CNS & Neurological Disorders - Drug Targets (Formerly Current Drug Targets - CNS & Neurological Disorders) - Volume 12, Issue 4, 2013

A growing literature suggests the association of low tissue levels and/or dietary intake of n-polyunsaturated fatty acids (PUFA) with depressive illnesses. Animal studies show that low tissue and/or dietary n-3 PUFAs can lead to behaviors and neurobiological effects associated with depression and can potentiate the consequences of stress, whereas higher levels have the opposite effect. These data support the involvement of n-3 PUFAs levels in the disease processes underlying depression. In addition, these pre-clinical findings indicate neurobiological mechanisms whereby n-3 PUFAs may contribute to the disease including control of serotonergic and dopaminergic function, modulation of brain-derived neurotrophic factor (BDNF) in the hippocampus, regulation of the hypothalamic-pituitary-adrenal axis, and effects on neuroinflammation. This evidence for a role for n-3 PUFA in the pathophysiology and treatment of depressive illness are reviewed. The implications of these finding for future pre-clinical research and clinical application are discussed.

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.

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.

Extracts of Hypericum perforatum (St. John's wort) have gained popularity as an alternative to synthetic antidepressants or behavioural therapy in the treatment of mild to moderate forms of depressive disorders. The present article reviews and discusses the available preclinical data that are in favour of or against the use of Hypericum perforatum as an antidepressant. Multiple chemical entities constitute extracts from Hypericum perforatum. The effects of Hypericum perforatum extracts have been compared with those of conventional antidepressants in different in vitro and in vivo biochemical studies of antidepressant-like activity and in behavioural pharmacology studies using animal models of depression. Recent investigations have indicated that Hypericum perforatum, like conventional antidepressants, is involved in the regulation of genes that control hypothalamic-pituitary-adrenal axis function and influence, at least in part, stress-induced effects on neuroplasticity and neurogenesis. From the available evidence it can be concluded that data supporting the use of Hypericum perforatum for the treatment of depression are present in literature. However, results from experiments carried out with extracts or pure compounds do not always resemble biochemical and pharmacological profile characteristic of synthetic antidepressants. In particular, the majority of findings in preclinical studies have been obtained with high doses of pure compounds and extracts that are not comparable to the concentrations of single active constituents after oral administration in humans.

The root extract, curcumin (diferuloylmethane), is a constituent of the ancient herbal medicine Jiawei-Xiaoyaosan that has been used for dyspepsia, stress, and mood disorders. Curcumin engenders a diverse profile of biological actions that result in changes in oxidative stress, inflammation, and cell-death pathways. Combined with its historical use in medical practice and its safety profile, curcumin has been studied for its potential therapeutic applications in cancer, aging, endocrine, immunological, gastrointestinal, and cardiac diseases. In addition, data in animal models and in humans have also begun to be collected in stroke, Alzheimer’s disease, and Parkinson’s disease. A compelling new body of literature is also mounting to support the efficacy of curcumin in stress and mood disorders. Current understanding of the biological basis for antidepressant-relevant biochemical and behavioral changes shows convergence with some mechanisms known for standard antidepressants. In addition, the mechanisms of the antidepressant-like pharmacology of curcumin also appear to overlap with those of other disease states. Thus, ancient wisdom might be built into this interesting and newly-appreciated natural molecule. Although curcumin is a primary ingredient in anti-aging pills, cosmetic creams, eye treatments, diet products, etc, a key hurdle to the development of curcumin for disease treatment and prevention is overcoming its low oral bioavailability. Although multiple approaches to this problem are being examined, a solution to the bioavailability issue will be needed to ensure appropriate tissue exposures of curcumin in clinical investigation. Progress in this regard is underway.

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 anti-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-γ-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.

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.

While many studies have investigated electroencephalographic (EEG) features of dementia, few have analysed the relationship between EEG and cerebrospinal fluid biomarkers in cognitive impairment. Seizures are frequently observed at the end stage of Alzheimer disease, and experimental animal studies support the view that epileptiform activity may contribute to the cognitive decline. In this paper, after reviewing literature findings concerning the role of EEG in dementia, we show the preliminary results of our study aimed to correlate the presence of epileptiform EEG patterns with cerebrospinal fluid biomarkers in order to better define the prognosis of dementia. Our study shows a clear relationship between phospho-tau protein levels and epileptiform EEG pattern. This finding seems to suggest in humans the observation made in animal models that not only β-amyloid protein, but also tau and phospho-tau proteins, are involved in the aberrant regulation of neural transmission possibly contributing to EEG deterioration, cognitive decline and worse prognosis. On the basis of the relationship between phospho-tau protein, cognitive decline and epileptogenicity we suspect that high liquoral phospho-tau levels and epileptiform EEG pattern may provide an early identification of patients with dementia and/or represent an aggressive phenotype of dementia. We propose that qualitative EEG analysis integrated with cerebrospinal biomarkers may be extensively used to better define dementia.

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.

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.

Frailty is an evolving concept that is generally defined in biomedical or psychosocial terms. It is not necessarily related to a specific single disease process. Passing by the theories of Selye (1936) on the exhaustion of the General Adaptation Syndrome,until reaching to the studies of Fried (2001) who, firstly, proposed diagnostic criteria for frailty, in this paper are explored different ways to understand this concept, until endeavour to give a possible modern view. The definition of a frailty syndrome characterized by a multi-system reduction in ?reserve capacity? remains widely accepted.

Different courses of Alzheimer disease are observed in clinical practice. The rapidly progressive form could be associated with the presence of a major microcirculatory involvement and hemodynamic insufficiency. This short review aims to provide an overview of the current knowledge of cerebrovascular contribution to Alzheimer disease presentation and progression, hypothesizing the possible vascular markers of rapidly progressive form.

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-theart 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 nonconventional 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.