Targeting glucose-dependent insulinotropic polypeptide receptor for neurodegenerative disorders

Introduction: Incretin hormones, glucose-dependent insulinotropic polypeptide (GIP), and glucagon-like peptide-1 (GLP-1) exert pleiotropic effects on endocrine pancreas and nervous system. Expression of GIP and GIP receptor (GIPR) in neurons, their roles in neurogenesis, synaptic plasticity, neurotransmission, and neuromodulation uniquely position GIPR for therapeutic applications in neurodegenerative disorders. GIP analogs acting as GIPR agonists attenuate neurobehavioral and neuropathological sequelae of neurodegenerative disorders in preclinical models, e.g. Alzheimer’s disease (AD), Parkinson’s disease (PD), and cerebrovascular disorders. Modulation of GIPR signaling offers an unprecedented approach for disease modification by arresting neuronal viability decline, enabling neuronal regeneration, and reducing neuroinflammation. Growth-promoting effects of GIP signaling and broad-based neuroprotection highlight the therapeutic potential of GIPR agonists.

Areas covered: This review focuses on the role of GIPR-mediated signaling in the central nervous system in neurophysiological and neuropathological conditions. In context of neurodegeneration, the article summarizes potential of targeting GIPR signaling for neurodegenerative conditions such as AD, PD, traumatic brain injury, and cerebrovascular disorders.

Expert opinion: GIPR represents a validated therapeutic target for neurodegenerative disorders. GIPR agonists impart symptomatic improvements, slowed neurodegeneration, and enhanced neuronal regenerative capacity in preclinical models. Modulation of GIPR signaling is potentially a viable therapeutic approach for disease modification in neurodegenerative disorders.     

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.     

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.     

The bright side of psychoactive substances: cannabinoid-based drugs in motor diseases

Introduction: Psychoactive substances are associated with the idea of drugs with high addictive liability, affecting mental states, cognition, emotion and motor behavior. However these substances can modify synaptic transmission and help to disclose some mechanisms underlying alterations in brain processing and pathophysiology of motor disease. Hence, the ‘bright side’ of e cannabinoid-based drugs must be thoroughly examined to be identified within the latter framework.

Areas covered: We will analyze the preclinical and clinical evidence of cannabinoid-based drugs, discussing their therapeutic value in basal ganglia motor disorders such as Parkinson’s disease and Huntington disease.

Expert commentary: Despite the knowledge acquired in the last years, the therapeutic potential of cannabinoid-based drugs should be further tested by novel routes of investigation. This should be focused on the role of cannabinoid signaling system in mitochondrial function as well as on the physical and functional interaction with other key receptorial targets belonging to this network.     

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.     

Membrane lipids as therapeutic targets for Parkinson’s disease: a possible link between Lewy pathology and membrane lipids

Introduction: Pathologically, Parkinson’s disease (PD) is characterized by nigral cell loss and Lewy pathology in the remaining neurons. Whereas the motor symptoms of PD show a marked response to dopamine replacement therapy, many of the non-motor symptoms are resistant to treatment. This suggests that in addition to nigral cell loss, widespread Lewy pathology in the nervous system is associated with the manifestations of PD.

Areas covered: Although the mechanism of Lewy body formation remains largely unknown, it is becoming clear that changes in the behavior of α-synuclein are critical in this process. α-Synuclein behaves differently depending on the lipid composition of membranes with which it interacts; therefore, one can postulate that the altered lipid composition of neuronal membranes may lead to Lewy pathology. The lipid composition of cellular membranes is consistently altered in the brains of patients with PD, and Lewy pathology is a common feature of several human lipidoses with mutations in enzymes that affect membrane lipids. This further supports the concept that alterations in the membrane lipids of neurons are central to Lewy pathology.

Expert opinion: This concept provides a new platform to establish models for the development of novel treatments for PD.     

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.     

Targeting LRRK2 in Parkinson’s disease: an update on recent developments

Introduction: LRRK2 research has progressed significantly in recent years with more reports of LRRK2 interactors and the development of more specific and sophisticated LRRK2 kinase inhibitors. Identification of bone fide LRRK2 substrates will provide new therapeutic targets in LRRK2-linked Parkinson’s disease (PD).

Areas covered: This review aims to put current LRRK2 research into perspective. Beginning with recent LRRK2 mammalian models employed for in vivo validation of LRRK2 substrates, followed by updates on reported LRRK2 interactors and their inferred mechanisms. Finally an overview of commonly used LRRK2 kinase inhibitors will be depicted.

Expert opinion: Identification of LRRK2 non-kinase functions suggests the possibility of alternative LRRK2 drug target sites and these should be further explored. Studies on the effects of LRRK2 kinase inhibition on its non-kinase function and its self-regulatory role will provide further insights on its pathophysiologic mechanisms. Development of robust measurements of LRRK2 inhibitor efficacy will be required. These would include identification of specific imaging ligands or direct biochemical assays that can accurately capture its intrinsic activity. Testing of new therapeutic drug targets in both LRRK2 carriers and non LRRK2-linked patients will be important since their phenotype is similar.     

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.     

Therapeutic potential of Panax ginseng and its constituents,ginsenosides and gintonin,in neurological and neurodegenerative disorders: a patent review

Introduction: Ginseng, Panax ginseng, has been used for various diseases and proven its great efficacy in managing central nervous system diseases.

Area covered: This article covers the therapeutic potential of patents on ginseng and its active constituents to develop therapies for neurodegenerative and neurological disorders, since 2010. The literature review was provided using multiple search engines including Google Patent, Espacenet and US Patent in the field of neurodegenerative diseases, Alzheimer’s disease, Parkinson’s disease, cognitive, and neurological disorders.

Expert opinion: The gathered data represented outstanding merits of ginseng in treatment of neurodegenerative and neurological disorders. These effects have been mediated by neurogenesis, anti-apoptotic and antioxidant properties, inhibition of mitochondrial dysfunction, receptor-operated Ca²⁺ channels, amyloid beta aggregation, and microglial activation as well as neurotransmitters modulation. However, these compounds have limited clinical application of for the prevention or treatment of neurodegenerative and neurological disorders. This might be due to incomplete data on their clinical pharmacokinetic and toxicity properties, and limited economic investments. There is an increasing trend in use of herbal medicines instead of chemical drugs, so it is time to make more attention to the application of ginseng, the grandfather of medicinal plants, from basic sciences to patients’ bed.     

Investigational drugs targeting 5-HT6 receptors for the treatment of Alzheimer’s disease

Introduction: There are significant efforts invested into the discovery and development of novel treatments for Alzheimer’s disease. While current discovery efforts and most scientific discussions seem to focus on disease-modifying therapy, there are several symptomatic therapy approaches that are being actively pursued. The goal of this review is to summarize the recent developments in the field of 5-HT6 receptor antagonists, a principle that has been extensively characterized preclinically and is now undergoing critical phases of clinical development.

Areas covered: The article covers the current status of 5-HT6 receptor antagonists in clinical development. It also discusses the underlying mechanisms for the observed procognitive effects. The article is based on a search for investigational drugs using the key words ‘5-HT6?, ‘cognition’, ‘dementia’, ‘Alzheimer’s disease’, ‘Phase II’ and ‘Phase III’ in various databases and from conference abstracts.

Expert opinion: After some period of little or no development activities, the field of 5-HT6 receptor antagonists attracted a lot of attention with three companies (GSK, Pfizer and Lundbeck) confirming aggressive development plans and initiating pivotal Phase II and III studies. These studies will be critical to prove that 5-HT6 receptor antagonists have a symptomatic efficacy profile that can be differentiated from that of currently used agents (cholinesterase inhibitors and the NMDA-antagonist memantine). Furthermore, there are several sets of data that point at a disease-modifying potential of this class of agents and these effects are likely to receive critical exploration if the ongoing symptomatic trials bring 5-HT6 antagonists closer to clinical use.     

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.     

Leucine-rich repeat kinase 2 inhibitors: a patent review (2014-2016)

Introduction: Leucine-rich repeat kinase 2 (LRRK2) is a member of the Tyrosine Kinase-Like (TKL) branch of the kinome tree and is a multi-domain protein that includes GTPase and kinase activity. While genome-wide association studies (GWAS) has linked LRRK2 with Crohn’s disease and leprosy, it has received the greatest attention due to it being implicated as one of the genetic loci associated with autosomal dominant inheritance in Parkinson’s disease (PD).

Areas covered: In this review, the small molecule patent literature from 2014–2016 with a focus on composition of matter and use patents was surveyed. Scifinder was primarily searched using ‘LRRK2? as the query to identify all relevant literature and then triaged for small molecule patents.

Expert opinion: The patent landscape around LRRK2 continues to develop. The early patents covered using existing kinase inhibitors for use against LRRK2. This evolved to compounds specifically designed for selectivity against LRRK2, but key exemplified compounds lacked sufficient brain exposure to affect sufficient efficacy. More recent compounds have addressed this deficiency and show greater potential for treating PD. While potency will be necessary to generate medicines with low human daily doses, brain penetration and safety will be the key differentiators for ultimately determining the most effective LRRK2 disease-modifying treatment for PD.     

The P2X7 receptor: a new therapeutic target in Alzheimer’s disease

Introduction: Alzheimer’s disease (AD) is a neurodegenerative illness with genetic risk as an etiological factor in a subset of cases. In AD with autosomal dominant inheritance, the extracellular β-amyloid (Aβ) aggregates and intracellular neurofibrillary tangles which consist of hyperphosphorylated tau, appear to be involved in the neuronal damage; however, other forms of AD may have a polygenetic causality. Microglial cells orchestrate pathophysiological events responsible for neuronal damage in AD. They surround Aβ aggregates and the stimulation of microglial P2X7 receptors (P2X7Rs) by high local concentrations of ATP which originates from damaged CNS cells, results in degeneration of nearby neurons.

Areas covered: We discuss the pathogenesis of Alzheimer’s disease, the role of P2X7 receptors and their potential as therapeutic targets. We also address the fundamental hurdles in the development of new therapeutic strategies for Alzheimer’s disease.

Expert opinion: There are many difficulties associated with the development of efficient pharmacological strategies for AD; the lack of good animal and cellular models for this illness is a key obstacle. None of the pharmacological strategies developed so far have led to an improvement of the treatment of AD. Hence, the consideration of blood-brain barrier-permeable P2X7R antagonists as possible therapeutic agents in AD is a must.     

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.     

Role of sphingomyelinases in neurological disorders

Introduction: Sphingomyelinases, which catalyze the hydrolysis of sphingomyelin to ceramide and phosphorylcholine, are abundant in the brain. These enzymes are a major, rapid source of ceramide production not only during physiological responses to receptor stimulation, but also in neurological disorders.

Areas covered: We covered an introduction to sphingomyelinases and its enzymatic product ceramide, in membrane domains or lipid rafts and the nucleus; followed by crosstalk between sphingomyelinase and cytosolic phospholipase A₂ (cPLA₂) catalysed products including arachidonic acid, functions of acid sphingomyelinase (aSMase) and neutral sphingomyelinase (N-SMase) in neurons, neuronal progenitor cells, glial cells, and brain endothelial cells; alterations in acid and N-SMases in Niemann Pick Disease Type A, major depression, Alzheimer’s disease, cerebral ischemia, and pain; and recent developments in identification of inhibitors to sphingomyelinases. As literature search methodology, we did key word searches using Pubmed.

Expert opinion: More research needs to be carried out to develop pharmacological agents that act on sphingomyelinases, for the prevention or treatment of neurological disorders.     

Sorbus alnifolia protects dopaminergic neurodegeneration in Caenorhabditis elegans

Context: The twigs of Sorbus alnifolia (Sieb. et Zucc.) K. Koch (Rosaceae) have been used to treat neurological disorders as a traditional medicine in Korea. However, there are limited data describing the efficacy of S. alnifolia in Parkinson’s disease (PD).

Objective: This study was conducted to identify the protective effects of the methanol extracts of S. alnifolia (MESA) on the dopaminergic (DA) neurodegeneration in Caenorhabditis elegans.

Materials and methods: To test the neuroprotective action of MESA, viability assay was performed after 48?h exposure to 1-methyl-4-phenylpyridine (MMP⁺) in PC12 cells and C. elegans (400?μM and 2?mM of MMP⁺, respectively). Fluorescence intensity was quantified using transgenic mutants such as BZ555 (Pdat-1::GFP) and and UA57 (Pdat-1::GFP and Pdat-1::CAT-2) to determine MESA’s effects on DA neurodegeneration in C. elegans. Aggregation of α-synuclein was observed using NL5901 strain (unc-54p::α-synuclein::YFP). MESA’s protective effects on the DA neuronal functions were examined by food-sensing assay. Lifespan assay was conducted to test the effects of MESA on the longevity.

Results: MESA restored MPP⁺-induced loss of viability in both PC12 cells and C. elegans (85.8% and 54.9%, respectively). In C. elegans, MESA provided protection against chemically and genetically-induced DA neurodegeneration, respectively. Moreover, food-sensing functions were increased 58.4% by MESA in the DA neuron degraded worms. MESA also prolonged the average lifespan by 25.6%. However, MESA failed to alter α-synuclein aggregation.

Discussion and conclusions: These results revealed that MESA protects DA neurodegeneration and recovers diminished DA neuronal functions, thereby can be a valuable candidate for the treatment of PD.     

The multiple faces of RAGE – opportunities for therapeutic intervention in aging and chronic disease

Introduction: This review focuses on the multi-ligand receptor of the immunoglobulin superfamily – receptor for advanced glycation endproducts (RAGE). The accumulation of the multiple ligands of RAGE in cellular stress milieux links RAGE to the pathobiology of chronic disease and natural aging.

Areas covered: In this review, we present a discussion on the ligands of RAGE and the implications of these ligand families in disease. We review the recent literature on the role of ligand–RAGE interaction in the consequences of natural aging; the macro- and microvascular complications of diabetes; obesity and insulin resistance; autoimmune disorders and chronic inflammation; and tumors and Alzheimer’s disease. We discuss the mechanisms of RAGE signaling through its intracellular binding effector molecule – the formin DIAPH1. Physicochemical evidence of how the RAGE cytoplasmic domain binds to the FH1 (formin homology 1) domain of DIAPH1, and the consequences thereof, are also reviewed.

Expert opinion: We discuss the modalities of RAGE antagonism currently in preclinical and clinical studies. Finally, we present the rationale behind potentially targeting the RAGE cytoplasmic domain–DIAPH1 interaction as a logical strategy for therapeutic intervention in the pathological settings of chronic diseases and aging wherein RAGE ligands accumulate and signal.     

Non human primate models for Alzheimer’s disease-related research and drug discovery

Introduction: Pathophysiological mechanisms underlying Alzheimer’s disease (AD) remain insufficiently documented for the identification of accurate diagnostic markers and purposeful target discovery and development. Nonhuman primates (NHPs) have important translational value given their close phylogenetic relationship to humans and similar developmental paths in (neuro)anatomy, physiology, genetics, and neural functions, as well as cognition, emotion, and social behavior.

Areas covered: This review deals with the past and future role of NHP-based research in AD pathophysiology, diagnosis and drug discovery, and touches upon ethical and legal aspects.

Expert opinion: Aging NHPs are not complete phenocopies of human AD. Conceivably, no other species or experimental model will ever develop the full spectrum of AD-typical alterations. Nevertheless, partial – and even negative – models can increase knowledge of disease mechanisms. Modeling complex brain disorders should not be based on a single model or species. Understanding brain diseases relies on knowledge of healthy brain functioning, and given their close phylogenetic relationship to humans, NHPs serve excellent tools in this respect. NHP-based studies remain essential in the development and validation of radiopharmaceuticals for early diagnostic imaging biomarkers, as well as in the efficacy and safety evaluation of new therapeutic approaches, with active immunization or vaccination approaches as front runners.