CNS & neurological disorders drug targets

Publications in this journal

• Article: N-3 (Omega-3) Polyunsaturated Fatty Acids in the Pathophysiology and Treatment of Depression: Pre-clinical Evidence.

  B Levant
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  ABSTRACT: Clinical and epidemiological evidence suggests that low dietary intake and/or tissue levels of n-3 (omega-3) polyunsaturated fatty acids (PUFA) are associated with depression. Animal studies indicate that low dietary and tissue levels of n-3 PUFA can lead to depression-associated behaviors and neurobiological effects, and can augment the effects of stress. Higher n-3 PUFA intake and tissue levels have the opposite effect. These findings support a role for decreased brain n-3 PUFAs in the multifactorial etiology of depression. In addition, these pre-clinical findings point to specific mechanisms through which n-3 PUFAs affect neurobiological substrates of depression including regulation of serotonergic and dopaminergic neurotransmission, hippocampal expression of brain-derived neurotrophic factor (BDNF), the hypothalamic-pituitary-adrenal axis, and neuroinflammation. This pre-clinical evidence for a role for n-3 PUFA in the pathophysiology and treatment of depression are reviewed. The implications of these finding for future pre-clinical research and clinical application are discussed.
  CNS & neurological disorders drug targets 04/2013;
• Article: G-Protein Signaling, Lipid Rafts and the Possible Sites of Action for the Antidepressant Effects of N-3 Polyunsaturated Fatty Acids.

  A H Cszysz, M M Rasenick
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  ABSTRACT: Dietary fish oil, a source of polyunsaturated fatty acids (n-3 PUFA), has become increasingly popular for antidepressant therapy, in part because about half of patients treated with conventional antidepressants either fail to remit or discontinue therapy due to side effects. The inception of n-3 PUFA as a putative depression therapeutic may have stemmed from reports suggesting that dietary n-3 PUFA deficiency is linked to both altered membrane PUFA content as well as clinical depression. Several studies have examined n-3 PUFA treatment in depression, either singly or in combination with conventional antidepressant drugs. While results have been encouraging, fish oil treatment remains controversial. At least some of the reason for this is the lack of a defined site of action for n-3 PUFA that would be consistent with an antidepressant effect. This review will address this issue. While it is possible, even likely, that n-3 PUFA have multiple sites of action, this chapter will focus on sites at which n-3 PUFA modify G protein signaling and how those sites relate to both depression and antidepressant action. Much of the focus herein will be on specialized membrane domains (lipid rafts) and the effects that agents modifying those rafts have on elements of G protein signaling cascades. The relevance of specific alterations of G protein signaling for both depression and antidepressant action will be discussed, as will the ability for n-3 PUFA to act either as an antidepressant or in concert with conventional antidepressants.
  CNS & neurological disorders drug targets 04/2013;
• Article: Towards Environmental Construct Validity in Animal Models of CNS Disorders: Optimizing Translation of Preclinical Studies.

  E L Burrows, A J Hannan
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  ABSTRACT: There is an enormous demand for new therapeutic interventions for a range of major disorders. The majority of clinical trials in recent years have been unsuccessful despite highly promising preclinical data. Therefore, an urgent issue confronting both the academic and commercial medical research sectors is how to optimize translation of preclinical studies. The vast majority of preclinical studies are currently performed using laboratory mice and rats. We will discuss the various opportunities for optimization of animal models of CNS disorders. One limitation of current approaches is that most studies are conducted on sedentary, unstimulated animals with unlimited access to food in the home cage, thus leading to metabolic and physiological compromise. Environmental enrichment, which enhances sensory stimulation, cognitive activity and physical exercise, has been demonstrated to induce dramatic effects on brain and behavior in both wild-type and genetically modified rodent models, relative to standard-housed littermate controls. Environmental enrichment also exerts beneficial effects outside the CNS, such as a reduction in excess body fat. We propose that therapeutic interventions which are found to show promise in standard-housed preclinical models should be subsequently tested under conditions of greater environmental enrichment to identify therapeutics which continue to show efficacy in housing contexts of superior 'environmental construct validity'. Other possible approaches to optimize the quality, validity and reporting of preclinical studies in animal models are also discussed.
  CNS & neurological disorders drug targets 04/2013;
• Article: Commentary: Linking Productive Autophagy to Neuroprotection: Potential Implications for Anti-ischemic Therapy.

  S Sugunan, G K Rajanikant
  CNS & neurological disorders drug targets 04/2013;
• Article: Frailty among Alzheimer's Disease Patients.

  G Koch, L Belli, T L Giudice, F Di Lorenzo, G M Sancesario, R Sorge, S Bernardini, A Martorana
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  ABSTRACT: Alzheimer's disease (AD) is strictly connected with aging and frailty. Although dementia contributes to frailty, it is not well established whether AD patients could be per se defined "frail". At the same time, it is not known whether among AD patients, which are a heterogeneous group of patients, it is possible to identify a subgroup of frail individuals. In this work we sought indices useful to identify "the frail AD". To do this we evaluated disease progression rate and response to pharmacological treatment (Mini Mental State Examination evaluation), cerebrospinal fluid biomarkers (amyloid-β42, total-tau and phospho-tau) levels, inflammatory indices (serum c-reactive protein, fibrinogen, D-Dimers) in a group of patients with a diagnosis of probable AD. Our results describe the clinical profile of patients which could be considered as non-responders and rapidly progressive AD. In the absence of other indices we conclude that patients with these features could well be considered "frail" among AD.
  CNS & neurological disorders drug targets 04/2013;
• Article: Omega-3 Fatty Acids and Hippocampal Neurogenesis in Depression.

  J X Kang, E D Gleason
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  ABSTRACT: The mammalian brain and central nervous system are especially dependent on the omega-3 (n-3) fatty acid docosahexaenoic acid (DHA) for normative signaling and function, and research suggests that n-3 fatty acid deficiencies are one contributing factor in the increasing prevalence of depressive disorders. However, the reasons for which n-3 fatty acids and mood are connected remain unknown. Atrophy in the hippocampus is one of the most significant neuroanatomical findings in depressed patients, and current therapies for depression tend to increase hippocampal neurogenesis. We recently discovered that the fat-1 transgenic mouse, which has enriched levels of DHA in the brain because it can convert n-6 to n-3 fatty acids, exhibits increased hippocampal neurogenesis. This finding suggests a mechanism by which omega-3 could influence depression and mood; here we expand on the argument that n-3 fatty acids, and DHA in particular, may help prevent and treat depression by virtue of their effects on neurogenesis in the hippocampus. Because DHA can be obtained through the diet, increasing DHA intake in depressed patients or those at risk for depression may be one way of managing the disease and perhaps providing aid to those who have not been able to achieve remission via pharmacological means.
  CNS & neurological disorders drug targets 04/2013;
• Article: Sundowning Syndrome: A Possible Marker of Frailty in Alzheimer's Disease?

  D Ferrazzoli, F Sica, G Sancesario
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  ABSTRACT: The term "sundowning" describes a clinical phenomenon characterized by late afternoon exacerbation of behavioural symptoms in dementia. Beyond this clinical definition, the debate around this concept is not properly solved, because many authors define it in different ways, mentioning various hypothetical etiological explanations. It represents a concrete problem, which is difficult to manage for physicians and caregivers, and is probably linked to various biological, psychological and social aspects. As recently reported, the sundowning phenomenon is a predictor of faster cognitive decline in Alzheimer's disease, and as such can represent a possible marker of frailty in this illness. This article presents an overview of the biological understanding and possible pharmacological and non-pharmacological treatment of this condition.
  CNS & neurological disorders drug targets 04/2013;
• Article: Development and Significance of the Frailty Concept in the Elderly: A Possible Modern View.

  D Ferrazzoli, G Sancesario
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  ABSTRACT: Significance of the frail person concept is discussed in this article. Historical view is proposed by authors to better understand its real impact in medicine and in particular in neurology and geriatrics.
  CNS & neurological disorders drug targets 04/2013;
• Article: How Natural is it for Nature to Help with Major Depressive Disorder?

  J M Witkin, X Li
  CNS & neurological disorders drug targets 04/2013;
• Article: Neuropeptide Systems and Schizophrenia.

  A L Lacrosse, M F Olive
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  ABSTRACT: Schizophrenia affects approximately 1% of the world population, and the majority of pharmacologically based treatments for this disorder are ligands that interact with monoaminergic transmission. However, there is a wealth of evidence that various neuropeptides are often co-released with monoamine neurotransmitters, and that ligands acting at neuropeptide receptors modulate monoaminergic transmission as well as schizophrenia-related behaviors in preclinical animal models. Such neuropeptide systems include neurotensin, cholecystokinin, corticotropin releasing factor, neuropeptide Y, oxytocin, opioid peptides, tachykinins, thyrotropin-releasing hormone, and orexins. The purpose of this review will be to summarize the existing preclinical and clinical literature on the role of various neuropeptide systems as modulators of schizophrenia-related behaviors, and the potential of targeting these systems for the development of novel antipsychotic medications.
  CNS & neurological disorders drug targets 04/2013;
• Article: Up-Regulation of TLR-4 in the Brain after Ischemic Kidney- Induced Encephalopathy in the Rat.

  M Salama, S M Farrag, S A Abulasrar, M M Amin, A A Ali, H Sheashaa, M Sobh, O Arias-Carrión
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  ABSTRACT: Ischemic acute kidney injury (AKI) is usually accompanied by neuroinflammation-induced encephalopathy. However, the specific mechanism remains unclear. Toll-like receptors (TLR), specifically TLR-4 has been linked to ischemic reperfusion injury in different organs like kidney, brain and liver. Here, we induced an ischemic reperfusion kidney injury in Sprague Dawley rats. All animals were evaluated using behavioral tests which revealed locomotor activity and motor disturbances in the AKI group. The brains were then examined by immunostaining with ionized calcium binding adaptor molecule 1 (microglial marker) and TLR-4 antibodies. The histological analysis revealed significant up-regulation of TLR-4 in the hippocampus and striatum in the AKI group. These data demonstrate for the first time, the triggering effect of TLR-4 on AKI-induced neuroinflammation in the brain that may lead to AKI-induced encephalopathy. This would also generate a novel hypothesis that using TLR blockers may have a role in preventing AKI effects on the brain.
  CNS & neurological disorders drug targets 04/2013;
• Article: Astrocyte-Microglia Cooperation in the Expression of a Pro-Inflammatory Phenotype.

  M Barbierato, L Facci, C Argentini, C Marinelli, S D Skaper, P Giusti
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  ABSTRACT: Glial cells not only serve supportive and nutritive roles for neurons, but also respond to protracted stress and insults by up-regulating inflammatory processes. The complexity of studying glial activation in vivo has led to the widespread adoption of in vitro approaches, for example the use of the bacterial toxin lipopolysaccharide (LPS, a ligand for toll-like receptor 4 (TLR4)) as an experimental model of glial activation. Astrocyte cultures frequently contain minor numbers of microglia, which can complicate interpretation of responses. In the present study, enriched (<5% microglia) astrocytes cultured from neonatal rat cortex and spinal cord were treated with the lysosomotropic agent L-leucyl-L-leucine methyl ester to eliminate residual microglia, as confirmed by loss of microglia-specific marker genes. L-Leucyl-L-leucine methyl ester treatment led to a loss of LPS responsiveness, in terms of nitric oxide and cytokine gene up-regulation and mediator (pro-inflammatory cytokines, nitric oxide) output into the culture medium. Surprisingly, when astrocyte/microglia co-cultures were then reconstituted by adding defined numbers of purified microglia to microglia-depleted astrocytes, the LPS-induced up-regulation of pro-inflammatory gene and mediator output far exceeded that observed from cultures containing the same numbers of microglia only. Similar behaviors were found when examining interleukin-1β release caused by activation of the purinergic P2X7 receptor. Given that astrocytes greatly outnumber microglia in the central nervous system, these data suggest that a similar interaction between microglia and astrocytes in vivo may be an important element in the evolution of an inflammatory pathology.
  CNS & neurological disorders drug targets 04/2013;
• Article: Conference Report: 3rd GTC Congress Report on Ubiquitin & Drug Discovery Feb 25-26, Palms Casino Resort, Las Vegas, NV, USA.

  H S Sharma, A Sharma
  CNS & neurological disorders drug targets 04/2013;
• Article: Nicotinic Receptors as Therapeutic Targets for Drug Addictive Disorders.

  S Rahman
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  ABSTRACT: Drug addiction is a chronic neuropsychiatric disorder which is characterized by a compulsion to take drugs and loss of control in limiting intake. The worldwide impact of drug addiction on morbidity and mortality is very high. Evidence from preclinical and clinical studies suggests that brain nicotinic acetylcholine receptors (nAChRs), play a critical role in various addictive disorders, including nicotine addiction and alcoholism. Thus, there is an increasing impetus in developing new therapeutics for addictive disorders by targeting brain nAChRs. This review highlights the important preclinical findings involving nAChR ligands in regulating nicotine, alcohol and other addictive drug-induced neurobiological changes in animal models and humans. A number of partial agonists or antagonists targeting nAChRs have shown therapeutic benefit in nicotine addiction and alcohol use disorders are also discussed. Furthermore, the role of nAChRs in other addictive disorders is reviewed. Overall, novel pharmacological agents that target brain nAChRs for future drug development are discussed.
  CNS & neurological disorders drug targets 04/2013;
• Article: Ageing as a Trait de Union Between Diabetes and Dementia for Frailty.

  R Semprini, M Ragonese, M Poggi, A Franzè, A Martorana
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  ABSTRACT: A frail patient is one who carries a sum of poly-pathologies, whose co-existence may shorten his life expectation. Diabetes mellitus type 2 and metabolic syndrome play a substantial role in it, but dementia has increasingly risen in importance. Interestingly, the insulin pathway was suggested to be responsible for the metabolic cascade that leads to amyloid-beta deposit and pathology. Nevertheless, a clear relationship between them was just experimentally, rather than clinically demonstrated. In this work the authors suggest a possible link between insulin, diabetes and Alzheimer's disease, whose co-existence could be responsible for physical and cognitive decline but not for frailty. We suggest that these factors could be responsible for frailty only if senescence-associated.
  CNS & neurological disorders drug targets 04/2013;
• Article: Innate Immunity in Alzheimer's Disease: A Complex Affair.

  M V Guillot-Sestier, T Town
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  ABSTRACT: Alzheimer's disease (AD) is characterized by three major histopathological hallmarks: β-amyloid deposits, neurofibrillary tangles and gliosis. While neglected for decades, the neuroinflammatory processes coordinated by microglia are now accepted as etiologic events in AD evolution. Microglial cells are found in close vicinity to amyloid plaques and display various activation phenotypes determined by the expression of a wide range of cytokines, chemokines, and innate immune surface receptors. During the development of AD pathology, microglia fails to restrict amyloid plaques and may contribute to neurotoxicity and cognitive deficit. Nevertheless, under specific activation states, microglia can participate in cerebral amyloid clearance. This review focuses on the complex relationship between microglia and Aβ pathology, and highlights both deleterious and beneficial roles of microglial activation states in the context of AD. A deeper understanding of microglial biology will hopefully pave the way for next-generation AD therapeutic approaches aimed at harnessing these enigmatic innate immune cells of the central nervous system.
  CNS & neurological disorders drug targets 04/2013;
• Article: mGlu2/3 Agonist-Induced Hyperthermia: An in Vivo Assay for Detection of mGlu2/3 Receptor Antagonism and its Relation to Antidepressant-Like Efficacy in Mice.

  S D Gleason, X Li, I A Smith, J D Ephlin, X S Wang, B A Heinz, J H Carter, M Baez, J Yu, D M Bender, J M Witkin
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  ABSTRACT: An assay to detect the on-target effects of mGlu2/3 receptor antagonists in vivo would be valuable in guiding dosing regimens for the exploration of biological effects of potential therapeutic import. Multiple approaches involving blockade of mGlu2/3 receptor agoinist-driven behavioral effects in mice and rats were investigated. Most of these methods failed to provide a useful method of detection of antagonists in vivo (e.g., locomotor activity). In contrast, the mGlu2/3 receptor agonist LY379268 produced dose-dependent increases in body temperature of mice. The hyperthermic effects of LY379268 was abolished in mGlu2 and in mGlu2/3 receptor null mice by not in mGlu3 null mice. Hyperthermia was not produced by an mGlu8 receptor agonist. Agonist-induced hyperthermia was prevented in a dose-dependent manner by structurally-distinct mGlu2/3 receptor antagonists. The blockade was stereo-specific. Moreover, this biological readout was responsive to both orthosteric and to negative allosteric modulators of mGlu2/3 receptors. Antagonism of agonist-induced hyperthermia predicted antidepressant-like efficacy in the mouse forced swim test. As with the hyperthermic response, the antidepressant-like effects of mGlu2/3 receptor antagonists were shown to be due to mGlu2 and not to mGlu3 or mGlu8 receptors through the use of receptor knock-out mice. The ability to rapidly assess on-target activity of mGlu2/3 receptor antagonists enables determination of parameters for setting efficacy doses in vivo. In turn, efficacy-related data in the preclinical laboratory can help to set expectations of therapeutic potential and dosing in humans.
  CNS & neurological disorders drug targets 04/2013;
• Article: Further Evaluation of the Neuropharmacological Determinants of the Antidepressant-Like Effects of Curcumin.

  J M Witkin, S Leucke, L K Thompson, R A Lynch, C D Ding, B Heinz, J T Catlow, S D Gleason, X Li
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  ABSTRACT: Curcumin, the major constituent of the spice tumeric produces a plethora of biological actions that have translated in vivo into behavioral and neurochemical effects in rodents that are also produced by clinically-used antidepressants. The present study was designed to provide a systematic replication of prior behavioral, pharmacological, and neurochemical experiments. In particular, the ability of curcumin to engender ani-immobility effects in the mouse forced-swim assay was established. Although prior work had shown curcumin to function as an inhibitor of the monoamine metabolizing enzyme, monoamine oxidase (MAO), neither MAOA nor MAOB was inhibitied by curcumin in the present study. Curcumin had also been reported previously to function as a cannabinoid CB1 receptor inverse agonist/antagonist. However, in our hands, curcumin did not potently alter GTP--35S binding indicative of functional CB1 antagonism (Kb = 2080 nM). Moreover, curcumin was not able to prevent the hypothermic effects of the cannabinoid receptor agonist (-)-cis-3-[2-Hydroxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3-hydroxypropyl)cyclohexanol (CP 55,940). Nonetheless, the anti-immobility effects of curcumin did not occur in CB1 -/- mice. Finally, a broad array of protein receptors and enzymes were evaluated in vitro for their potential interaction with and/or functional engagement with curcumin. Of the more than 100 targets screened, curcumin had very low potency in most. Of those targets with appreciable activity, curcumin had affinities for the human cloned muscarinic receptor subtypes (Ki = 1.3-3.1 uM). Moreover, the plasma and brain levels of curcumin at behaviorally-active doses were below quantitative limits. Given these findings, it is concluded that the prominent antidepressant-like behavioral effects of curcumin, replicated here and in multiple acute and chronic rodent models detailed in the literature, are the result of as yet undisclosed mechanisms of action. The scientific and patient communities await the full scale clinical evaluation of a sufficiently bioavailable curcumin analog in major depressive disorder.
  CNS & neurological disorders drug targets 04/2013;
• Article: Strength and Weaknesses of Cerebrospinal Fluid Biomarkers in Alzheimer's Disease and Possible Detection of Overlaps with Frailty Process.

  A Stefani, E Olivola, M S Bassi, V Pisani, P Imbriani, A Pisani, M Pierantozzi
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  ABSTRACT: With the increase of human lifespan and refinement of diagnostic techniques dementia, and Alzheimer's disease (AD) in particular, have become a multi-decade process with a complex pathogenesis. The prognosis of AD patients, especially in late stages, may be strongly influenced by factors that go far beyond the well-recognized cascades (tau deposition, amyloid plaques). In this context, AD and Frailty, a multidimensional process of the elderly, inevitably overlap. Not surprisingly, the routine biomarkers collectable in the cerebrospinal fluid, while highly relevant in allowing specific diagnoses, becoming limiting when used to define severity and rate of progression of cognitive impairment. In reviewing merits and pitfalls of routine cerebrospinal fluid profile for AD, this manuscript will examine the state-of-the-art related to a parallel field, the extrapyramidal disorders. For synucleinopathies, we will discuss the possibility to detect factors directly involved in earliest disease pathology (alpha-synuclein, tau-proteins) together with indexes of disease progression (i.e. dopamine-metabolite ratio and loss of blood-brain barrier integrity). This approach might guarantee the capability of monitoring putative disease-modifying strategies. However, we will show the likelihood that non-conventional approaches already proposed for Frail subjects (such as exercise-mediated neuro-protection) might prove to be a useful aid for an ageing brain already impaired by AD alterations. A crucial test for these hypotheses would be to apply this sort of interventional, and not merely pharmacological, therapy to homogeneous patient cohorts.
  CNS & neurological disorders drug targets 04/2013;
• Article: Co-Enzyme Q10 to Treat Neurological Disorders: Basic Mechanisms, Clinical Outcomes, and Future Research Direction.

  M Salama, T F Yuan, S Machado, E Murillo-Rodríguez, J A Vega, M Menéndez-González, A E Nardi, O Arias-Carrión
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  ABSTRACT: Coenzyme Q10 (CoQ10) plays a pivotal role in mitochondrial respiratory chain which is the cell power supply. CoQ10 serves as a physiological electron (e-) shuttle from complexes I and II to complex III, as well as a potent antioxidant. Neurons are characterized by high rates of metabolic activity and need to respond promptly to activity-dependent fluctuations in bioenergetic demand. Consequently, it is not surprising that mitochondrial alterations can promote neuronal dysfunction and degeneration. In several neurological disorders, dysfunction of the respiratory chain leads to reduced ATP levels and increased generation of reactive oxygen species. CoQ10 supplementation has been widely used to treat aging, stroke, neuromuscular diseases, Parkinson's disease, Alzheimer's disease, progressive supranuclear palsy, autosomal recessive cerebellar ataxias, amyotrophic lateral sclerosis and Huntington's disease. Here we discuss a large number of preclinical and clinical trials for CoQ10. The mechanisms underlying the disease-modifying effects of CoQ10 are the principle subject of the current integrative review. The rational applications as a therapeutic agent in neurological disorders are discussed.
  CNS & neurological disorders drug targets 04/2013;