caspase-3/9 activation in mono-neuron cultures, but TGF-β1 alleviated MPP⁺-induced microglial activation and inflammatory cytokine production in microglia-enriched cultures. This effect of TGF-β1 inhibiting microglial inflammatory response was blocked by Smad3 inhibitor SIS3. Importantly, neuronal exposure to supernatants of primary microglia that had been treated with TGF-β1 reduced dopaminergic neuronal loss and caspase-3/9 activation induced by MPP⁺-treated microglial supernatants. These findings establish that TGF-β1 exerts neuroprotective property in PD by inhibiting microglial inflammatory response via Smad3 signaling.     

Ischemic tau protein gene induction as an additional key factor driving development of Alzheimer’s phenotype changes in CA1 area of hippocampus in an ischemic model of Alzheimer’s disease

Background

Tauopathies are a class of neurodegenerative illnesses associated with the aberrant accumulation of the tau protein in the brain. The best known out of these diseases is Alzheimer’s disease, a disorder where the microtubule associated tau protein becomes hyperphosphorylated (which lowers its binding affinity to microtubules) and accumulates inside neurons in the form of tangles. In this study, we attempt to find out whether brain ischemia may play an important role in tau protein gene alterations.

Implication of Complement System and its Regulators in Alzheimer’s Disease

Alzheimer’s disease (AD) is an age-related neurodegenerative disease that affects approximately 24 million people worldwide. A number of different risk factors have been implicated in AD, however, neuritic (amyloid) plaques are considered as one of the defining risk factors and pathological hallmarks of the disease. Complement proteins are integral components of amyloid plaques and cerebral vascular amyloid in Alzheimer brains. They can be found at the earliest stages of amyloid deposition and their activation coincides with the clinical expression of Alzheimer''s dementia. This review emphasizes on the dual key roles of complement system and complement regulators (CRegs) in disease pathology and progression. The particular focus of this review is on currently evolving strategies for design of complement inhibitors that might aid therapy by restoring the fine balance between activated components of complement system, thus improving the cognitive performance of patients. This review discusses these issues with a view to inspiring the development of new agents that could be useful for the treatment of AD.Key Words: Alzheimer’s disease, neurodegeneration, inflammation, β-amyloid peptide, complement, complement regulators, CD59, complement therapeutics.     

Pivotal role of nitrogen heterocycles in Alzheimer’s disease drug discovery

Alzheimer’s disease (AD) is a detrimental neurodegenerative disease that progressively worsens with time. Clinical options are limited and only provide symptomatic relief to AD patients. The search for effective anti-AD compounds is ongoing with a few already in Phase III clinical trials, yet to be approved. Heterocycles containing nitrogen are important to biological processes owing to their abundance in nature, their function as subunits of biological molecules and/or macromolecular structures, and their biological activities. The present review discusses previously used strategies, SAR, relevant in vitro and in vivo studies, and success stories of nitrogen-containing heterocyclic compounds in AD drug discovery. Also, we propose strategies for designing and developing novel potent anti-AD small molecules that can be used as treatments for AD.     

The efficacy and safety of memantine for the treatment of Alzheimer’s disease

Introduction: Currently, five pharmacotherapeutic options are available to treat Alzheimer’s disease: memantine; the three cholinesterase inhibitors donepezil, galantamine, and rivastigmine; and combination treatments with memantine and one cholinesterase inhibitor. Selection of the best course of treatment is based upon the evidence gathered by systematic reviews and meta-analyses of randomized controlled trials.

Areas covered: This article provides a risk–benefit analysis of these treatments using evidence from meta-analyses on their safety and their efficacy.

Expert opinion: Memantine improves cognitive functions and behavioral disturbances more efficiently than the placebo, both as monotherapy and in combination with donepezil. Although memantine monotherapy and combination therapy are associated with a few individual adverse events such as somnolence, it is well-tolerated and its safety (all-cause discontinuation) is comparable or superior to that of the placebo (agitation). Pooled cholinesterase inhibitors are superior to the placebo in the improvement of cognitive functions, but not behavioral disturbances and they are not well-tolerated, as evaluated by the high discontinuation rate. Donepezil (10 mg/day) and oral rivastigmine and galantamine monotherapies carry the risk for some adverse events including gastrointestinal symptoms. Therefore, we consider that combined treatment with memantine and donepezil is the most useful treatment for Alzheimer’s disease.     

Effects of rivastigmine on common symptomatology of Alzheimer’s disease (EXPLORE)

Abstract

Objective:

To evaluate, in a real-world clinical setting, the efficacy of rivastigmine in the management of six symptoms commonly associated with Alzheimer's disease (AD).     

Variability in PXR-mediated induction of CYP3A4 by commercial preparations and dry extracts of St. John’s wort

St. John’s wort (SJW, Hypericum perforatum) is a well-tolerated herbal medicine widely used for the treatment of mild and moderate depressions. In the last 5 years, SJW has been implicated in drug interactions, which are largely mediated by the induction of the drug metabolizing enzymes, especially CYP3A4. There is still some controversy regarding the exact mechanism of induction and the identity of the SJW constituents involved. We investigated in LS174T cells the induction of CYP3A4 by ten SJW extracts, six commercial preparations, and the purified SJW constituent hyperforin. The content of hyperforin among the commercial preparations of SJW varied 62-fold (range 0.49–30.57 mg/dose). The CYP3A4 induction was mediated by PXR, but not by CAR. The magnitude of the induction correlated statistically significantly with the content of hyperforin in commercial SJW preparations (R = 0.87, p = 0.004) and in dry extracts (R = 0.65, p = 0.03), but not with their content of flavonoids or hypericin. Most of the CYP3A4 induction response occurred in the hyperforin range encountered in the blood of patients treated with SJW preparations. A temperature-induced decrease in the hyperforin content of a selected dry SJW extract abolished the induction of CYP3A4. In conclusion, commercial SJW preparations still exhibit an enormous variability in CYP3A4 induction, which is mediated by hyperforin and PXR. SJW preparations with lower hyperforin content should reduce the frequency of clinical interactions involving this herbal drug. This work was partly funded by the Deutsche Forschungsgemeinschaft (DFG) grant WO505/2-2.     

Oleanolic acid alleviates oxidative stress in Alzheimer’s disease by regulating stanniocalcin-1 and uncoupling protein-2 signalling

Oxidative stress is thought to play an important role in the occurrence and development of Alzheimer's disease (AD) and antioxidants may delay or even treat AD. Oleanolic acid (OA) exhibits antioxidant properties against many diseases. However, its effects on oxidative stress in AD remain unclear. Here, we explored the role and mechanism of action of OA in N2a/APP695swe cells exposed to oxidative stress. The cells were incubated with different concentrations of OA (0, 5, 8, 10, 15, and 25 μmol/L) for 24 hours. Higher concentrations of OA (10, 15, and 25 μmol/L) significantly suppressed the apoptosis, caspase-3 activity, reactive oxygen species level, and β amyloid (Aβ) content and increased the viability of these cells. OA (10 μmol/L) also increased the expression of stanniocalcin-1 (STC-1) and uncoupling protein-2 (UCP2) in N2a/APP695swe cells. STC-1 interference markedly reversed the effect of OA on UCP2, indicating that OA may regulate UCP2 expression in N2a/APP695swe cells via STC-1. Moreover, UCP2 inhibition significantly reversed the OA-mediated effects on cell viability, caspase-3 activity, reactive oxygen species, and Aβ level. Thus, OA regulates UCP2 expression via STC-1 to alleviate oxidative stress and Aβ level in N2a/APP695swe cells.     

AVP-786 for the treatment of agitation in dementia of the Alzheimer’s type

Introduction: Agitation is common and distressing in patients with Alzheimer-type dementia, but safe, effective treatments remain elusive. Psychological treatments are first-line options, but they have limited efficacy. Off-label psychotropic medications are frequently used, but they also have limited effectiveness, and their use may have harmful side effects, including death.

Areas covered: This review discusses the history leading to the conception of AVP-786 (deuterated (d6)-dextromethorphan/quinidine), its pharmacokinetic and pharmacodynamic profiles and safety issues, together with an overview of recent clinical trials. Data were found in the medical literature, in US and EU clinical trial registries and in information provided by the manufacturer.

Expert opinion: AVP-786 is one of six investigational compounds in recent phase III clinical development for agitation in Alzheimer disease (AD). Quinidine and deuteration appear to prolong dextromethorphan’s plasma half-life and facilitate brain penetration. The FDA granted fast-track designation to AVP-786 and allowed use of data generated on dextromethorphan-quinidine (AVP-923, Nuedexta®) for regulatory filings. AVP-923 reduced agitation in AD and was well tolerated in a phase II RCT that included more than 200 patients. A phase III clinical development program of AVP-786 for AD agitation was recently initiated. This program is expected to start generating results in July 2018.