CNS & Neurological Disorders - Drug Targets (Formerly Current Drug Targets - CNS & Neurological Disorders) - Volume 12, Issue 8, 2013

Parkinson's disease (PD) is a chronic and progressive neurodegenerative disease with worldwide increasing incidence. PD is the second most prevalent neurodegenerative disease and the first that involves motor symptoms. The great majority of cases, defined as sporadic with non-familial disease, show a highly variable risk of disease due to environmental and genetic factors that remain largely unknown. Furthermore, the neurodegenerative process typically initiates decades prior to the appearance of hallmark motor symptoms; therefore, clinical diagnosis is enabled only when most of the relevant neurons have died and current treatment is palliative at best. Here, we review the application of genomic scale microarray based research aimed to enable early diagnosis and identify novel targets for therapeutic intervention. We demonstrate that blood leukocytes can serve as a feasible and reliable tissue source to test for diseaseinduced and treatment-related transcript changes. We cover our reports of transcription and alternative splicing modifications in PD patient's leukocytes based on 3’ and exon microarray analyses and the identified inflammatory modulations. We further describe the effects of deep brain stimulation (DBS) neurosurgery on the leukocyte transcripts as reflecting the patient's neurological status. A focus is gained on common genes identified both in the molecular signature of human PD leukocytes and in brain RNA from engineered PD mouse models subjected to risk and protection manipulations. Finally, we discuss potential future directions of high-throughput RNA research as facilitators of the PD knowledge base through next generation sequencing technologies of both long and short RNA transcripts including microRNAs.

Pathological aggregation of alpha-synuclein as Lewy-bodies and neurites is a hallmark of a group of neurodegenerative disorders named alpha-synucleinopathies. It is becoming apparent that alpha-synuclein facilitates presynaptic neuronal function in the brain, and events leading to its aggregation produce marked disruption of neurotransmitter release mechanism. We discuss here the literature related to the function of alpha-synuclein at the neuronal synapse in synucleinopathies brains and corresponding animal models.

Parkinson’s disease (PD) and L-DOPA-induced dyskinesia, a major complication of treatment of PD, are associated with molecular and functional alterations occurring into the medium spiny neurons (MSNs) of the dorsal striatum, a key areas involved in the control of motor activity. MSNs are regulated by several neurotransmitter systems including dopamine, glutamate and adenosine via activation of distinct receptors. Increasing evidence suggest that interactions among systems are mediated by different mechanisms including the formation of receptor heterodimers. The current view of G protein-coupled receptors organization, in fact, assumes that they do not work as monomeric units, but are part of heterodimeric complexes or of high order heteromers, where other receptors and ancillary proteins are coclustered. This organization implies that the pharmacological and signalling properties of these receptors may depend on the molecular composition of the receptor heteromers where they are clustered and may be differentially modulated in physiological or pathological conditions. Here, we provide an overview of the functional implications of physical interactions among dopamine, glutamate and adenosine receptors, their relevance for striatal MSNs activity and their involvement in the physiopathology of PD and dyskinesia.

A critical step in the development of effective therapeutics to treat Parkinson’s disease (PD) is the identification of molecular pathogenic mechanisms underlying this chronically progressive neurodegenerative disease. However, while animal models have provided valuable information about the molecular basis of PD, the lack of faithful cellular and animal models that recapitulate human pathophysiology is delaying the development of new therapeutics. The reprogramming of somatic cells to induced pluripotent stem cells (iPSC) using delivery of defined combinations of transcription factors is a groundbreaking discovery that opens great opportunities for modeling human diseases, including PD, since iPSC can be generated from patients and differentiated into disease-relevant cell types, which would capture the patients’ genetic complexity. Furthermore, human iPSC-derived neuronal models offer unprecedented access to early stages of the disease, allowing the investigation of the events that initiate the pathologic process in PD. Recently, human iPSC-derived neurons from patients with familial and sporadic PD have been generated and importantly they recapitulate some PD-related cell phenotypes, including abnormal α-synuclein accumulation in vitro, and alterations in the autophagy machinery. This review highlights the current PD iPSC-based models and discusses the potential future research directions of this field.

Metabotropic glutamate (mGlu) receptors are G protein-coupled receptors expressed primarily on neurons and glial cells modulating the effects of glutamatergic neurotransmission. The pharmacological manipulation of these receptors has been postulated to be valuable in the management of some neurological disorders. Accordingly, the targeting of mGlu5 receptors as a therapeutic approach for Parkinson’s disease (PD) has been proposed, especially to manage the adverse symptoms associated to chronic treatment with classical PD drugs. Thus, the specific pharmacological blocking of mGlu5 receptors constitutes one of the most attractive non-dopaminergic-based strategies for PD management in general and for the L-DOPA-induced diskynesia (LID) in particular. Overall, we provide here an update of the current state of the art of these mGlu5 receptor-based approaches that are under clinical study as agents devoted to alleviate PD symptoms.

We review the genetic and clinical features of spinobulbar muscular atrophy (SBMA), a progressive neuromuscular disorder caused by a CAG/glutamine tract expansion in the androgen receptor. SBMA was the first polyglutamine disease to be discovered, and we compare and contrast it with related degenerative disorders of the nervous system caused by expanded glutamine tracts. We review the cellular and animals models that have been most widely used to study this disorder, and highlight insights into disease pathogenesis derived from this work. These model systems have revealed critical aspects of the disease, including its hormone dependence, a feature that underlies disease occurrence only in men with the mutant allele. We discuss how this and other findings have been translated to clinical trials for SBMA patients, and examine emerging therapeutic targets that have been identified by recent work.

Research on the FKBP5 gene and FKBP51 protein has more than doubled since the discovery that polymorphisms in this gene could alter treatment outcomes and depressive behavior in humans. This coincided with other data suggesting that the stress hormone axis contributes to the development of numerous mental illnesses. As a result, FKBP51 now lies at the heart of the research of many stress related psychiatric disorders, which has led to advances in the understanding of this protein and its role in humans and in animal models. Specifically, FKBP5-/- mice and a naturally existing overexpression of FKBP5 in 3 genera of new world monkeys have helped understand the effects of FKBP5 in vivo. This review will highlight these finding as well as discuss the current evolutionary need for the FKBP5 gene.

The most relevant biological action of aldosterone in epithelial tissues is the regulation of sodium reabsorption through binding to the mineralocorticoid receptor (MR). Glucocorticoids also bind with high affinity to MR, which is usually protected by the enzyme 11β-hydroxysteroid dehydrogenase. This activity prevents MR activation by cortisol despite the large prevalence of this steroid in plasma. Nonetheless, there are some aspects of the mechanism of action of MR that are not entirely explained by this competitive metabolic mechanism of protection. The picture is even more complicated in those tissues such as the nervous system where the enzyme is expressed at very low levels or is directly absent in various areas of the brain. Therefore, other cellular and molecular mechanisms must also intervene to allow specific aldosterone biological effects in the presence of overwhelming concentrations of glucocorticoids. In this article, we discuss some possible mechanisms that permit the specificity of action for each type of steroid, including those related to the recently discovered novel molecular mechanism of activation of corticosteroid receptors and the structural requirements of a given ligand to favor the mineralocorticoid action via MR. The relative contribution of these mechanisms may vary in different target cells allowing the fine tuning of cellular functions depending on the degree of cooperation between steroids, receptors, chaperones associated to receptors, and other factors. All these regulatory interactions can be altered in some pathophysiological situations, most of them related to stressing situations.

Isolation of glucocorticoids (GCs) from adrenal glands followed by synthesis led rapidly to their first clinical application, about 70 years ago, for treatment of rheumatoid arthritis. To this day GCs are used in diseases that have an inflammatory component. However, their use is carefully monitored because of harmful side effects. GCs are also synonymous with stress and adaptation. In CNS, GC binds and activates high affinity mineralocorticoid receptor (MR) and low affinity glucocorticoid receptor (GR). GR, whose expression is ubiquitous, is only activated when GC levels rise as during circadian peak and in response to stress. Numerous recent studies have yielded important and new insights on the mechanisms concerning pulsatile secretory pattern of GCs as well as various processes that tightly control their synthesis via hypothalamic-pituitary-adrenal (HPA) axis involving regulated release of corticotropin-releasing hormone (CRH) and adrenocorticotropic hormone (ACTH) from hypothalamus and pituitary, respectively. GR modulates neuronal functions and viability through both genomic and non-genomic actions, and importantly its transcriptional regulatory activity is tightly locked with GC secretory pattern. There is increasing evidence pointing to involvement of GC-GR in neurodegenerative disorders. Patients with Alzheimer’s or Parkinson’s or Huntington’s disease show chronically high cortisol levels suggesting changes occurring in controls of HPA axis. In experimental models of these diseases, chronic stress or GC treatment was found to exacerbate both the clinical symptoms and neurodegenerative processes. However, recent evidence also shows that GC-GR can exert neuroprotective effects. Thus, for any potential therapeutic strategies in these neurodegenerative diseases we need to understand the precise modifications both in HPA axis and in GR activity and find ways to harness their protective actions.

In recent years, it has been established that environmental stress leaves enduring traces at distinct sites on the chromatin, accompanied by permanent alterations of gene transcription. This process depends on duration and extent of the discharge of stress hormones. Here, we aimed at identifying genes that are both regulated by the glucocorticoid receptor (GR) and display epigenetic features of transcriptional control. We used neuronal Neuro-2a cells as model system; cells were transiently transfected with GR and exposed to dexamethasone (Dex) for 2 days, either under conditions of cell proliferation or after serum deprivation-induced growth arrest. In parallel, Neuro-2a cells were treated with the histone deacetylase inhibitor trichostatin A. Comparison of gene expression profiles obtained from wholegenome microarray analyses revealed a network of genes that were GR-dependent and under control of epigenetic factors. Gene set enrichment analysis was performed in order to obtain insight into functional mechanisms implicated in stress hormone physiology. Dex response varied between proliferating and growth-arrested cells; enrichment was found for genes associated with metabolic pathways in proliferating cells, and for genes linked to inflammation in growth-arrested cells. The set of genes that were regulated by Dex under both growth conditions (proliferation and arrest) as well as by trichostatin A - (under cell proliferation) was enriched in mRNA transcripts encoding proteins which play a role in development and homeostasis. In summary, this study introduces a conceptual approach and incipient proof-of-concept for the identification of candidate genes that might be epigenetically programmed by activated GR.

Substantial evidence supports that progesterone exerts many functions in the central and peripheral nervous system unrelated to its classical role in reproduction. In this review we first discussed progesterone effects following binding to the classical intracellular progesterone receptors A and B and several forms of membrane progesterone receptors, the modulation of intracellular signalling cascades and the interaction of progesterone reduced metabolites with neurotransmitter receptors. We next described our results involving animal models of human neuropathologies to elucidate the protective roles of progesterone. We described: (a) the protective and promyelinating effects of progesterone in experimental spinal cord injury; (b) the progesterone protective effects exerted upon motoneurons in the degenerating spinal cord of Wobbler mouse model of amyotropic lateral sclerosis; (c) the protective and anti-inflammatory effects of progesterone in the murine experimental autoimmune encephalomyelitis model of multiple sclerosis and after lysolecithin demyelination; (d) the progesterone prevention of nociception and neuropathic pain which follow spinal cord injury; and (e) the protective effect of progesterone in experimental ischemic stroke. Whenever available, the molecular mechanisms involved in these progesterone effects were examined. The multiplicity of progesterone beneficial effects has opened new venues of research for neurological disorders. In this way, results obtained in animal models could provide the basis for novel therapeutic strategies and pre-clinical studies.

The gonadal steroid 17β-estradiol (E2) has shown powerful cytoprotective effect on cells. In addition to classical genomic mechanisms of action, E2 also exerts non-classical effects on intracellular signal transduction. Extensive studies during the past two decades have provided evidence that the E2-induced non-classical signaling on second messenger molecules plays a critical role in the neuroprotective effect of E2. These observations provide a unique basis for developing non-classical estrogen-like signaling activators that may have potential for clinical use in neuroprotection. In spite of the extensive research over the past decade reviewed here, we are just starting to appreciate the importance and potential of these compounds. Hence, we first describe the molecular characteristics and effects of these activators. Second, we survey recent data as to possible mechanisms underlying the ameliorative actions of selective non-classical estrogen-like signaling activation. In addition, the pitfalls and future aspects of “non-classical”-line activators and its clinical relevance will also be discussed.

Due to its efficacy and acceptability, paroxetine is situated in the top ten of drugs prescribed for the treatment of major depression and essentially all anxiety disorders. Adults under paroxetine treatment report relief after 4-6 weeks of administration; furthermore, this drug can be prescribed for periods lasting longer than one year. Therefore, paroxetine treatment has a pattern of ingestion that is mainly chronic rather than acute. There is a considerable number of reviews in the literature concerning the effects of paroxetine on the serotonergic system; however, the alterations caused by chronic ingestion of this drug in other neurotransmitter systems have received little attention. For this reason, we consider very important to review the experimental studies concerning the effects of chronic paroxetine intake on neurotransmitter levels, neuronal firing rate and the expression of receptors and transporters in different neurotransmitter systems in the brain. According to the experimental data analyzed in this work, we can establish that long-term paroxetine intake has the ability to increase GABA, glutamate, dopamine and noradrenaline levels in the brain. Furthermore, high levels of AMPA, orexine-1,2 and histamine-1 receptors have been reported in different brain regions after treatment with paroxetine over several weeks. In addition, paroxetine has differential effects on neuropeptide systems, such as galanine, opioid receptors and substance P. Available data lead us to establish that chronic ingestion of paroxetine induces changes in several neurotransmitters and neuropeptides, thus illuminating how each one may contribute to the antidepressant and anxiolytic response elicited by this drug. We consider that all reported changes in the neurotransmitter systems should be further considered to individualize clinical treatment and, in the case of patients taking a drug “cocktail”, to gain better control over drug interactions and adverse effects.

The major neuropathologic hallmarks in Alzheimer's disease (AD) consist of neuronal cell loss in selected brain regions, as well as deposition of extracellular senile plaques and intracellular neurofibrillary tangles. Further to these lesions, neuroinflammation is a feature of AD pathology and is thought to contribute to the neurodegeneration. Inflammation clearly occurs in pathologically vulnerable regions of the AD brain, with increased expression of acute phase proteins and pro-inflammatory cytokines. The healthy properties of green tea and apple are linked closely to their content of phenolic compounds. Although the beneficial effects of these compounds are clear, relatively few studies have focused on their anti-inflammatory effects in vivo. The aim of the present study was to test whether daily consumption of a beverage with high antioxidant power combining extracts of green tea and apple over a period of eight months would affect biomarkers of inflammation in AD patients in initial phase, moderate phase and a control group. Administration of the antioxidant beverage (AB) to the three groups did not produce a significant change in serum levels of the antiinflammatory cytokines interleukin-4 and interleukin-10. In contrast, AB decreased serum levels of the pro-inflammatory cytokines interleukin-2 (AD moderate phase vs control group at eight months), interferon-γ (control group vs AD moderate phase and AD initial phase vs placebo beverage at four months) and tumor necrosis factor-α (AD initial phase vs AD moderate phase at four months). AB was more effective against inflammation in the early period of AD, and could be used as a natural complementary therapy to alleviate or improve symptoms of inflammation in early stages of AD.

Multiple sclerosis (MS) is a chronic disease resulting from targeted destruction of central nervous system (CNS) myelin. MS is suggested to be an autoimmune disease involving the pathogenic activation of CD4+ T cells by a foreign antigen in the peripheral blood. The activated CD4+ T cells liberate inflammatory cytokines that facilitate the breakdown of the blood-brain barrier (BBB) promoting their passage into the CNS. Inside the CNS, CD4+ T cells become re-activated by myelin proteins sharing a similar structure to the foreign antigen that initially triggered the immune response. The CD4+ T cells continue to liberate inflammatory cytokines, such as tumor necrosis factor α (TNFα), which activates macrophages and antibodies responsible for the phagocytosis of myelin. Acute CNS lesions can be re-myelinated, however, the repair of chronic demyelinating lesions is limited, leading to permanent neurological deficits. Although current MS treatments reduce severity and slow disease progression, they do not directly repair damaged myelin. Henceforth, recent treatment strategies have focused on neurotrophins, such as nerve growth factor (NGF) for myelin repair. NGF promotes axonal regeneration, survival, protection and differentiation of oligodendrocytes (OGs) and facilitates migration and proliferation of oligodendrocyte precursors (OPs) to the sites of myelin damage. NGF also directly regulates key structural proteins that comprise myelin. Interestingly, NGF also induces the production of brain-derived neurotrophic factor (BDNF), another integral neurotrophin involved in myelination. The intricate signaling between neurotrophins and cytokines that governs myelin repair supports the role of NGF as a leading therapeutic candidate in white matter disorders, such as MS.

Evaluation of potential analgesic therapeutics and the elaboration of the neurobiology of pain have heavily relied on pain models developed in rodents. However, a limitation of rodents is their phylogenetic distance from humans, which could in part account for the failure of some preclinical findings to translate to clinical utility. By contrast, given their genetic closeness and phenotypic similarities to humans, it is suggested that there be greater utilization of non-human primates (NHP) in preclinical pain studies. Methods to induce chronic pain-like states and quantify changes in nociception that have been developed in rodents could be adapted to the NHP. Similarly, human experimental injury-induced sensitization, which attempts to temporarily mimic the neuropathology and symptoms observed in the chronic pain state, could be adapted to the NHP. The NHP could then serve as a platform to validate human experimental models as well as proof-of-concept studies. Beyond experimentally modeled pain states, a number of naturally occurring disease states, such as osteoarthritis, are expressed by NHP, which could be utilized for both hypothesis testing and proof-of-concept studies. While NHP studies are logistically cumbersome, it is envisioned that NHP pain models will add value to current preclinical data and greatly facilitate the discovery of novel analgesic treatments.

The blood-brain barrier significantly impedes treatment of central nervous system disorders by preventing drug entry into the brain. Several strategies have been developed to overcome this problem, but progress has been hampered due to a lack of efficacious drug delivery systems (DDS). Now, owing to DDS, therapeutic compounds can be transported to the site of action and accumulate there. This modern approach allows one to decrease the required dose of drug and, therefore, minimize toxicity and side effects. Also, treatment efficiency is increased. Highly organized nanostructures made of biological, polymeric or carbon-based materials are promising carriers in drug delivery to the brain, due to their unique and easily tailorable properties. The drug can be either attached to or entrapped in a carrier. To achieve greater site specificity and selectivity, DDS can be also modified with suitable ligands, providing identification of the molecular site of action. This review illustrates recent advances in using highly-organized structures: dendrimers, fullerenes, liposomes, micelles, nanogels, nanoparticles and nanotubes for this purpose. We also discuss advantages and limitations of each system.