PDEs as drug targets for CNS immune disorders

PDEs are important second messenger systems governing a host of cellular functions involved in neural signal transduction in the CNS and inflammatory cell signaling in the immune system. The contributions of PDE family members as novel treatments that target neuroinflammation as a pathophysiological process in the neuropathogenesis of diverse neurological and psychiatric brain disorders with prominent immune system correlates are discussed.     

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.     

Antioxidants as treatment for neurodegenerative disorders

Oxidative stress is a ubiquitously observed hallmark of neurodegenerative disorders. Neuronal cell dysfunction and cell death due to oxidative stress may causally contribute to the pathogenesis of progressive neurodegenerative disorders, such as Alzheimer’s disease and Parkinson’s disease, as well as acute syndromes of neurodegeneration, such as ischaemic and haemorrhagic stroke. Neuroprotective antioxidants are considered a promising approach to slowing the progression and limiting the extent of neuronal cell loss in these disorders. The clinical evidence demonstrating that antioxidant compounds can act as protective drugs in neurodegenerative disease, however, is still relatively scarce. In the following review, the available data from clinical, animal and cell biological studies regarding the role of antioxidant neuroprotection in progressive neurodegenerative disease will be summarised, focussing particularly on Alzheimer’s disease, Parkinson’s disease, Huntington’s disease and amyotrophic lateral sclerosis. The general complications in developing potent neuroprotective antioxidant drugs directed against these long-term degenerative conditions will also be discussed. The major challenges for drug development are the slow kinetics of disease progression, the unsolved mechanistic questions concerning the final causalities of cell death, the necessity to attain an effective permeation of the blood–brain barrier and the need to reduce the high concentrations currently required to evoke protective effects in cellular and animal model systems. Finally, an outlook as to which direction antioxidant drug development and clinical practice may be leading to in the near future will be provided.     

Antioxidants as treatment for neurodegenerative disorders

Oxidative stress is a ubiquitously observed hallmark of neurodegenerative disorders. Neuronal cell dysfunction and cell death due to oxidative stress may causally contribute to the pathogenesis of progressive neurodegenerative disorders, such as Alzheimer's disease and Parkinson's disease, as well as acute syndromes of neurodegeneration, such as ischaemic and haemorrhagic stroke. Neuroprotective antioxidants are considered a promising approach to slowing the progression and limiting the extent of neuronal cell loss in these disorders. The clinical evidence demonstrating that antioxidant compounds can act as protective drugs in neurodegenerative disease, however, is still relatively scarce. In the following review, the available data from clinical, animal and cell biological studies regarding the role of antioxidant neuroprotection in progressive neurodegenerative disease will be summarised, focussing particularly on Alzheimer's disease, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis. The general complications in developing potent neuroprotective antioxidant drugs directed against these long-term degenerative conditions will also be discussed. The major challenges for drug development are the slow kinetics of disease progression, the unsolved mechanistic questions concerning the final causalities of cell death, the necessity to attain an effective permeation of the blood-brain barrier and the need to reduce the high concentrations currently required to evoke protective effects in cellular and animal model systems. Finally, an outlook as to which direction antioxidant drug development and clinical practice may be leading to in the near future will be provided.     

Designing drugs with multi-target activity: the next step in the treatment of neurodegenerative disorders

Introduction: Neurodegenerative diseases have had devastating effects on patients' quality of life. These complex diseases have several pathways that are affected to initiate cell death. Current therapies, designed to address only a single target, fall short in mitigating or preventing disease progression, and disease-modifying drugs are desperately needed. Over the past several years, a new paradigm has emerged which has as a goal the targeting of multiple disease etiological pathways. Such “multi-targeted designed drugs” (MTDD) have shown great promise in preclinical studies as neuroprotective agents, as well as being able to afford symptomatic relief to blunt the day-to-day burden of these illnesses.

Areas covered: In this review, the authors evaluate the use of chemical scaffolds that led themselves exquisitely to the development of MTDDs in central nervous system disorders. Some of the examples discussed have also transitioned into the clinic, which underscores the importance of pursuing drug discovery programs within the multifunctional arena.

Expert opinion: Currently, very little can be done to slow the progress of neurodegeneration. The multifaceted profile of neurodegeneration necessitates a change in paradigm toward the design of compounds that address several drug targets simultaneously. With successful compounds in clinical trials as well as compounds moving into the clinic, support is growing and the feasibility of this approach is now becoming recognized. This review shows that several small molecule scaffolds can be successfully utilized to design MTDD compounds with good CNS pharmacokinetics.     

Epigenetic targets of HDAC inhibition in neurodegenerative and psychiatric disorders

Epigenetic chromatin remodeling and modifications of DNA represent central mechanisms for regulation of gene expression during brain development and in memory formation. Emerging evidence implicates epigenetic modifications in disorders of synaptic plasticity and cognition. This review focuses on recent findings that HDAC inhibitors can ameliorate deficits in synaptic plasticity, cognition, and stress-related behaviors in a wide range of neurologic and psychiatric disorders including Huntington's disease, Parkinson's disease, anxiety and mood disorders, Rubinstein-Taybi syndrome, and Rett syndrome. These agents may prove useful in the clinic for the treatment of the cognitive impairments that are central elements of many neurodevelopmental, neurological, and psychiatric disorders.     

Targeting JNK3 for the treatment of neurodegenerative disorders

c-Jun N-terminal kinases (JNKs) have been recognized as important enzymes in cellular function. JNK3, which is predominantly found in CNS neurons, has been implicated in several neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease and stroke. In particular, JNK3 has been found to have an upstream role in neuronal ischemic apoptosis. JNK3 is highly expressed and activated in postmortem brains of individuals that suffered from Alzheimer's disease. Furthermore, mice that are deficient in JNK3 are more resistant to 1-methyl-4-phenyl-1,2,4,6-tetrahydropyridine (a neurotoxin that mimics the neuropathological characteristics of Parkinson's disease) than their wild-type littermates. Because of the involvement of JNK3 in neuronal diseases, the inhibition of this enzyme is an attractive therapeutic target.     

The Hedgehog signaling pathway--implications for drug targets in cancer and neurodegenerative disorders

The Hedgehog (Hh) pathway is a highly conserved signaling cascade involved in many developmental processes. Among others, these include patterning of the ventral neural tube and establishment of left-right asymmetry of the embryo. Additionally, the pathway regulates the development of numerous tissues and cell types. Mutations in elements of the pathway are associated with congenital diseases and defects, and ectopic Hh signaling activity is implicated in the development of a number of neoplasms. While little is known of Hh signaling function in the adult organism, a role of the pathway in maintenance of adult organs and cell types, including several neuronal subtypes in the central nervous system, is beginning to emerge. Elements of the Hh pathway are therefore potential drug targets for the treatment of cancers and degenerative diseases like Parkinson's disease, and the recent isolation of synthetic molecules capable of modulating the activity of the Hh cascade through a direct interaction with elements of the pathway is promising.     

Excitotoxicity: Bridge to various triggers in neurodegenerative disorders

Glutamate is one of the most prominent neurotransmitter in the body, present in over 50% of nervous tissue and plays an important role in neuronal excitation. This neuronal excitation is short-lived and is followed by depression. Multiple abnormal triggers such as energy deficiency, oxidative stress, mitochondrial dysfunction, calcium overload, etc can lead to aberration in neuronal excitation process. Such an aberration, serves as a common pool or bridge between abnormal triggers and deleterious signaling processes with which central neurons cannot cope up, leading to death. Excitotoxicity is the pathological process by which nerve cells are damaged and killed by excessive stimulation by neurotransmitters such as glutamate and similar substances. Such excitotoxic neuronal death has been implicated in spinal cord injury, stroke, traumatic brain injury, hearing loss and in neurodegenerative diseases of the central nervous system such as stroke, epilepsy, multiple sclerosis, Alzheimer disease, Amyltropic lateral sclerosis, Parkinson’s disease, Huntington disease and alcohol withdrawal. This review mainly emphasizes the triggering events which sustain neuronal excitation, role of calcium, mitochondrial dysfunction, ROS, NO, chloride homeostasis and eicosanoids pathways. Further, a brief introduction about the recent research occurring in the treatment of various neurodegenerative diseases, including a summary of the presumed physiologic mechanisms behind the pharmacology of these disorders.     

AMPA receptor potentiators for the treatment of CNS disorders

Glutamate alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptors mediate most of the excitatory neurotransmission in the mammalian central nervous system and also participate in forms of synaptic plasticity thought to underlie memory and learning, and the formation of neural networks during development. Molecular cloning techniques have shown that the AMPA receptor family is composed of four different subunits named GluR1-4 or GluRA-D (newly termed as Glu(A1)-Glu(A4)) and native AMPA receptors are most likely tetramers generated by the assembly of one or more of these subunits, yielding homomeric or heteromeric receptors. Additional complexity among AMPA receptors is conferred by alternative splicing of RNA for each subunit giving rise to flip and flop variants. Clinical and experimental data have suggested that positive modulation of AMPA receptors may be therapeutically effective in the treatment of cognitive deficits. Several classes of AMPA receptor potentiators have been reported, including pyrroliddones (piracetam, aniracetam), benzothiazides (cyclothiazide), benzylpiperidines (CX-516, CX-546) and more recently biarylpropylsulfonamides (LY392098, LY404187 and LY503430). These molecules enhance cognitive function in rodents, which appears to correlate with increased hippocampal activity. In addition, clinical studies have suggested that AMPA receptor modulators enhance cognitive function in elderly subjects, as well as patients suffering from neurological and psychiatric disorders. Several independent studies have suggested that AMPA receptors can increase BDNF expression by both calcium-dependent and independent pathways. For example, recent studies have shown that AMPA receptors interact with the protein tyrosine kinase, Lyn. Activation of Lyn can recruit the mitogen-activated protein kinase (MAPK) signalling pathway and increase the expression of BDNF. Therefore, in addition to directly enhancing glutamatergic synaptic transmission, AMPA receptor activation can increase the expression of BDNF in vitro and in vivo. This may account for activity of AMPA receptor potentiators in rodent models predictive of antidepressant activity (forced swim and tail suspension tests). The increase in neurotrophin expression also may contribute to the functional, neuroprotective and neurotrophic actions of LY404187 and LY503430 after infusion of 6-OHDA into the substantia nigra. In conclusion, several potent, selective and systemically active AMPA receptor potentiators have been reported. Data indicate that these molecules modulate glutamatergic transmission, enhance synaptic transmission, long-term potentiation (LTP) and increase neurotrophin expression. Therefore, these AMPA receptor potentiators offer an exciting new class of drugs with potential for treating (1) cognitive impairment associated with Alzheimer's disease and schizophrenia, (2) depression, (3) slowing the progression and potentially enhancing recovery from Parkinson's disease.     

Advances in the treatment of neurodegenerative disorders employing nanoparticles

Nanoparticles could potentially revolutionise treatment for neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD) and strokes. Nanotechnologies hold great promise in brain therapy as they protect the therapeutic agent and allow its sustained release; the nanoparticles can be used as gene delivery vehicles. The application of neurotrophic factors is able to modulate neuronal survival and synaptic connectivity and it is a promising therapeutic approach for many neurodegenerative diseases, however, due to limitations posed by the restrictive blood brain barrier (BBB), it is very difficult to ensure long-term administration in the brain. Drug delivery to the brain remains the major challenge for the treatment of all neurodegenerative diseases because of the numerous protective barriers surrounding the central nervous system (CNS). New therapeutics with the capacity to cross the BBB is critically needed for treatment of these diseases. In recent years, nanotechnology had patented new formulations and has evolved as a new treatment for brain diseases, especially for neurodegenerative diseases, where genetically engineered cells can be used to deliver specific growth factors to target cells. Overall, the aim of this review is to summarize the last patents, clinical trials and news related with nanoparticles technology for the treatment of neurodegenerative diseases.     

Folate and homocysteine metabolism: therapeutic targets in cardiovascular and neurodegenerative disorders

Individuals with elevated homocysteine levels are at increased risk for cardiovascular disease and stroke, and neurodegenerative disorders such as Alzheimer's and Parkinson's diseases Homocysteine is a modified form of the amino acid methionine that is tightly regulated by enzymes requiring folate. By impairing DNA repair mechanisms and inducing oxidative stress, homocysteine can cause the dysfunction or death of cells in the cardiovascular and nervous systems. Dietary folate stimulates homocysteine removal and may thereby protect cells against disease processes. The enzymes involved in homocysteine and folate metabolism provide novel targets for drug discovery.     

Nanotechnology for neurodegenerative disorders

The efficacy, cellular uptake and specific transport of drugs and/or imaging agents to target organs, tissues and cells are common issues in the diagnosis and treatment of different disorders. In the case of neurodegenerative diseases, they represent complex problems, since brain targeting remains a still unsolved challenge in pharmacology, due to the presence of the blood–brain barrier, a tightly packed layer of endothelial cells that prevents unwanted substances to enter the brain. Engineered nanomaterials, objects with dimensions of 1–100 nm, are providing interesting biomedical tools potentially able to solve these problems, thanks to their physico-chemical features and to the possibility of multi-functionalization, allowing to confer them different features at the same time, including the ability to cross the blood–brain barrier. This review focuses on the state-of-the-art of nanomaterials suitable for therapy and diagnostic imaging of the most common neurodegenerative disorders, as well as for neuroprotection and neuronal tissue regeneration. Finally, their potential neurotoxicity is discussed, and future nanotechnological approaches are described.     

Novel drugs and therapeutic targets for severe mood disorders.

Monoaminergic-based drugs remain the primary focus of pharmaceutical industry drug discovery efforts for mood disorders, despite serious limitations regarding their ability to achieve remission. The quest for novel therapies for unipolar depression and bipolar disorder has generally centered on two complementary approaches: (1) understanding the presumed therapeutically relevant biochemical targets of currently available medications, and using that knowledge to design new drugs directed at both direct biochemical targets and downstream targets that are regulated by chronic drug administration; and (2) developing pathophysiological models of the illness to design therapeutics to attenuate or prevent those pathological processes. This review describes several promising drugs and drug targets for mood disorders using one or both of these approaches. Agents interacting with non-catecholamine neurotransmitter systems with particular promise for unipolar and bipolar depression include excitatory amino acid neurotransmitter modulators (eg, riluzole, N-methyl-D-aspartate antagonists, and AMPA receptor potentiators) and neuropeptide antagonists (targeting corticotropin releasing factor-1 and neurokinin receptors). Potential antidepressant and mood-stabilizing agents targeting common intracellular pathways of known monoaminergic agents and lithium/mood stabilizers are also reviewed, such as neurotrophic factors, extracellular receptor-coupled kinase (ERK) mitogen-activated protein (MAP) kinase and the bcl-2 family of proteins, and inhibitors of phosphodiesterase, glycogen synthase kinase-3, and protein kinase C. A major thrust of drug discovery in mood disorders will continue efforts to identify agents with rapid and sustained onsets of action (such as intravenous administration of ketamine), as well as identify drugs used routinely in non-psychiatric diseases for their antidepressant and mood-stabilizing properties.