Mitochondrial disturbances, tryptophan metabolites and neurodegeneration: medicinal chemistry aspects

Neurodegenerative disorders, e.g. Parkinson's, Huntington's and Alzheimer's diseases are distinct clinical and pathological entities sharing a number of leading features in their underlying processes. These common features involve the disturbances in the normal functioning of the mitochondria and the alterations in the delicate balance of tryptophan metabolism. The development of agents capable of halting the progression of these diseases is in the limelight of neuroscience research. This review highlights the role of mitochondria in the development of neurodegenerative processes with special focus on the involvement of neuroactive kynurenines both as pathological agents and potential targets and tools for future therapeutic approaches by providing a comprehensive summary of the main streams of rational drug design and giving an insight into present clinical achievements.     

Neuroprotective and neurotrophic actions of glucagon-like peptide-1: an emerging opportunity to treat neurodegenerative and cerebrovascular disorders

Like type-2 diabetes mellitus (T2DM), neurodegenerative disorders and stroke are an ever increasing, health, social and economic burden for developed Westernized countries. Age is an important risk factor in all of these; due to the rapidly increasing rise in the elderly population T2DM and neurodegenerative disorders, both represent a looming threat to healthcare systems. Whereas several efficacious drugs are currently available to ameliorate T2DM, effective treatments to counteract pathogenic processes of neurodegenerative disorders are lacking and represent a major scientific and pharmaceutical challenge. Epidemiological data indicate an association between T2DM and most major neurodegenerative disorders, including Alzheimer's and Parkinson's diseases. Likewise, there is an association between T2DM and stroke incidence. Studies have revealed that common pathophysiological features, including oxidative stress, insulin resistance, abnormal protein processing and cognitive decline, occur across these. Based on the presence of shared mechanisms and signalling pathways in these seemingly distinct diseases, one could hypothesize that an effective treatment for one disorder could prove beneficial in the others. Glucagon-like peptide-1 (GLP-1)-based anti-diabetic drugs have drawn particular attention as an effective new strategy to not only regulate blood glucose but also to reduce apoptotic cell death of pancreatic beta cells in T2DM. Evidence supports a neurotrophic and neuroprotective role of GLP-1 receptor (R) stimulation in an increasing array of cellular and animal neurodegeneration models as well as in neurogenesis. Herein, we review the physiological role of GLP-1 in the nervous system, focused towards the potential benefit of GLP-1R stimulation as an immediately translatable treatment strategy for acute and chronic neurological disorders.     

Glycogen synthase kinase 3 (GSK-3) inhibitors: a patent update (2014-2015)

Introduction: Glycogen synthase kinase (GSK-3) is a serine/threonine kinase that phosphorylates more than one hundred different sequences within proteins in a variety of different pathways. It is a key component of a remarkably large number of cellular processes and diseases. Imbalance of GSK-3 activity is involved in various prevalent pathological diseases, such as diabetes, neurodegenerative diseases and cancer. Understanding its role in different disorders has been central in the last several decades and there has been a significantly large development of GSK-3 inhibitors, some of which, show promising results for the treatment of these devastating diseases.

Areas covered: This review covers patent literature on GSK-3 inhibitors and their applications published and/or granted between 2014 and 2015.

Expert opinion: GSK-3 inhibitors have gained a prominent role in regenerative medicine based in their ability to modulate stem cells. Moreover, some allosteric modulators of GSK-3 emerge as safe compounds for chronic treatments.     

Targeting protein aggregation in neurodegeneration--lessons from polyglutamine disorders

Polyglutamine diseases, such as Huntington's disease, are among the most common inherited neurodegenerative disorders. They share salient clinical and pathological features with major sporadic neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease and amyotropic lateral sclerosis. Over the last decade, protein aggregation has emerged as a common pathological hallmark in neurodegenerative diseases and has, therefore, attracted considerable attention as a likely shared therapeutic target. Because of their clearly defined molecular genetic basis, polyglutamine diseases have allowed researchers to dissect the relationship between neurodegeneration and protein aggregation. In this review, the authors discuss recent progress in understanding polyglutamine-mediated neurotoxicity, and discuss the most promising therapeutic strategies being developed in the polyglutamine diseases and related neurodegenerative disorders.     

Targeting protein aggregation in neurodegeneration – lessons from polyglutamine disorders

Polyglutamine diseases, such as Huntington’s disease, are among the most common inherited neurodegenerative disorders. They share salient clinical and pathological features with major sporadic neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease and amyotropic lateral sclerosis. Over the last decade, protein aggregation has emerged as a common pathological hallmark in neurodegenerative diseases and has, therefore, attracted considerable attention as a likely shared therapeutic target. Because of their clearly defined molecular genetic basis, polyglutamine diseases have allowed researchers to dissect the relationship between neurodegeneration and protein aggregation. In this review, the authors discuss recent progress in understanding polyglutamine-mediated neurotoxicity, and discuss the most promising therapeutic strategies being developed in the polyglutamine diseases and related neurodegenerative disorders.     

Coenzyme Q10 in neurodegenerative diseases

Coenzyme Q(10) (ubiquinone), which serves as the electron acceptor for complexes I and II of the mitochondrial electron transport chain and also acts as an antioxidant, has the potential to be a beneficial agent in neurodegenerative diseases in which there is impaired mitochondrial function and/or excessive oxidative damage. Substantial data have accumulated to implicate these processes in the pathogenesis in certain neurodegenerative disorders, including Parkinson's disease, Huntington's disease and Friedreich's ataxia. Although no study to date has unequivocally demonstrated that coenzyme Q(10) can slow the progression of a neurodegenerative disease, recent clinical trials in these three disorders suggest that supplemental coenzyme Q(10) can slow the functional decline in these disorders, particularly Parkinson's disease.     

The case for therapeutic proteostasis modulators

A functional ubiquitin proteasome pathway (UPP) is vital for all eukaryotic cellular systems and therefore any alteration in this critical component of proteostasis machinery has rpotential pathological consequences. A proteostasis imbalance can be induced by environmental pollutants, age or genetic factors. Though the exact underlying mechanisms are unclear, a decrease in proteasome activity weakens the homeostatic cellular capacity to remove proteins that are either misfolded or need to be replenished, which favors the development of neurodegenerative, cardiac and other conformational diseases. In contrast, induction of proteasome activity is an attribute of many diseases including muscle wasting, sepsis, cachexia and uraemia. In the case of misfolded protein disorders, higher degradation of a single protein leads to the pathophysiological consequences due to the absence of functional protein. Therefore, selective proteostasis inhibition is a potential treatment strategy for misfolded protein disorders, while broad-spectrum proteasome inhibitor drugs are designed to target tumor metastasis. In contrast, for muscle wasting and neurodegeneration, the use of proteostasis-activating or modulating compounds could be more effective.     

The case for therapeutic proteostasis modulators

A functional ubiquitin proteasome pathway (UPP) is vital for all eukaryotic cellular systems and therefore any alteration in this critical component of proteostasis machinery has rpotential pathological consequences. A proteostasis imbalance can be induced by environmental pollutants, age or genetic factors. Though the exact underlying mechanisms are unclear, a decrease in proteasome activity weakens the homeostatic cellular capacity to remove proteins that are either misfolded or need to be replenished, which favors the development of neurodegenerative, cardiac and other conformational diseases. In contrast, induction of proteasome activity is an attribute of many diseases including muscle wasting, sepsis, cachexia and uraemia. In the case of misfolded protein disorders, higher degradation of a single protein leads to the pathophysiological consequences due to the absence of functional protein. Therefore, selective proteostasis inhibition is a potential treatment strategy for misfolded protein disorders, while broad-spectrum proteasome inhibitor drugs are designed to target tumor metastasis. In contrast, for muscle wasting and neurodegeneration, the use of proteostasis-activating or modulating compounds could be more effective.     

Role of FK506 binding proteins in neurodegenerative disorders

Protein misfolding has been implicated in the pathophysiology of several neurodegenerative 'amyloidoses' that includes Alzheimer's, Parkinson's, Huntington's disease, frontotemporal dementia and amyotrophic lateral sclerosis. Accumulation of misfolded proteins into ordered fibrillar intra- or extracellular amyloids results in brain lesions that in turn lead to injury and neuronal loss. The appearance of protein aggregates in the diseased brain hints at an inability of cellular chaperones to properly assist folding of client proteins. Not surprisingly, studies involving cell-based and animal models of the neurodegenerative diseases have shown that overexpression of molecular chaperones can provide neuroprotection. Together with identification of new targets for symptomatic relief of motor and non-motor defects in neurodegenerative disorders, there is a critical unmet clinical need for the development of novel neuroprotective molecules. One such promising class of compounds are neuroimmunophilin ligands (NILs). Derived from FK506 (tacrolimus), NILs have been shown to be efficacious in a number of neurodegenerative disorders. The ability of these nonimmunosuppressive NILs to protect neurons is modulated, in part, by a large family of co-chaperone proteins called the FK506 binding proteins (FKBPs). This review focuses on the roles of FKBPs in neurodegenerative disorders with an emphasis on the cellular mechanisms responsible for their neuroprotective and neurotrophic activities. We discuss the structural features of FKBPs and the mode of action of NILs. For brevity, we limit our discussion to those FKBPs that are particularly enriched in the nervous system. We hope that such information will aid in the rational design of new and improved NILs for ameliorating neurodegenerative disorders.     

Antioxidant strategies in protection against neurodegenerative disorders

The most common neurodegenerative diseases include Alzheimer’s disease, Parkinson’s disease and stroke; they are devastating clinical problems which lack effective treatments. Although the aetiology of these diseases is not fully understood, oxidative stress is believed to be a contributing causative factor. In addition to conventional therapies, antioxidant strategies in protection against neurodegenerative conditions have been increasingly addressed, as evidenced by an increasing number of animal studies, clinical reports and patents regarding these processes in recent years. The effectiveness of antioxidants in protecting against neurodegenerative disorders lies mainly in their ability to cross the blood–brain barrier, their potential in terms of subcellular distribution occurring in membranes, in the cytoplasm and especially in mitochondria, and their multifunctional capacity as well as their synergistic actions. The naturally occurring antioxidants with different properties collaborate as an array to defend against oxidative stress. Single antioxidant supplementation would not then be expected to have a remarkable influence on neurodegenerative diseases, which may involve free radicals. Thus, using combinations of antioxidants with different subcellular distributions and different properties for prophylaxis or treatment would probably improve therapeutic outcomes. Based on their multifactoral aetiology, the development of novel antioxidants with anti-inflammatory and metal-chelating properties and the ability to improve metabolism, for example by increasing ATP production rate or a new formulation of antioxidants with other agents, which have different functions, will become the new strategies in protecting against neurodegenerative disorders.     

Prolyl oligopeptidase: a potential target for the treatment of cognitive disorders

Prolyl oligopeptidase (POP) is a ubiquitous post-proline cleaving enzyme that is highly expressed in brain. Current knowledge about the biochemical features of POP and the pharmacological action of its specific inhibitors has indicated that POP participates in several aspects of the central nervous system (CNS), including learning, memory and mood. Furthermore, a role has been suggested for POP in pathological processes such as eating and mood disorders, hypertension and cell-cycle disturbances, in addition to its proposed connection with the neurodegenerative processes which occur in Alzheimer's, Huntington's and Parkinson's diseases. The milestones responsible for the accelerated development of POP inhibitors include the discovery that these compounds reverse memory loss in animal models of drug- or lesion-induced amnesia and the observation that the expression of POP correlates with age. Today, several POP inhibitors have already been evaluated in preclinical trials as potential drugs for the treatment of natural memory deficits that occur with aging or the pathological memory loss characteristic of Alzheimer's disease. Thus, the results that are emerging from basic research on POP function will facilitate the fine-tuning of more efficient drugs to target this protease.     

Excitotoxicity and N-methyl-D-Aspartate receptors

A great deal of new information has been generated over the past decade in the excitatory amino acid (EAA) field. Not only have endogenous EAA such as glutamate and aspartate become recognized as the leading neurotransmitter candidates at the majority of excitatory synapses in the mammalian central nervous system, but it is becoming increasingly evident that the well-established neurotoxic (excitotoxic) properties of these agents may play an important role in the pathophysiology of neurodegenerative diseases. Several EAA receptor subtypes have been identified through which the excitotoxicity of EAA might be expressed. One of these—the N-methyl-D -aspartate (NMDA) receptor—has become a primary focus of attention because of evidence suggesting it may be involved in a wide range of both neurophysiological and pathological processes. Antagonists that powerfully block both the excitatory and neurotoxic actions of EAA agonists at the NMDA receptor or associated ion channel have been identified and are being developed as potential neuroprotective agents for use in the management of neurological disorders. In this article, the potential role of excitotoxic mechanisms in neurodegenerative diseases and the prospects for controlling such disease processes by the application of antiexcitotoxin drugs will be examined.     

Dietary chelators as antioxidant enzyme mimetics: implications for dietary intervention in neurodegenerative diseases

Following recent reviews on the role of metal ions in oxidative stress and neurodegenerative diseases, this article reports advances in the study of dietary components for the control of these conditions. Poor metal ion homeostasis is credited with pathological roles in the progression of a number of disorders including Alzheimer's disease, Parkinson's disease and multiple sclerosis. Synthetic metal ion chelators continue to show promise as a new therapeutic approach for neurodegenerative disorders. Dietary chelators, unlike most vitamins, are, however, capable of negating or even reversing the roles of metal ions by: (i) decorporation of metal ions, (ii) redox silencing, (iii) dissolution of deposits, and (iv) generation of an antioxidant enzyme mimetic. This review gives a critical evaluation of recent progress in, and potential for, dietary control of neurodegeneration on the basis of the formation of antioxidant enzyme mimetics.     

Ubiquitin-like protein conjugation and the ubiquitin-proteasome system as drug targets

The ubiquitin-proteasome system (UPS) and ubiquitin-like protein (UBL) conjugation pathways are integral to cellular protein homeostasis. The growing recognition of the fundamental importance of these pathways to normal cell function and in disease has prompted an in-depth search for small-molecule inhibitors that selectively block the function of these pathways. However, our limited understanding of the molecular mechanisms and biological consequences of UBL conjugation is a significant hurdle to identifying drug-like inhibitors of enzyme targets within these pathways. Here, we highlight recent advances in understanding the role of some of these enzymes and how these new insights may be the key to developing novel therapeutics for diseases including immuno-inflammatory disorders, cancer, infectious diseases, cardiovascular disease and neurodegenerative disorders.     

Apoptotic mechanisms involved in neurodegenerative diseases: experimental and therapeutic approaches

Alzheimer's disease (AD) and Parkinson's disease (PD) are two of the most significant neurodegenerative disorders in the developed world. However, although these diseases were described almost a century ago, the molecular mechanisms that lead to the neuronal cell death associated with these diseases are not yet clear, and vigorous research efforts have failed to identify effective treatment options. In the present review, we evaluate the potential mechanisms underlying apoptosis and neuronal death in neurodegenerative disorders. A role for mitochondria in the release of proapoptotic proteins, such as cytochrome c and apoptosis-inducing factor (AIF) etc., is discussed along with key processes involving oxidative stress and activation of glutamate receptors. We also deliberate the implication of DNA damage, primarily p53 induction and reentry in the cell cycle. Finally, we postulate that multitargeting therapies comprising antioxidants, cell cycle inhibitors and modulating agents of COX-2 or c-JUN kinase pathways could be suitable strategies to prevent or delay the process of neuronal cell death in neurodegenerative disorders. Thus, the aim of this review is to discuss the pathways involved in the pathogenesis of neurodegenerative diseases such as AD, PD and Huntington's disease (HD). Furthermore, current and future pharmacotherapeutics will be considered.     

HtrA proteins as targets in therapy of cancer and other diseases

Importance of the field: The HtrA family proteins are serine proteases that are involved in important physiological processes, including maintenance of mitochondrial homeostasis, apoptosis and cell signaling. They are involved in the development and progression of several pathological processes such as cancer, neurodegenerative disorders and arthritic diseases.

Areas covered in this review: We present characteristics of the human HtrA1, HtrA2 and HtrA3 proteins, with the stress on their function in apoptosis and in the diseases. We describe regulation of the HtrAs' proteolytic activity, focusing on allosteric interactions of ligands/substrates with the PDZ domains, and make suggestions on how the HtrA proteolytic activity could be modified. Literature cited covers years 1996 – 2010.

What the reader will gain: An overview of the HtrAs' function/regulation and involvement in diseases (cancer, neurodegenerative disorders, arthritis), and ideas how modulation of their proteolytic activity could be used in therapies.

Take home message: HtrA2 is the best target for cancer drug development. An increase in the HtrAs' proteolytic activity could be beneficial in cancer treatment, by stimulation of apoptosis, anoikis or necrosis of cancer cells, or by modulation of the TGF-β signaling cascade; modulation of HtrA activity could be helpful in therapy of neurodegenerative diseases and arthritis.     

Nanotechnology-Based Drug Delivery Systems for Targeting, Imaging and Diagnosis of Neurodegenerative Diseases

Neurodegenerative disorders are becoming prevalent with the increasing age of the general population. A number of difficulties have emerged for the potential treatment of neurodegenerative diseases, as these disorders may be multi systemic in nature. Due to limitations regarding the blood brain barrier (BBB) structure, efflux pumps and metabolic enzyme expression, conventional drug delivery systems do not provide efficient therapy for neurodegenerative disorders. Nanotechnology can offer impressive improvement of the neurodegenerative disease treatment by using bio-engineered systems interacting with biological systems at a molecular level. This review focuses on the nano-enabled system applications for the treatment and diagnosis of neurodegenerative diseases, in particular Alzheimer’s, Parkinson’s and Prion diseases.