Gene expression profiling and therapeutic interventions in neurodegenerative diseases: a comprehensive study on potentiality and limits

Introduction: Neurodegenerative diseases are incurable debilitating disorders of the nervous system that affect approximately 30 million people worldwide. Despite profuse efforts attempting to define the molecular mechanisms underlying neurodegeneration, many aspects of these pathologies remain elusive. The novelty of their mechanisms represents a challenge to biology, to their related biomarkers identification and drug discovery. Because of their multifactorial aspects and complexity, gene expression analysis platforms have been extensively used to investigate altered pathways during degeneration and to identify potential biomarkers and drug targets.

Areas covered: This work offers an overview of the gene expression profiling studies carried out on Alzheimer's disease, Huntington's disease, Parkinson's disease and prion disease specimens. Therapeutic approaches are also discussed.

Expert opinion: Although many therapeutic approaches have been tested, some of them acting on several altered cellular pathways, no effective cures for these neurodegenerative diseases have been identified. Microarray technology must be associated with functional proteomics and physiology in an effort to identify specific and selective biomarkers and druggable targets, thus allowing the successful discovery of disease-modifying therapeutic treatments.     

Targeting EPO and EPO receptor pathways in anemia and dysregulated erythropoiesis

Introduction: Recombinant human erythropoietin (rhEPO) is a first-line therapeutic for the anemia of chronic kidney disease, cancer chemotherapy, AIDS (Zidovudine therapy), and lower-risk myelodysplastic syndrome. However, rhEPO frequently elevates hypertension, is costly, and may affect cancer progression. Potentially high merit therefore exists for defining new targets for anti-anemia agents within erythropoietin (EPO) and EPO receptor (EPOR) regulatory circuits.

Areas covered: EPO production by renal interstitial fibroblasts is subject to modulation by several regulators of hypoxia-inducible factor 2a (HIF2a) including Iron Response Protein-1, prolyl hydroxylases, and HIF2a acetylases, each of which holds potential as anti-anemia drug targets. The cell surface receptor for EPO (EPOR) preassembles as a homodimer, together with Janus Kinase 2 (JAK2), and therefore it remains attractive to develop novel agents that trigger EPOR complex activation (activating antibodies, mimetics, small-molecule agonists). Additionally, certain downstream transducers of EPOR/JAK2 signaling may be druggable, including Erythroferrone (a hepcidin regulator), a cytoprotective Spi2a serpin, and select EPOR-associated protein tyrosine phosphatases.

Expert opinion: While rhEPO (and biosimilars) are presently important mainstay erythropoiesis-stimulating agents (ESAs), impetus exists for studies of novel ESAs that fortify HIF2a’s effects, act as EPOR agonists, and/or bolster select downstream EPOR pathways to erythroid cell formation. Such agents could lessen rhEPO dosing, side effects, and/or costs.     

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.     

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.     

Targeting mitochondrial dysfunction in neurodegenerative disease: Part I

Importance of the field: The socioeconomic burden of an aging population has accelerated the urgency of novel therapeutic strategies for neurodegenerative disease. One possible approach is to target mitochondrial dysfunction, which has been implicated in the pathogenesis of numerous neurodegenerative disorders.

Areas covered in this review: This review examines the role of mitochondrial defects in aging and neurodegenerative disease, ranging from common diseases such as Alzheimer's and Parkinson's disease to rare familial disorders such as the spinocerebellar ataxias. The review is provided in two parts; in this first part, we discuss the mitochondrial defects that have been most extensively researched: oxidative stress; bioenergetic dysfunction and calcium deregulation.

What the reader will gain: This review provides a comprehensive examination of mitochondrial defects observed in numerous neurodegenerative disorders, discussing therapies that have reached clinical trials and considering potential novel therapeutic strategies to target mitochondrial dysfunction.

Take home message: This is an important area of clinical research, with several novel therapeutics already in clinical trials and many more in preclinical stages. In part II of this review we will focus on possible novel approaches, looking at mitochondrial defects which have more recently been linked to neurodegeneration.     

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.     

Solid lipid nanoparticles as a drug delivery system for the treatment of neurodegenerative diseases

ABSTRACT

Introduction: The failure of many molecules as CNS bioactive compounds is due to many restrictions: poor water solubility, intestinal absorption, in vivo stability, bioavailability, therapeutic effectiveness, side effects, plasma fluctuations, and difficulty crossing physiological barriers, like the brain blood barrier (BBB), to deliver the drug directly to the site of action.

Area covered: Nanotechnology-based approaches with the employment of liposomes, micelles, dendrimers, and solid lipid nanoparticles (SLN) as drug delivery systems, are used to overcome the above reported limitations. Here, we focus on the delivery of drugs based on SLN formulation to treat neurodegenerative diseases. Notably, SLN have the ability to protect drugs from chemical and enzymatic degradation, direct the active compound towards the target site with a substantial reduction of toxicity for the adjacent tissues, and pass physiological barriers increasing bioavailability without resorting to high dosage forms.

Expert opinion: We believe that SLN could represent a suitable tool to pass the BBB and permit drugs to reach damaged areas of the CNS in patients affected by neurodegenerative pathologies, such as Alzheimer’s and Parkinson’s diseases.     

Cognitive impairment with diabetes mellitus and metabolic disease: innovative insights with the mechanistic target of rapamycin and circadian clock gene pathways

ABSTRACT

Introduction: Dementia is the 7th leading cause of death that imposes a significant financial and service burden on the global population. Presently, only symptomatic care exists for cognitive loss, such as Alzheimer’s disease.

Areas covered: Given the advancing age of the global population, it becomes imperative to develop innovative therapeutic strategies for cognitive loss. New studies provide insight to the association of cognitive loss with metabolic disorders, such as diabetes mellitus.

Expert opinion: Diabetes mellitus is increasing in incidence throughout the world and affects 350 million individuals. Treatment strategies identifying novel pathways that oversee metabolic and neurodegenerative disorders offer exciting prospects to treat dementia. The mechanistic target of rapamycin (mTOR) and circadian clock gene pathways that include AMP activated protein kinase (AMPK), Wnt1 inducible signaling pathway protein 1 (WISP1), erythropoietin (EPO), and silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1) provide novel strategies to treat cognitive loss that has its basis in metabolic cellular dysfunction. However, these pathways are complex and require precise regulation to maximize treatment efficacy and minimize any potential clinical disability. Further investigations hold great promise to treat both the onset and progression of cognitive loss that is associated with metabolic disease.     

Metabotropic glutamate receptor 5 as a potential therapeutic target in Huntington’s disease

Introduction: Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder caused by a polyglutamine expansion in the amino-terminal region of the huntingtin (htt) protein, which underlies the loss of striatal and cortical neurons. Glutamate has been implicated in a number of neurodegenerative diseases, and several studies suggest that the metabotropic glutamate receptor 5 (mGluR5) may represent a target for the treatment of HD.

Areas covered: The main goal of this review is to discuss the current data in the literature regarding the role of mGluR5 in HD and evaluate the potential of mGluR5 as a therapeutic target for the treatment of HD. mGluR5 is highly expressed in the brain regions affected in HD and is involved in movement control. Moreover, mGluR5 interacts with htt and mutated htt profoundly affects mGluR5 signaling. However, mGluR5 stimulation can activate both neuroprotective and neurotoxic signaling pathways, depending on the context of activation.

Expert opinion: Although the data published so far strongly indicate that mGluR5 plays a major role in HD-associated neurodegeneration, htt aggregation and motor symptoms, it is not clear whether mGluR5 stimulation can diminish or intensify neuronal cell loss and HD progression. Thus, future experiments will be necessary to further investigate the outcome of drugs acting on mGluR5 for the treatment of neurodegenerative diseases.     

Intranasal delivery of therapeutic proteins for neurological diseases

Introduction: Among the range of therapeutic protein candidates for new generation treatments of neurological diseases, neurotrophic factors and recombinant antibodies hold the greatest potential. However, major difficulties in their safe and effective delivery to the brain severely limit these applications. The BBB restricts the exchange of proteins between the plasma and the CNS. Moreover, therapeutic proteins often need to be selectively targeted to the brain, while minimizing their biodistribution to systemic compartments, to avoid peripheral side effects. The intranasal delivery of proteins has recently emerged as a non-invasive, safe and effective method to target proteins to the CNS, bypassing the BBB and minimizing systemic exposure.

Areas covered: We critically summarize the main experimental and mechanistic facts about the simple and non-invasive nasal delivery approach, which provides a promising strategy and a potential solution for the severe unmet medical need of safely and effectively delivering protein therapeutics to the brain.

Expert opinion: The intranasal route for the effective delivery of recombinant therapeutic proteins represents an emerging and promising non-invasive strategy. Future studies will achieve a detailed understanding of pharmacokinetic and mechanisms of delivery to optimize formulations and fully exploit the nose-to-brain interface in order to deliver proteins for the treatment of neurological diseases. This expanding research area will most likely produce exciting results in the near future towards new therapeutical approaches for the CNS.     

Targeting GSK3 signaling as a potential therapy of neurodegenerative diseases and aging

ABSTRACT

Introduction: Glycogen synthase kinase 3 (GSK3) is at the center of cellular signaling and controls various aspects of brain functions, including development of the nervous system, neuronal plasticity and onset of neurodegenerative disorders.

Areas covered: In this review, recent efforts in elucidating the roles of GSK3 in neuronal plasticity and development of brain pathologies; Alzheimer’s and Parkinson’s disease, schizophrenia, and age-related neurodegeneration are described. The effect of microglia and astrocytes on development of the pathological states is also discussed.

Expert opinion: GSK3β and its signaling pathway partners hold great promise as therapeutic target(s) for a multitude of neurological disorders. Activity of the kinase is often elevated in brain disorders. However, due to the wide range of GSK3 cellular targets, global inhibition of the kinase leads to severe side-effects and GSK3 inhibitors rarely reach Phase-2 clinical trials. Thus, a selective modulation of a specific cellular pool of GSK3 or specific down- or upstream partners of the kinase might provide more efficient anti-neurodegenerative therapies.     

Targeting toll-like receptor 4 to modulate neuroinflammation in central nervous system disorders

ABSTRACT

Introduction: Adverse immune activation contributes to many central nervous system (CNS) disorders. All main CNS cell types express toll-like receptor 4 (TLR 4). This receptor is critical for a myriad of immune functions such as cytokine secretion and phagocytic activity of microglia; however, imbalances in TLR 4 activation can contribute to the progression of neurodegenerative diseases.

Areas covered: We considered available evidence implicating TLR 4 activation in the following CNS pathologies: Alzheimer’s disease, Parkinson’s disease, ischemic stroke, traumatic brain injury, multiple sclerosis, multiple systems atrophy, and Huntington’s disease. We reviewed studies reporting effects of TLR 4-specific antagonists and agonists in models of peripheral and CNS diseases from the perspective of possible future use of TLR 4 ligands in CNS disorders.

Expert opinion: TLR 4-specific antagonists could suppress neuroinflammation by reducing overproduction of inflammatory mediators; however, they may interfere with protein clearance mechanisms and myelination. Agonists that specifically activate myeloid differentiation primary-response protein 88 (MyD88)-independent pathway of TLR 4 signaling could facilitate beneficial glial phagocytic activity with limited activity as inducers of proinflammatory mediators. Deciphering the disease stage-specific involvement of TLR 4 in CNS pathologies is crucial for the future clinical development of TLR 4 agonists and antagonists.     

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.     

Targeting ApoE4/ApoE receptor LRP1 in Alzheimer's disease

Introduction: Progressive neuronal loss is a key feature in Alzheimer's disease (AD), which is the most common neurodegenerative disorder in the aging population. Currently, there are no therapeutic means to intervene neuronal damage in AD and therefore innovative approaches to discover novel strategies for the treatment of AD are needed. Based on the prevailing amyloid cascade hypothesis, it is conceivable that lowering the β-amyloid (Aβ) levels is sufficient to slow down the disease process, if started early enough.

Areas covered: Here, we review genetic and biological functions related to apolipoprotein E (ApoE) and low-density lipoprotein receptor-related protein 1 receptor (LRP1)-mediated clearance of Aβ. Furthermore, we discuss the AD-related therapeutic potential of targeting to ApoE receptor LRP1 at the blood-brain barrier (BBB) and in the periphery.

Expert opinion: Due to the recent setbacks in the clinical trials targeting AD, it is instrumental to seek alternative therapeutic approaches, which aim to reduce the accumulation of Aβ in the brain tissue. As the ApoE/LRP1-mediated clearance of Aβ across the BBB is the key event in the regulation of Aβ transcytosis from brain to periphery, direct targeting of this protein entity at the BBB holds a great potential in the treatment of AD.     

Targeting disease through novel pathways of apoptosis and autophagy

Introduction: Apoptosis and autophagy impact cell death in multiple systems of the body. Development of new therapeutic strategies that target these processes must address their complex role during developmental cell growth as well as during the modulation of toxic cellular environments.

Areas covered: Novel signaling pathways involving Wnt1-inducible signaling pathway protein 1 (WISP1), phosphoinositide 3-kinase (PI3K), protein kinase B (Akt), β-catenin and mammalian target of rapamycin (mTOR) govern apoptotic and autophagic pathways during oxidant stress that affect the course of a broad spectrum of disease entities including Alzheimer's disease, Parkinson's disease, myocardial injury, skeletal system trauma, immune system dysfunction and cancer progression. Implications of potential biological and clinical outcome for these signaling pathways are presented.

Expert opinion: The CCN family member WISP1 and its intimate relationship with canonical and non-canonical wingless signaling pathways of PI3K, Akt1, β-catenin and mTOR offer an exciting approach for governing the pathways of apoptosis and autophagy especially in clinical disorders that are currently without effective treatments. Future studies that can elucidate the intricate role of these cytoprotective pathways during apoptosis and autophagy can further the successful translation and development of these cellular targets into robust and safe clinical therapeutic strategies.     

Targeting α-synuclein as a therapeutic strategy for Parkinson’s disease

Introduction: α-Synuclein, a neuronal protein, plays a central role in the pathophysiology of Parkinson’s disease (PD), the second most prevalent neurodegenerative disorder. Cases of PD have increased tremendously over the past decade necessitating the identification of new therapeutic targets to reduce patient morbidity and to improve PD patients’ quality of life.

Areas covered: The purpose of this article is to provide an update on the role of α-synuclein in fibrils formation and review its role as an effective immunotherapeutic target for PD. The rapidly expanding evidence for the contribution of α-synuclein to the pathogenesis of PD led to the development of antibodies against the C terminus of α-synuclein and other molecules involved in the inflammatory signaling pathways that were found to contribute significantly to initiation and progression of the disease.

Expert opinion: The readers will obtain new insights on the mechanisms by which α-synuclein can trigger the development of PD and other related degenerative disorders along with the potential role of active and passive antibodies targeted against specific form of α-synuclein aggregates to clear neurotoxicity, stop the propagation of the prion-like behavior of these oligomers and reverse neuronal degeneration associated with PD.     

Sigma receptor modulators: a patent review

Introduction: Sigma receptors are involved in several central nervous system (CNS) disorders, including mood disorders (depression and anxiety), psychosis, schizophrenia, movement disorders (i.e., Parkinson's disease) and memory deficits (i.e., Alzheimer's disease). Recently, the involvement of sigma receptors in neuropathic pain and cancer has also been observed.

Areas covered: This review aims at highlighting the research advancements published in the patent literature between 1986 and 2012, dividing patents according to both their time frame and applicants. The review especially focuses on the development of sigma receptor modulators and their application over the years with respect to CNS diseases, neuropathic pain and neurodegenerative pathologies. The literature was sought through Espacenet, Orbit, ISI Web and PubMed databases.

Expert opinion: In recent years, considerable progress in the knowledge of the biology and pharmacology of sigma receptors has encouraged research on the potential benefits of sigma modulators in a wide range of pathologies. So far, only few potent agonists and antagonists of sigma receptors are in clinical trial for acute and chronic neurodegenerative diseases (SA4503 and ANAVEX 2-73) or neuropathic pain (E-52862).     

Targeting leucine-rich repeat kinase 2 in Parkinson's disease

Introduction: Parkinson's disease (PD), is a common progressive neurodegenerative disorder, and missense mutations in the LRRK2 gene are the most common single genetic cause of autosomal dominant PD and polymorphic variants modulate risk in sporadic PD. Earlier research focused on LRRK2 genetics, but with the recent discoveries of LRRK2 substrates/interactors, LRRK2-specific mechanisms are being unveiled.

Areas covered: As a multi-domain protein, LRRK2 possess diverse functions that range from housekeeping, signaling to clearance of proteins. Proteins that interact with LRRK2 have drawn attention to several pathophysiologic pathways that could potentially be targeted in the development of new therapies. This review will discuss the possible physiological roles of LRRK2 based on recently reported interactors as well as place LRRK2 in the disease context. Current LRRK2 inhibition studies and reports about LRRK2 biomarkers will also be discussed as they are important considerations for LRRK2 translational treatment options.

Expert opinion: The discovery of LRRK2 as a pathogenic gene in PD has contributed enormously to our understanding of clinical genetics. One of the challenges is to understand the physiologic role of LRRK2 and its specific function that gets disrupted when it is mutated. In vivo LRRK2 models have provided insights but they do not full recapitulate human PD. The identification of LRRK2 interactors opens the opportunities for identification of new therapeutic targets. Ways of quantification of kinase activity in vivo and determining what constitutes physiologic inhibition will need to be further investigated before specific pharmacologic agents can be meaningfully utilized.