Strategies For Treatment Of Neurodegenerative Disorders Research Articles

A New Generation of IMiDs as Treatments for Neuroinflammatory and Neurodegenerative Disorders.

The immunomodulatory imide drug (IMiD) class, which includes the founding drug member thalidomide and later generation drugs, lenalidomide and pomalidomide, has dramatically improved the clinical treatment of specific cancers, such as multiple myeloma, and it combines potent anticancer and anti-inflammatory actions. These actions, in large part, are mediated by IMiD binding to the human protein cereblon that forms a critical component of the E3 ubiquitin ligase complex. This complex ubiquitinates and thereby regulates the levels of multiple endogenous proteins. However, IMiD-cereblon binding modifies cereblon's normal targeted protein degradation towards a new set of neosubstrates that underlies the favorable pharmacological action of classical IMiDs, but also their adverse actions-in particular, their teratogenicity. The ability of classical IMiDs to reduce the synthesis of key proinflammatory cytokines, especially TNF-α levels, makes them potentially valuable to reposition as drugs to mitigate inflammatory-associated conditions and, particularly, neurological disorders driven by an excessive neuroinflammatory element, as occurs in traumatic brain injury, Alzheimer's and Parkinson's diseases, and ischemic stroke. The teratogenic and anticancer actions of classical IMiDs are substantial liabilities for effective drugs in these disorders and can theoretically be dialed out of the drug class. We review a select series of novel IMiDs designed to avoid binding with human cereblon and/or evade degradation of downstream neosubstrates considered to underpin the adverse actions of thalidomide-like drugs. These novel non-classical IMiDs hold potential as new medications for erythema nodosum leprosum (ENL), a painful inflammatory skin condition associated with Hansen's disease for which thalidomide remains widely used, and, in particular, as a new treatment strategy for neurodegenerative disorders in which neuroinflammation is a key component.

NMDA receptor antagonists as potential therapy in cerebellar degenerative disorders

Cerebellar degeneration remains a poorly studied topic. Excitotoxicity, i.e. neuronal damage and death due to excess activation of postsynaptic N-methyl-D-aspartate receptors (NMDAR) by glutamate, is considered to be a universal mechanism of most neurodegenerative conditions. The use of antagonists that predominantly block NMDAR in cases of excitotoxicity is a very promising treatment strategy for neurodegenerative disorders. This review presents the known structure and function of NMDAR. Information on studies investigating the use of NMDAR antagonists in the treatment of neurodegenerative diseases is provided. Creation of new therapies to correct excitotoxicity in various neurodegenerative disorders, for example, spinocerebellar ataxias, requires further study of the subunit composition and the role of NMDAR in the cerebellum. Treatment methods that combine the use of extrasynaptic NMDAR antagonists or synaptic NMDAR agonists with drugs that affect the total amount of glutamate in the synaptic cleft are promising.

Targeting the core of neurodegeneration: FoxO, mTOR, and SIRT1.

The global increase in lifespan noted not only in developed nations, but also in large developing countries parallels an observed increase in a significant number of non-communicable diseases, most notable neurodegenerative disorders. Neurodegenerative disorders present a number of challenges for treatment options that do not resolve disease progression. Furthermore, it is believed by the year 2030, the services required to treat cognitive disorders in the United States alone will exceed $2 trillion annually. Mammalian forkhead transcription factors, silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae), the mechanistic target of rapamycin, and the pathways of autophagy and apoptosis offer exciting avenues to address these challenges by focusing upon core cellular mechanisms that may significantly impact nervous system disease. These pathways are intimately linked such as through cell signaling pathways involving protein kinase B and can foster, sometimes in conjunction with trophic factors, enhanced neuronal survival, reduction in toxic intracellular accumulations, and mitochondrial stability. Feedback mechanisms among these pathways also exist that can oversee reparative processes in the nervous system. However, mammalian forkhead transcription factors, silent mating type information regulation 2 homolog 1, mechanistic target of rapamycin, and autophagy can lead to cellular demise under some scenarios that may be dependent upon the precise cellular environment, warranting future studies to effectively translate these core pathways into successful clinical treatment strategies for neurodegenerative disorders.

Anti-Amyloid Aggregating Gold Nanoparticles: Can they Really be Translated from Bench to Bedside for Alzheimer's Disease Treatment?

Alzheimer's disease (AD) is characterized by deposition of amyloid-β protein aggregates and an appropriate treatment strategy is urgently needed, as the number of diagnosed cases continues to increase. The management of AD and other brain-associated diseases is limited by the blood brain barrier and its selective control of drug passage. In fact, most of the promising drugs have restricted curative effects on AD owing to their lower bioavailability. Gold nanoparticles (AuNPs) have emerged as attractive therapeutic agents and have distinctive properties that could contribute to the development of a novel treatment strategy for neurodegenerative disorders. In this review article, we attempt to identify promising ways of developing competent AD therapeutic agents from anti-amyloid aggregating AuNPs. Initially, we discuss the current status of anti-amyloid inhibitors, the abilities of AuNPs to inhibit amyloid aggregation, and mechanistic aspects, and then describe plausible modifications that could aid the translation of AuNP-based therapeutics into neuromedicines. The review highlights some interesting characteristics that might effectively bridge the gap between laboratory and bedside treatments.

Methyl lucidone exhibits neuroprotective effects on glutamate-induced oxidative stress in HT-22 cells via Nrf-2/HO-1 signaling

Oxidative stress causes neuronal cell death in various neurodegenerative diseases, such as Alzheimer’s disease, ischemia, and Parkinson’s disease. Therefore, reducing intracellular reactive oxygen species (ROS) has been evaluated as an effective treatment strategy for neurodegenerative disorders. Methyl lucidone (MLC) extracted from Lindera erythrocarpa Makino (Lauraceae) has been previously reported to exhibit microglial-mediated neuroprotective effects via inhibiting neuroinflammation. However, the antioxidant effects of MLC are still unclear. The aim of this study was to determine the neuroprotective mechanism of MLC in HT-22 neurons against oxidative stress induced by glutamate. In results, the pretreatment of MLC significantly enhanced the viability of HT-22 cells under glutamate-induced oxidative conditions, suggesting that MLC has a neuronal mechanism to protect neurons without microglial regulation. Also, the glutamate effect to increase ROS production was effectively blocked by MLC without any free radical scavenging activity. To induce this antioxidant effect, MLC upregulated the expression of heme oxygenase 1 (HO-1) and nuclear translocation of nuclear factor-E2-related factor 2 (Nrf-2), known as an intracellular antioxidant enzyme, and its transcription factor. Additionally, Akt phosphorylation regulating Nrf-2 was confirmed to be involved in the neuroprotective signaling activated by MLC. These results indicate that MLC may play a role as an antioxidant agent to inhibit neurodegenerative processes via activating antioxidant signaling pathways that include Nrf-2 and phosphatidylinositol 3-kinase (PI3K).

Role of viruses, prions and miRNA in neurodegenerative disorders and dementia.

Dementia is known as loss of cellular communications in the brain at a region caused by multi-factorial diseases and pathogenic infections. Approximately eighty percent reported cases of Alzheimer's disease are followed by vascular dementia. The common symptoms of dementia include memory loss, concentration problems, thinking, and language solving situations. Dementia is a multifactorial disease but based on latest research; various reports have been published describing the linkage and role of viruses, prions and miRNAs in neurodegeneration and neurodegenerative disorders resulting into dementia and due to this we selected to review and provide latest information related to dementia. MiRNAs are small non-coding RNAs carrying genetic regulatory information contributing to neurological disorders among human and animals. A prion is an infectious agent made of protein material. Recently, it has been reported that prions play a significant role in signaling processes, resulting in amyloidogenesis and neurological disorders. Viruses attack human immune system and central nervous system and affect classical pathways of neurodegenerative diseases. Comprehensive understandings of the expression profiles and activities of these miRNAs, Prions, Viruses will illuminate their roles as potential therapeutic targets in neurodegeneration and may lead to the discovery of breakthrough treatment strategies for neurodegenerative disorders and dementia. The provided information will further be significant not only in neuro-scientific research, but also in designing and development of management strategies for dementia.

Yeast-based screening of natural product extracts results in the identification of prion inhibitors from a marine sponge

ABSTRACTOne of the major medical challenges of the twenty-first century is the treatment of incurable and fatal neurodegenerative disorders caused by misfolded prion proteins. Since the discovery of these diseases a number of studies have been conducted to identify small molecules for their treatment, however to date no curative treatment is available. These studies can be highly expensive and time consuming, but more recent experimental approaches indicate a significant application for yeast prions in these studies. We therefore used yeast prions to optimize previous high-throughput methods for the cheaper, easier and more rapid screening of natural extracts. Through this approach we aimed to identify natural yeast-prion inhibitors that could be useful in the development of novel treatment strategies for neurodegenerative disorders. We screened 500 marine invertebrate extracts from temperate waters in Australia allowing the identification of yeast-prion inhibiting extracts. Through the bioassay-driven chemical investigation of an active Suberites sponge extract, a group of bromotyrosine derivatives were identified as potent yeast-prion inhibitors. This study outlines the importance of natural products and yeast prions as a first-stage screen for the identification of new chemically diverse and bioactive compounds.

Targeting Gpr52 lowers mutant HTT levels and rescues Huntington's disease-associated phenotypes.

See Huang and Gitler (doi:10.1093/brain/awy112) for a scientific commentary on this article.Lowering the levels of disease-causing proteins is an attractive treatment strategy for neurodegenerative disorders, among which Huntington's disease is an appealing disease for testing this strategy because of its monogenetic nature. Huntington's disease is mainly caused by cytotoxicity of the mutant HTT protein with an expanded polyglutamine repeat tract. Lowering the soluble mutant HTT may reduce its downstream toxicity and provide potential treatment for Huntington's disease. This is hard to achieve by small-molecule compound drugs because of a lack of effective targets. Here we demonstrate Gpr52, an orphan G protein-coupled receptor, as a potential Huntington's disease drug target. Knocking-out Gpr52 significantly reduces mutant HTT levels in the striatum and rescues Huntington's disease-associated behavioural phenotypes in a knock-in Huntington's disease mouse model expressing endogenous mutant Htt. Importantly, a novel Gpr52 antagonist E7 reduces mutant HTT levels and rescues Huntington's disease-associated phenotypes in cellular and mouse models. Our study provides an entry point for Huntington's disease drug discovery by targeting Gpr52.

Implication of Oncogenic Signaling Pathways as a Treatment Strategy for Neurodegenerative Disorders – Contemporary Approaches

Recent evidence has associated the aberrant, proximal re-expression of various cell cycle control elements with neuronal cell vulnerability in Alzheimer's and Parkinson's diseases, as a common chronic neurodegeneration. This phenomenon associated with oncogenic transduction pathway activation has attracted the interest of scientists all over the world for a few years now. The purpose of this paper is to outline areas of research related to oncogenic factors or medicines in the context of potential applications for future treatment of the above mentioned chronic and, largely, incurable diseases.

Wnt1, FoxO3a, and NF-κB oversee microglial integrity and activation during oxidant stress

Elucidating the underlying mechanisms that govern microglial activation and survival is essential for the development of new treatment strategies for neurodegenerative disorders, since microglia serve not only as guardian sentries of the nervous system, but also play a significant role in determining neuronal and vascular cell fate. Here we show that endogenous and exogenous Wnt1 in inflammatory microglial cells is necessary for the prevention of apoptotic early membrane phosphatidylserine exposure and later DNA degradation, since blockade of Wnt1 signaling abrogates cell survival during oxidative stress. Wnt1 prevents apoptotic demise through the post-translational phosphorylation and maintenance of FoxO3a in the cytoplasm to inhibit an apoptotic cascade that relies upon the loss of mitochondrial membrane permeability, cytochrome c release, Bad phosphorylation, and activation of caspase 3 and caspase 1 as demonstrated by complimentary gene knockdown studies of FoxO3a. Furthermore, subcellular trafficking and gene knockdown studies of NF-κB p65 illustrate that microglial cell survival determined by Wnt1 during oxidative stress requires NF-κB p65. Our work highlights Wnt1 and the control of novel downstream transcriptional pathways as critical components for the oversight of nervous system microglial cells.

TNF-α Inhibition as a Treatment Strategy for Neurodegenerative Disorders: New Drug Candidates and Targets

As the average ages of North Americans and Europeans continue to rise; similarly the incidence of "old age" associated illnesses likewise increases. Most notably among these ailments are conditions linked to dementia-related neurodegenerative disorders, such as Alzheimer's disease (AD), Parkinson's disease (PD) and stroke. While in the early stages, these conditions are associated with cellular dysfunction in distinctly different brain regions, thus affecting different neuronal cell types; it is most likely that the final stages share similar cellular and molecular processes leading to neuronal death and ultimately overt clinical symptoms. In this regard, different environmental and genetic triggers ranging from head trauma to protein mutations and toxicological exposure may instigate a cascade of intracellular events that ultimately lead to neuronal death. One strong candidate trigger protein, and thus a potential target for therapeutic manipulation is the potent pro-inflammatory / pro-apoptotic cytokine, tumor necrosis factor-alpha (TNF-alpha). TNF-alpha is secreted by the brain resident marcophage (the microglial cell) in response to various stimuli. It has been demonstrated to play a major role in central nervous system (CNS) neuroinflammation-mediated cell death in AD, PD and amyotrophic lateral sclerosis (ALS) as well as several other CNS complications. Recently, agents that modulate the levels of circulating peripheral TNF-alpha protein have been shown to be worthwhile therapeutic agents with the use of Enbrel (Etanercept) and Remicade (Infliximab), both of which display beneficial properties against rheumatoid arthritis and other peripheral inflammatory diseases. Unfortunately, these agents are largely unable to penetrate the blood-brain barrier, which severely limits their use in the setting of neuroinflammation in the CNS. However, thalidomide, a small molecule drug, can inhibit TNF-alpha protein synthesis and, unlike larger molecules, is readily capable of crossing the blood-brain barrier. Thus thalidomide and its analogs are excellent candidate agents for use in determining the potential value of anti-TNF-alpha therapies in a variety of diseases underpinned by inflammation within the nervous system. Consequently, we have chosen to discuss the relevance of unregulated TNF-alpha expression in illnesses of the CNS and, to an extent, the peripheral nervous system. Additionally, we consider the utilization of thalidomide-derived agents as anti-TNF-alpha therapeutics in the setting of neuroinflammation.

Molecular mechanisms of microglial activation

Microglial cells are brain macrophages which serve specific functions in the defense of the central nervous system (CNS) against microorganisms, the removal of tissue debris in neurodegenerative diseases or during normal development, and in autoimmune inflammatory disorders of the brain. In cultured microglial cells, several soluble inflammatory mediators such as cytokines and bacterial products like lipopolysaccharide (LPS) were demonstrated to induce a wide range of microglial activities, e.g. increased phagocytosis, chemotaxis, secretion of cytokines, activation of the respiratory burst and induction of nitric oxide synthase. Since heightened microglial activation was shown to play a role in the pathogenesis of experimental inflammatory CNS disorders, understanding the molecular mechanisms of microglial activation may lead to new treatment strategies for neurodegenerative disorders, multiple sclerosis and bacterial or viral infections of the nervous system.