Repurposing small-molecule drugs for modulating toxic protein aggregates in neurodegenerative diseases

Neurodegenerative diseases (NDs) are often age-related disorders that can cause dementia in people, usually over 65 years old, are still lacking effective therapies. Some NDs have recently been linked to toxic protein aggregates, for example Alzheimer’s disease, Parkinson’s disease, Amyotrophic lateral sclerosis and Huntington disease; therefore, mulating toxic protein aggregates would be a promising therapeutic strategy. Moreover, drug repurposing, in other words exploiting drugs that are already in use for another indication, has been attracting mounting attention for potential therapeutic purposes in NDs. Thus, in this review, we focus on summarizing a series of repurposed small-molecule drugs for eliminating or inhibiting toxic protein aggregates and further discuss their intricate molecular mechanisms to improve the current ND treatment. Taken together, these findings will shed new light on exploiting more repurposed small-molecule drugs targeting different types of toxic proteins to fight NDs in the future.     

Potential of transglutaminase 2 as a therapeutic target

Importance of the field: Increased expression and activity of transglutaminase 2 – a calcium-dependent enzyme which catalyzes protein cross-linking, polyamination or deamidation at selective glutamine residues – are involved in the etiopathogenesis of several pathological conditions, such as neurodegenerative disorders, autoimmune diseases and inflammatory diseases. Inhibition of enzyme activity has potential for therapeutic management of these diseases.

Areas covered in this review: The major results achieved in the last twelve years of research in the field of inhibition of tranglutaminase activity using cell cultures as well as in vivo models of high-social-impact or widespread diseases, such as CNS neurodegenerative disorders, celiac sprue, cancer and fibrotic diseases.

What the reader will gain: Beneficial effects of enzyme activity inhibition have been observed in neurodegeneration and fibrosis in vivo models by delivery of the competitive inhibitor cystamine and more recently designed inhibitors, such as thiomidaziolium or norleucine derivatives, which irreversibly bind the active site cysteine residue. Transglutaminase 2 targeting with specific antibodies has also been shown to be a promising tool for celiac disease treatment.

Take home message: New insights from transglutaminase inhibition studies dealing with side effects of in vivo administration of pan-transglutaminase inhibitors will help in design of novel therapeutic approaches to various diseases.     

Curcumin and neurodegenerative diseases: a perspective

Introduction: Curcumin, a dietary polyphenol found in the curry spice turmeric, possesses potent antioxidant and anti-inflammatory properties and an ability to modulate multiple targets implicated in the pathogenesis of chronic illness. Curcumin has shown therapeutic potential for neurodegenerative diseases including Alzheimer's disease (AD) and Parkinson's disease (PD).

Areas covered: This article highlights the background and epidemiological evidence of curcumin's health benefits and its pharmacodynamic and pharmacokinetic profile. Curcumin's ability to counteract oxidative stress and inflammation and its capacity to modulate several molecular targets is reviewed. We highlight the neuroprotective properties of curcumin including pre-clinical evidence for its pharmacological effects in experimental models of AD and PD. The bioavailability and safety of curcumin, the development of semi-synthetic curcuminoids as well as novel formulations of curcumin are addressed.

Expert opinion: Curcumin possesses therapeutic potential in the amelioration of a host of neurodegenerative ailments as evidenced by its antioxidant, anti-inflammatory and anti-protein aggregation effects. However, issues such as limited bioavailability and a paucity of clinical studies examining its therapeutic effectiveness in illnesses such as AD and PD currently limit its therapeutic outreach. Considerable effort will be required to adapt curcumin as a neuroprotective agent to be used in the treatment of AD, PD and other neurodegenerative diseases.     

帕金森患者脑脊液组织型谷氨酰胺转移酶测定分析

目的测定脑脊液(CSF)组织型谷氨酰胺转移酶(tTG),以探讨tTG与帕金森氏病(PD)的关系,进而寻找PD诊断的临床指标。方法选取于门诊或住院治疗的PD患者54例,以及同期住院的非PD患者,腰穿抽取脑脊液,测定tTG浓度。结果PD患者脑脊液tTG浓度为(69.1±3.1)pg/ml,两组比较有统计学意义(P<0.05)。结论测定脑脊液tTG浓度是反映PD患者神经元凋亡的有效手段,用于指导临床治疗。     

银杏叶提取物对神经退行性疾病的作用机制及研究进展

随着人口老龄化的加快,神经退行性疾病的发病率呈逐年上升的趋势。神经退行性疾病具有病因复杂、病程长、难治愈等特点,目前银杏叶提取物的神经保护作用已被广泛认可,但其有效成分及其具体作用机制尚未明确。本文将根据神经退行性疾病的发病机制来探讨银杏叶提取物对神经的保护作用,主要从其改善Aβ聚集、抗炎、抗氧化、抗凋亡、保护线粒体、调节能量代谢等角度来研究其治疗神经退行性疾病的机制。     

Fruitful research: drug target discovery for neurodegenerative diseases in Drosophila

Introduction: Although vertebrate model systems have obvious advantages in the study of human disease, invertebrate organisms have contributed enormously to this field as well. The conservation of genome structure and physiology among organisms poses unexpected peculiarities, and the redundancy in certain gene families or the presence of polymorphisms that can slightly alter gene expression can, in certain instances, bring invertebrate systems, such as Drosophila, closer to humans than mice and vice versa. This necessitates the analysis of disease pathways in multiple model organisms.

Areas covered: The author highlights findings from Drosophila models of neurodegenerative diseases that have occurred in the past few years. She also highlights and discusses various molecular, genetic and genomic tools used in flies, as well as methods for generating disease models. Finally, the author describes Drosophila models of Alzheimer's, Parkinson's tri-nucleotide repeat diseases, and Fragile X syndrome and summarizes insights in disease mechanisms that have been discovered directly in fly models.

Expert opinion: Full genome genetic screens in Drosophila can lead to the rapid identification of drug target candidates that can be subsequently validated in a vertebrate system. In addition, the Drosophila models of neurodegeneration may often show disease phenotypes that are absent in equivalent mouse models. The author believes that the extensive contribution of Drosophila to both new disease drug target discovery, in addition to target validation, makes them indispensible to drug discovery and development.     

Role of analytical ultracentrifugation in assessing the aggregation of protein biopharmaceuticals

In developing and manufacturing protein biopharmaceuticals, aggregation is a parameter that needs careful monitoring to ensure the quality and consistency of the final biopharmaceutical drug product. The analytical method of choice used to perform this task is size-exclusion chromatography (SEC). However, it is becoming more and more apparent that considerable care is required in assessing the accuracy of SEC data. One old analytical tool that is now reappearing to help in this assessment is analytical ultracentrifugation (AUC). Developments in AUC hardware and, more importantly, recent developments in AUC data analysis computer programs have converged to provide this old biophysical tool with the ability to extract very high resolution size information about the molecules in a given sample from a simple sedimentation velocity experiment. In addition, AUC allows sample testing to be conducted in the exact or nearly exact liquid formulation or reconstituted liquid formulation of the biopharmaceutical in the vial, with minimal surface area contact with extraneous materials. As a result, AUC analysis can provide detailed information on the aggregation of a biopharmaceutical, while avoiding many of the major problems that can plague SEC, thus allowing AUC to be used as an orthogonal method to verify SEC aggregation information and the associating properties of biopharmaceuticals.     

Cytochrome P450 in the central nervous system as a therapeutic target in neurodegenerative diseases

Cytochromes P450 (CYPs) constitute a family of enzymes that can be found in the endoplasmic reticulum (ER), mitochondria or the cell surface of the cells. CYPs are characterized by carrying out the oxidation of organic compounds and they are mainly recognized as mediators of the biotransformation of xenobiotics to polar hydrophilic metabolites that can be eliminated from the organism. However, these enzymes play a key role in many other physiological processes, being involved in diverse indispensable metabolic pathways since they metabolize many endogenous substrates. Various CYP isoforms are expressed in the brain, and it is believed that this could be in part due to the particular function of brain CYPs. In the brain, CYPs are involved in the cholesterol turnover, the biosynthesis of dopamine, serotonin, morphine, hormones, and protective lipid mediators (epoxyeicosatrienoic acids), in addition to their already recognized role in xenobiotics detoxification and psychotropic drug metabolism. Increasing evidence suggests that this group of enzymes is fundamental for the normal functioning and maintenance of brain homeostasis. This review is focused on highlighting the importance of CYP-mediated endogenous metabolism in the central nervous system (CNS) and its relationship with recent findings regarding CYP involvement in neurodegenerative diseases. Some therapeutic approaches focused on CYP regulation are also discussed.     

The second virial coefficient as a predictor of protein aggregation propensity: A self-interaction chromatography study

The second osmotic virial coefficients (b₂) of four proteins – lysozyme, recombinant human lactoferrin, concanavalin A and catalase were measured by self-interaction chromatography (SIC) in solutions of varying salt type, concentration and pH. Protein aggregate sizes based on the initial hydrodynamic radius of the protein solution species present were measured using dynamic light scattering, and the relationship between b₂ and protein aggregate size was studied. A linear correlation was established between b₂ values and protein aggregate hydrodynamic size for all proteins, and for almost all solution conditions. Aggregate sizes of <∼10 nm, indicative of non-aggregated protein systems, were consistently observed to have b₂ values >0. The observed b₂ trends as a function of solution conditions were very much protein dependent, with notable trends including the existence of attractive interactions (negative b₂ values) at low ionic strengths for catalase and concanavalin A, and the highly positive b₂ values observed for lactoferrin over a wide range of solution conditions, reflecting lactoferrin’s innately high stability. It is concluded that the quantification of protein–protein interactions using SIC based b₂ data is a potentially valuable screening tool for predicting protein aggregation propensity.     

Neuronal apoptosis as a therapeutic target in neurodegenerative disease

Apoptosis is a form of physiological or programmed cell death. It has been speculated that this process might account for the death of selective neuronal populations in certain progressive neurodegenerative disorders, including Alzheimer’s disease (AD) and Parkinson’s disease (PD) and some circumstantial evidence to support this view has been forthcoming. Increased understanding of the molecular pathophysiology of neuronal apoptosis may therefore present significant new therapeutic targets, to slow or halt neurodegeneration. This article reviews patents from the last five years which claim the use of apoptotic modulators in neurodegenerative disease. Although there are a significant number of claims, very few are buttressed with strong experimental evidence; this is usually from cell culture studies, rather than animal models of neurodegenerative disease; only a single human clinical study was identified. Thus, although treatment of neurodegenerative disease by means of manipulating apoptosis is an area of much activity and holds promise for the future, clinical application of current patents is unlikely in the near future. Extant medications may conceivably exert some of their action through effects on apoptosis.     

Endothelium as a therapeutical target in peripheral occlusive arterial diseases: consideration for pharmacological interventions

The aim of this review is to consider the role of endothelium in the establishment of injury induced by ischaemia and reperfusion with particular emphasis on the vascular beds of the legs. We review the main abnormalities found in the macro-and microcirculation in these conditions and discuss the various theories put forward to explain the mechanism by which endothelial injury is induced. Endothelial cells play a key role in maintaining patent and functional capillaries. When blood vessels are damaged they become unresponsive to vasodilatatory stimuli and intraluminal thrombosis may occur. The relative contribution of platelets and leukocytes in the formation of final ischaemic damage is widely discussed. Furthermore, the role of reperfusion in causing damage to post-ischaemic vascular beds is considered as well. The degree to which post-ischaemic injury is reversible might define the opportunity for therapeutic interventions.     

Clinical pharmacology of flurbiprofen: a novel inhibitor of platelet aggregation

Summary

Studies are renewed of the inhibitory effect of flurbiprofen, given in doses ranging from 50?mg to 200?mg per day for 1 week, on platelet aggregation measured by biological tests (adenosine diphosphate and collagen methods). Flurbiprofen at doses of 50?mg and 100?mg daily had a peak time of action of between 1 and 2 hours, the effect usually disappearing after 24 hours, and 100?mg flurbiprofen caused a similar decrease in platelet aggregation to 1 g aspirin daily. In a clinical study of 72 patients with chronic glomerulonephritis treated with doses of flurbiprofen up to 200?mg daily there was a significant correlation between the parameters of aggregation measured and treatment, and between proteinuria and adenosine diphosphate aggregation when the flurbiprofen dose did not exceed 100?mg daily.     

Mitochondria and neurodegenerative diseases: the promising role of nanotechnology in targeted drug delivery

Introduction: Neurodegenerative diseases (NDs) represent a group of different clinical entities that, despite the specific primary etiologies, share a common signature in terms of a general mitochondrial dysfunction with consequent oxidative stress accumulation. As these two events occur early during neurodegenerative process, they could be considered ideal therapeutic targets.

Areas covered: This review describes the nanotechnologies explored for the specific targeted delivery of drugs, in order to precisely direct molecules into the intended site, where they can practice their therapeutic effects.

Expert opinion: Conventional drug delivery systems cannot provide adequate restoration and connection patterns that are essential for a functional recovery in NDs. Since orally delivered antioxidants are easily destroyed by acids and enzymes, only a small portion of consumed antioxidants gets absorbed, leading to low bioavailability and low concentration at the target site. In this scenario, the identification of new proenergetic drugs, in combination with the development of methods for selectively delivering biologically active molecules into mitochondria, will potentially launch new therapeutic approaches for the treatment of NDs, where energetic imbalance plays a central role.     

Targeted delivery of a novel group of site-directed transglutaminase inhibitors to the liver using liposomes: a new approach for the potential treatment of liver fibrosis

Liver fibrosis and its end-stage disease cirrhosis are a main cause of mortality and morbidity worldwide. Thus far, there is no efficient pharmaceutical intervention for the treatment of liver fibrosis. Liver fibrosis is characterized by excessive accumulation of the extracellular matrix (ECM) proteins. Transglutaminase (TG)-mediated covalent cross-linking has been implicated in the stabilization and accumulation of ECM in a number of fibrotic diseases. Thus, the use of tissue TG2 inhibitors has potential in the treatment of liver fibrosis. Recently, we introduced a novel group of site-directed irreversible specific inhibitors of TGs. Here, we describe the development of a liposome-based drug-delivery system for the site-specific delivery of these TG inhibitors into the liver. By using anionic or neutral-based DSPC liposomes, the TG inhibitor can be successfully incorporated into these liposomes and delivered specifically to the liver. Liposomes can therefore be used as a potential carrier system for site-specific delivery of the TG2 inhibitors into the liver, opening up a potential new avenue for the treatment of liver fibrosis and its end-stage disease cirrhosis.     

Developing drugs that target the Wnt pathway: recent approaches in cancer and neurodegenerative diseases

Introduction: Wnt/β-catenin signaling is an evolutionarily conserved pathway that has a crucial role in embryonic and adult life. Dysregulation of Wnt/β-catenin pathway has been associated with various diseases, including cancer and neurodegenerative disorders, including Parkinson’s disease (PD). Several molecular components of the signaling have been proposed as innovative targets for cancer therapy, and very recently, some of them have been also evaluated as potential therapeutic targets for PD.

Areas covered: This review focuses on the role of Wnt/β-catenin pathway in the pathogenensis of cancer and PD, examining some recent therapeutic approaches that are ongoing in preclinical and clinical studies. The possibilities that this signaling offers for diagnosis and prognosis of neoplastic diseases, and the concerns of targeting this pathway are also discussed.

Expert opinion: Despite the stimulating results obtained in preclinical studies on cancer and other disease models, the clinical experience with Wnt modulators is still in its infancy, and is mainly restricted to anticancer therapy. Even with concerns of the safety of drugs targeting Wnt signaling, the attention of researchers worldwide is increasing to this issue in terms of their therapeutic potential for diseases such as PD, for which no cure exists.     

Dissecting the role of AMP-activated protein kinase in human diseases

AMP-activated protein kinase (AMPK), known as a sensor and a master of cellular energy balance, integrates various regulatory signals including anabolic and catabolic metabolic processes. Accompanying the application of genetic methods and a plethora of AMPK agonists, rapid progress has identified AMPK as an attractive therapeutic target for several human diseases, such as cancer, type 2 diabetes, atherosclerosis, myocardial ischemia/reperfusion injury and neurodegenerative disease. The role of AMPK in metabolic and energetic modulation both at the intracellular and whole body levels has been reviewed elsewhere. In the present review, we summarize and update the paradoxical role of AMPK implicated in the diseases mentioned above and put forward the challenge encountered. Thus it will be expected to provide important clues for exploring rational methods of intervention in human diseases.     

Play in advance against neurodegeneration: exploring enteric glial cells in gut-brain axis during neurodegenerative diseases

Introduction: New investigations have shown that ‘activated’ enteric glial cells (EGCs), astrocyte-like cells of the enteric nervous system (ENS), represent a possible extra-CNS trigger point of the neurodegenerative processes in impaired intestinal permeability conditions. The early modulation of enteric glia-mediated neuroinflammation might optimize neuroprotective treatments outcomes currently used in neurodegenerative diseases.

Areas covered: We discussed recent clinical and preclinical data existing on the Pubmed database, concerning the glial role in neurodegeneration. We focused on the gut as possible “entrance door” for endoluminal neurotoxic agents that induce neurological impairments during leaky gut conditions. Moreover, we reviewed the paradigmatic studies linking the leaky gut-induced priming of EGCs to the induction of late neurodegenerative processes in Parkinson’s disease and other neurodegenerative disorders.

Expert opinion: The previous appearance of neuropathological markers in the ENS emphasizes the extra-CNS origin of neurodegenerative disorders, by directing their therapies toward peripheral management of neurodegeneration. In light of the EGCs changes resulting from a switch-on of activated phenotype in leaky gut syndrome, EGCs sampling could be predictive for neuropathological conditions detection, anticipating their symptomatic manifestation in the CNS.     

Antipsychotic drug use in neurodegenerative disease in the elderly: problems and potential from a pharmacological perspective

The past decade has seen the introduction of several new antipsychotics for the treatment of schizophrenia. These drugs demonstrate substantially lower levels of extrapyramidal side effects (EPS) than the classical antipsychotics, as well as having (often poorly supported) claims of increased efficacy at ameliorating certain schizophrenic syndromes. Increasingly, these ‘atypical’ drugs are being used in the treatment of psychotic or related behavioural disturbances in patients with neurodegenerative disease. Thus, some newer antipsychotics are particularly valuable in ameliorating the L-dopa-induced psychosis in Parkinson’s disease, while behavioural problems in dementing disorders, such as those occurring in Alzheimer’s disease, are also frequently treated by antipsychotic drugs. The relationship between drug pharmacology and neurotransmitter pathology is essential to understanding the relative efficacy of individual antipsychotic drugs in treating the psychotic and behavioural disturbances of neurodegenerative disorders.     

Endothelin and erectile dysfunction: a target for pharmacological intervention?

Although erectile dysfunction (ED) is not life threatening, this common problem can significantly affect the quality of life and psychological and social well-being. The Massachusetts male ageing study (1,290 men aged 40 - 70 years) showed that 52% of men reported some degree of ED (17.1% mild, 25.2% moderate, 9.6% total). In the UK, an estimated 17 - 19% of men are thought to suffer from ED. This problem is more common with advancing age and since this proportion of the population is increasing, the prevalence of ED is expected to rise. Endothelin-1 (ET-1) belongs to a family of potent vasoconstrictor peptides consisting of 21 amino acids. We review the evidence showing that ET-1 plays a role via (ET_A and ET_B receptors) in the regulation of cavernosal smooth muscle tone. We also consider the various risk factors that are involved in the pathogenesis of ED and how these relate to the action of ET-1. In particular, the role of diabetes, hypertension, smoking and dyslipidaemia are discussed. The pharmaceutical industry has declared an interest in the development of ET antagonists for use in the treatment of various diseases including ED. We briefly comment on experimental ET-1 antagonists that may be of therapeutic benefit in ED.