Role of Wnt Signaling in the Control of Adult Hippocampal Functioning in Health and Disease: Therapeutic Implications

It is well recognized the role of the Wnt pathway in many developmental processes such as neuronal maturation, migration, neuronal connectivity and synaptic formation. Growing evidence is also demonstrating its function in the mature brain where is associated with modulation of axonal remodeling, dendrite outgrowth, synaptic activity, neurogenesis and behavioral plasticity. Proteins involved in Wnt signaling have been found expressed in the adult hippocampus suggesting that Wnt pathway plays a role in the hippocampal function through life. Indeed, Wnt ligands act locally to regulate neurogenesis, neuronal cell shape and pre- and postsynaptic assembly, events that are thought to underlie changes in synaptic function associated with long-term potentiation and with cognitive tasks such as learning and memory. Recent data have demonstrated the increased expression of the Wnt antagonist Dickkopf-1 (DKK1) in brains of Alzheimer´s disease (AD) patients suggesting that dysfunction of Wnt signaling could also contribute to AD pathology. We review here evidence of Wnt-associated molecules expression linked to physiological and pathological hippocampal functioning in the adult brain. The basic aspects of Wnt related mechanisms underlying hippocampal plasticity as well as evidence of how hippocampal dysfunction may rely on Wnt dysregulation is analyzed. This information would provide some clues about the possible therapeutic targets for developing treatments for neurodegenerative diseases associated with aberrant brain plasticity.     

Mitochondrial dysfunction and neuroinflammation in Parkinson disease

Parkinson disease(PD) is an age-related neurodegenerative disease. Wide spread α-synuclein aggregation and progressive loss of dopaminergic(DA) neurons in the substantia nigra are major neuropathological hallmarks of PD. The molecular mechanisms are not well understood. In recent years, mitochondrial dysfunctionis considered to play a central role in pathogenesis and progression of PD. The parkinsonian toxins(MPTP/MPP+and rotenone)have been reported to inhibit mitochondrial complex I and lead to disturbed oxidative phosphorylation and mitochondrial dynamics, increased reactive oxygen species(ROS) production and reduced mitochondrial membrane potential, thus causing DA neuron degeneration. Mitochondrial dysfunction was also shown to elicit the aggregation of α-synuclein, which in turn interfered with mitochondrial function in a vicious cycle. In sensitive neurons, all these intracellular changes may be devastating for cell survival. On the other hand, inflammasome activation is identified as pivotal inflammatory mechanism that drives progressive DA neuropathology. Inflammasome is intracellular multiprotein complex that can be activated to trigger caspase-1 cleavage in response to neurotoxic insults. Cleaved caspase-1 further promotes the maturation of the proinflammatory cytokines, and thereby results in neuroinflammation and neuronal death. Patients with PD and preclinical PD models showed extensive activation of microglial NLRP3 inflammasome. Targeting NLRP3 inflammasome has been regarded as a potential therapeutic strategy in PD. Moreover, α-synuclein is strongly linked to inflammasome activation. NLRP3 inflammasome activation by pathological α-synuclein fibrils in mouse microglia resulted in a delayed but substantial release of cleaved IL-1β, but not IL-18. NLRP3 inhibitor abolished fibrillar α-synuclein-induced NLRP3 inflammasome activation in vitro. Inhibition of inflammasome by NLRP3 inhibitor significantly ameliorated nigrostriatalα-synuclein pathology, DA neoron degeneration and motor deficits in multiple rodent PD models. These findings suggest a bi-directional relationship between microglial inflammation and neuronal α-synuclein pathology. Roles of caspase-1 and inflammasome in α-synuclein aggregation and cell death were also reported in neuronal M17-a Syn cells. Furthermore, accumulating experimental evidence supports a complex association between mitochondria and neuroinflammation in PD. In complex I inhibitory pesticides-related PD, mitochondrial dysfunction and oxidative stress induced neuroinflammation via microglial NLRP3-dependent pathways. Mitochondria-targeted antioxidant ameliorated both mitochondrial oxidative stress and NLRP3 inflammasome activation, suggesting probable upstream role of mitochondria in inflammasome activation. This result is confirmed by two in vivo studies indicating mitochondrion-driven activation of NLRP3 inflammasome and neurotoxicity in rotenone and Mito Park mouse models of PD. Conversely, inflammatory mediators produced by activated microglia can strongly affect mitochondrial oxidative phosphorylation and ROS production, eventually leading to neurodegeneration. Additionally,functional mitophagy was shown to be vital for mitochondrial quality control. When mitophagy was impaired due to some reasons such as mutation in PD-associated genes PINK1 and parkin, accumulation of dysfunctional or damaged mitochondriamay be responsible for neuroinflammation and neurodegeneration. Collectively, the available data highlight the roles of mitochondria dysfunction and neuroinflammation in neurodegeneration of PD.Identifying crosstalk and interaction among mitochondria impairment, neuroinflammation and neurodegeneration may provide insights into the pathogenesis and eventually develop novel therapeutic approaches against PD.     

Personality pathology,depression and HPA axis functioning

Hypothalamic pituitary adrenal (HPA) axis functioning, as measured by the dexamethasone suppression test (DST), has been extensively investigated in major depressive disorder (MDD). Evaluating DST response in MDD patients while simultaneously considering clinically relevant personality disorders may further clarify the contribution of both personality pathology and HPA axis function to depressive symptoms. The present study measured personality pathology by administering the revised version of the Millon Clinical Multiaxial Inventory (MCMI-II) in a sample of 25 patients diagnosed with MDD. Analyses revealed that suppressors (n = 19) scored significantly higher than non-suppressors (n = 6) on six of the 13 MCMI-II personality disorder scales: Avoidant, Schizoid, Self-Defeating, Passive-Aggressive, Schizotypal and Borderline. Increased personality pathology was associated with normal suppression of cortisol following the DST. This suggests that suppression of the DST may be associated with depressive states linked with personality pathology while the more biologically based depression is associated with abnormal HPA pathophysiology. Copyright 2001 John Wiley & Sons, Ltd.     

Neurobiological and clinical effects of the antidepressant tianeptine

The precise neurobiological processes involved in depression are not clear, but it is recognized that numerous factors are involved, including changes in neurotransmitter systems and brain plasticity. Neuroplasticity refers to the ability of the brain to adapt functionally and structurally to stimuli. Impairment of neuroplasticity in the hippocampus, amygdala and cortex is hypothesized to be the mechanism by which cognitive function, learning, memory and emotions are altered in depression. The mechanisms underlying alterations in neuroplasticity are believed to relate to changes in neurotransmitters, hormones and growth factors. Structural changes in the hippocampus that have been proposed to be associated with depression include dendritic atrophy, reduced levels of cerebral metabolites, decreased adult neurogenesis (generation of new nerve cells) and reduced volume. Increased dendritic branching occurs in the basolateral nucleus of the amygdala. Reduced neuronal size and glial cell density occur in the prefrontal cortex. Clinically, tianeptine is an antidepressant effective in reducing symptoms of depression in mild to moderate-to-severe major depression, including over the long term. Tianeptine is also effective in alleviating the symptoms of depression-associated anxiety. It is generally well tolerated, with little sedation or cognitive impairment. The efficacy profile of tianeptine could be explained by its neurobiological properties observed in animal models. Tianeptine prevents or reverses stress-associated structural and cellular changes in the brain and normalizes disrupted glutamatergic neurotransmission. In particular, in the hippocampus, it prevents stress-induced dendritic atrophy, improves neurogenesis, reduces apoptosis and normalizes metabolite levels and hippocampal volume. Tianeptine also has beneficial effects in the amygdala and cortex and can reverse the effects of stress on neuronal and synaptic functioning. The neurobiological properties of tianeptine may provide an explanation not only for its antidepressant activity, but also for its anxiolytic effects in depressed patients and its lack of adverse effects on cognitive function and memory.     

Membrane lipids as therapeutic targets for Parkinson’s disease: a possible link between Lewy pathology and membrane lipids

Introduction: Pathologically, Parkinson’s disease (PD) is characterized by nigral cell loss and Lewy pathology in the remaining neurons. Whereas the motor symptoms of PD show a marked response to dopamine replacement therapy, many of the non-motor symptoms are resistant to treatment. This suggests that in addition to nigral cell loss, widespread Lewy pathology in the nervous system is associated with the manifestations of PD.

Areas covered: Although the mechanism of Lewy body formation remains largely unknown, it is becoming clear that changes in the behavior of α-synuclein are critical in this process. α-Synuclein behaves differently depending on the lipid composition of membranes with which it interacts; therefore, one can postulate that the altered lipid composition of neuronal membranes may lead to Lewy pathology. The lipid composition of cellular membranes is consistently altered in the brains of patients with PD, and Lewy pathology is a common feature of several human lipidoses with mutations in enzymes that affect membrane lipids. This further supports the concept that alterations in the membrane lipids of neurons are central to Lewy pathology.

Expert opinion: This concept provides a new platform to establish models for the development of novel treatments for PD.     

Cytokine-induced changes in mood and behaviour: implications for 'depression due to a general medical condition', immunotherapy and antidepressive treatment

Several lines of evidence indicate that cytokine-mediated communication pathways between the immune system and the brain are involved in the pathophysiology of depression: (1) . Depression is highly prevalent in various medical conditions, including infectious, autoimmune and neurodegenerative diseases. This clinical association cannot be attributed solely to psychological distress, and it probably reflects direct activation of illness-induced physiological processes. (2). Experiments in humans and in animals demonstrate that exposure to cytokines induces depressive-like mood and behavioural alterations. (3). Cytokine immunotherapy in cancer and hepatitis patients elicits a major depressive episode in a large percentage of the patients. (4). Several types of depression that are not directly associated with a physical disease (e.g. major depression, melancholia, dysthymia) were also associated with cytokine hypersecretion. (5). Antidepressant drugs possess anti-inflammatory characteristics, which may partly account for their therapeutic effect. Congruently, antidepressants were found to reverse cytokine-induced major depression in humans and depressive-like behaviours in animals. (6). Cytokines affect brain systems that were implicated in the aetiology of depression, including the hypothalamus-pituitary-adrenal axis and monoaminergic systems. These conclusions strongly suggest that during medical conditions elevated levels of cytokines directly contribute to the induction of depression. Therefore, illness-associated depression should not be underestimated (in terms of prevalence and severity), and should be treated with antidepressant drugs, which may act on the specific physiological mechanisms of this disorder.     

Agonism of Peroxisome Proliferator Receptor-Gamma may have Therapeutic Potential for Neuroinflammation and Parkinson's Disease

Evidence suggests inflammation, mitochondria dysfunction, and oxidative stress play major roles in Parkinson's disease (PD), where the primary pathology is the significant loss of dopaminergic neurons in the substantia nigra (SN). Current methods used to treat PD focus mainly on replacing dopamine in the nigrostriatal system. However, with time these methods fail and worsen the symptoms of the disease. This implies there is more to the treatment of PD than just restoring dopamine or the dopaminergic neurons, and that a broader spectrum of factors must be changed in order to restore environmental homeostasis. Pharmacological agents that can protect against progressive neuronal degeneration, increase the level of dopamine in the nigrostriatal system, or restore the dopaminergic system offer various avenues for the treatment of PD. Drugs that reduce inflammation, restore mitochondrial function, or scavenge free radicals have also been shown to offer neuroprotection in various animal models of PD. The activation of peroxisome proliferator receptor- gamma (PPAR-gamma ) has been associated with altering insulin sensitivity, increasing dopamine, inhibiting inflammation, altering mitochondrial bioenergetics, and reducing oxidative stress - a variety of factors that are altered in PD. Therefore, PPAR-gamma activation may offer a new clinically relevant treatment approach to neuroinflammation and PD related neurodegeneration. This review will summarize the current understanding of the role of PPAR-gamma agonists in neuroinflammation and discuss their potential for the treatment of PD.     

Cytokines in dementias

Knowledge regarding putative inflammatory component(s) participating in Alzheimer's disease (AD) and in vascular dementia (VAD) remains scarce. Recently, we have demonstrated the presence of inflammatory components, such as cytokines, in the CSF of demented patients. Although the initial events triggering the neurodegenerative processes in AD versus VAD may be different and thus lead to different neuropathological outcome, they may initiate a similar cascade of cytokine production in response to neuronal injury. The cytokines released in the CNS may in turn, act in a similar manner in both diseases, amplifying certain pathological changes such as amyloidogenesis and amyloid accumulation in the blood vessels, white matter lesions and angiogenesis. This hypothesis is supported by clinical studies demonstrating the presence of white matter infarcts and cerebrovascular pathology in patients with AD as well as the presence of senile plaques in patients with VAD. This review will focus on the production of pro-inflammatory and anti-inflammatory cytokines in dementia, and their putative role for glia cell activation, amyloidogenesis, vascular changes, white matter damage and neurodegeneration.     

Fluoxetine prevents MPTP-induced loss of dopaminergic neurons by inhibiting microglial activation

Parkinson’s disease (PD) is characterized by degeneration of nigrostriatal dopaminergic (DA) neurons. Mice treated with MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) exhibit microglial activation-induced oxidative stress and inflammation, and nigrostriatal DA neuronal damage, and thus serve as an experimental model of PD. Here, we report that fluoxetine, one of the most commonly prescribed antidepressants, prevents MPTP-induced degeneration of nigrostriatal DA neurons and increases striatal dopamine levels with the partial motor recovery. This was accompanied by inhibiting transient expression of proinflammatory cytokines and inducible nitric oxide synthase; and attenuating microglial NADPH oxidase activation, reactive oxygen species/reactive nitrogen species production, and consequent oxidative damage. Interestingly, fluoxetine was found to protect DA neuronal damage from 1-methyl-4-phenyl-pyridinium (MPP⁺) neurotoxicity in co-cultures of mesencephalic neurons and microglia but not in neuron-enriched mesencephalic cultures devoid of microglia. The present in vivo and in vitro findings show that fluoxetine may possess anti-inflammatory properties and inhibit glial activation-mediated oxidative stress. Therefore, we carefully propose that neuroprotection of fluoxetine might be associated with its anti-inflammatory properties and could be employed as novel therapeutic agents for PD and other disorders associated with neuroinflammation and microglia-derived oxidative damage.     

Psychoneuroimmunology Meets Neuropsychopharmacology: Translational Implications of the Impact of Inflammation on Behavior

The potential contribution of chronic inflammation to the development of neuropsychiatric disorders such as major depression has received increasing attention. Elevated biomarkers of inflammation, including inflammatory cytokines and acute-phase proteins, have been found in depressed patients, and administration of inflammatory stimuli has been associated with the development of depressive symptoms. Data also have demonstrated that inflammatory cytokines can interact with multiple pathways known to be involved in the development of depression, including monoamine metabolism, neuroendocrine function, synaptic plasticity, and neurocircuits relevant to mood regulation. Further understanding of mechanisms by which cytokines alter behavior have revealed a host of pharmacologic targets that may be unique to the impact of inflammation on behavior and may be especially relevant to the treatment and prevention of depression in patients with evidence of increased inflammation. Such targets include the inflammatory signaling pathways cyclooxygenase, p38 mitogen-activated protein kinase, and nuclear factor-κB, as well as the metabolic enzyme, indoleamine-2,3-dioxygenase, which breaks down tryptophan into kynurenine. Other targets include the cytokines themselves in addition to chemokines, which attract inflammatory cells from the periphery to the brain. Psychosocial stress, diet, obesity, a leaky gut, and an imbalance between regulatory and pro-inflammatory T cells also contribute to inflammation and may serve as a focus for preventative strategies relevant to both the development of depression and its recurrence. Taken together, identification of mechanisms by which cytokines influence behavior may reveal a panoply of personalized treatment options that target the unique contributions of the immune system to depression.     

Anxiety in Parkinson's disease: a critical review of experimental and clinical studies

Parkinson's disease (PD) is the second most common neurodegenerative disorder affecting about 1% of the population older than 60 years. Classically, PD is considered as a movement disorder, and its diagnosis is based on the presence of a set of cardinal motor signs that are the consequence of a pronounced death of dopaminergic neurons in the substantia nigra pars compacta. There is now considerable evidence showing that the neurodegenerative processes leading to sporadic PD begin many years before the appearance of the characteristic motor symptoms, and that additional neuronal fields and neurotransmitter systems are also involved in PD, including olfactory structures, amygdala, caudal raphe nuclei, locus coeruleus, and hippocampus. Accordingly, adrenergic and serotonergic neurons are also lost, which seems to contribute to the anxiety in PD. Non-motor features of PD usually do not respond to dopaminergic medication and probably form the major current challenge in the clinical management of PD. Additionally, most studies performed with animal models of PD have investigated their ability to induce motor alterations associated with advanced phases of PD, and some studies begin to assess non-motor behavioral features of the disease. The present review attempts to examine results obtained from clinical and experimental studies to provide a comprehensive picture of the neurobiology and current and potential treatments for anxiety in PD. The data reviewed here indicate that, despite their high prevalence and impact on the quality of life, anxiety disorders are often under-diagnosed and under-treated in PD patients. Moreover, there are currently few clinical and pre-clinical studies underway to investigate new pharmacological agents for relieving these symptoms, and we hope that this article may inspire clinicians and researchers devote to the studies on anxiety in PD to change this scenario. This article is part of a Special Issue entitled 'Anxiety and Depression'.     

Schistosoma mansoni antigens as modulators of the allergic inflammatory response in asthma

Epidemiologic evidence has accumulated suggesting that helminth infection or their products protect against the development of autoimmune and allergic diseases. The mechanisms underlying this protection may include regulatory cells and cytokines. Both helminth infection and allergic diseases drive the immune system toward the Th2 type response with high production of IgE. However, while this antibody response is associated with the pathogenesis of allergic diseases, IgE production in regions endemic for parasite diseases, such as schistosomiasis, might be associated with a protection against infection. In individuals chronically exposed to Schistosoma sp infection, regulatory cells and cytokines which may develop to protect the host against harmful parasite antigens may also protect the host against allergic diseases. We have demonstrated that helminthic infections are associated with a poor response to allergy skin-prick tests and with low asthma pathology. This review summarizes the immune response that is associated with the pathology of allergic diseases such as asthma and with the resistance to helminth infections. Moreover, it is discussed how helminth infection, particularly Schistosoma mansoni or their products may influence the development of atopic asthma.     

The potential utility of 5-HT1A receptor antagonists in the treatment of cognitive dysfunction associated with Alzheimer s disease.

The 5-HT1A receptor has been extensively studied over the last two decades. There is a plethora of information describing its anatomical, physiological and biochemical roles in the brain. In addition, the development of selective pharmacological tools coupled with our understanding of psychiatric pathology has lead to multiple hypotheses for the therapeutic utility of 5-HT1A agents and in particular 5-HT1A receptor antagonists. Over the last decade it has been suggested that 5-HT1A receptor antagonists may have therapeutic utility in such diseases as depression, anxiety, drug and nicotine withdrawal as well as schizophrenia. However, a very compelling rationale has been developed for the therapeutic potential of 5-HT1A receptor antagonists in Alzheimer s disease and potentially other diseases with associated cognitive dysfunction. Receptor blockade by a 5-HT1A receptor antagonist appears to enhance activation and signaling through heterosynaptic neuronal circuits known to be involved in cognitive processes and, as such, represents a novel therapeutic approach to the treatment of cognitive deficits associated with Alzheimer s disease and potentially other disorders with underlying cognitive dysfunction.     

Adult neurogenesis and neural stem cells as a model for the discovery and development of novel drugs

Neurogenesis occurs in discrete regions of the adult brain, particularly the hippocampus. It is enhanced in the hippocampus of animal models and patients with neurological diseases and disorders, such as Alzheimer's disease (AD) and epilepsy. Adult hippocampal neurogenesis is modulated by drugs used for treating AD and depression, particularly galantamine, memantine and fluoxetine. This reveals that adult neurogenesis and newly generated neuronal cells of the adult hippocampus are involved in neurological diseases and disorders and that adult neurogenesis and neural stem cells (NSCs) of the adult hippocampus are the target of drugs used for treating AD and depression. Hence, adult neurogenesis and NSCs open new opportunities for our understanding of the pathology of the nervous system and new avenues to discover and develop novel drugs for treating neurogical diseases and disorders; drugs that would target specifically the NSCs of the neurogenic regions in the adult brain, or neurogenic drugs, and that would reverse or compensate deficits and impairments associated with neurological diseases and disorders, particularly those associated with the hippocampus. Adult NSCs represent a model to discover and develop novel drugs for treating neurological diseases and disorders. These drugs may also have potential for regenerative medicine and the treatment of brain tumors.     

Novel Therapeutic Targets in Depression and Anxiety: Antioxidants as a Candidate Treatment

There is growing evidence that the imbalance between oxidative stress and the antioxidant defense system may be associated with the development neuropsychiatric disorders, such as depression and anxiety. Major depression and anxiety are presently correlated with a lowered total antioxidant state and by an activated oxidative stress (OS) pathway. The classical antidepressants may produce therapeutic effects other than regulation of monoamines by increasing the antioxidant levels and normalizing the damage caused by OS processes. This chapter provides an overview of recent work on oxidative stress markers in the animal models of depression and anxiety, as well as patients with the aforementioned mood disorders. It is well documented that antioxidants can remove the reactive oxygen species (ROS) and reactive nitrogen species (RNS) through scavenging radicals and suppressing the OS pathway, which further protect against neuronal damage caused oxidative or nitrosative stress sources in the brain, hopefully resulting in remission of depression or anxiety symptoms. The functional understanding of the relationship between oxidative stress and depression and anxiety may pave the way for discovery of novel targets for treatment of neuropsychiatric disorders.     

Vitamin D Treatment Attenuates Neuroinflammation and Dopaminergic Neurodegeneration in an Animal Model of Parkinson’s Disease,Shifting M1 to M2 Microglia Responses

Microglia-mediated neuroinflammation has been described as a common hallmark of Parkinson’s disease (PD) and is believed to further exacerbate the progressive degeneration of dopaminergic neurons. Current therapies are unable to prevent the disease progression. A significant association has been demonstrated between PD and low levels of vitamin D in patients serum, and vitamin D supplement appears to have a beneficial clinical effect. Herein, we investigated whether vitamin D administered orally in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced preclinical animal model of PD protects against glia-mediated inflammation and nigrostriatal neurodegeneration. Vitamin D significantly attenuated the MPTP-induced loss of tyrosine hydrlase (TH)-positive neuronal cells, microglial cell activation (Iba1-immunoreactive), inducible nitric oxide synthase (iNOS) and TLR-4 expression, typical hallmarks of the pro-inflammatory (M1) activation of microglia. Additionally, Vitamin D was able to decrease pro-inflammatory cytokines mRNA expression in distinct brain areas of the MPTP mouse. Importantly, we also assessed the anti-inflammatory property of vitamin D in the MPTP mouse, in which it upregulated the anti-inflammatory cytokines (IL-10, IL-4 and TGF-β) mRNA expression as well as increasing the expression of CD163, CD206 and CD204, typical hallmarks of alternative activation of microglia for anti-inflammatory signalling (M2). Collectively, these results demonstrate that vitamin D exhibits substantial neuroprotective effects in this PD animal model, by attenuating pro-inflammatory and up-regulating anti-inflammatory processes.     

Novel strategies for discovering inhibitors of Dengue and Zika fever

Neurogenesis occurs in discrete regions of the adult brain, particularly the hippocampus. It is enhanced in the hippocampus of animal models and patients with neurological diseases and disorders, such as Alzheimer's disease (AD) and epilepsy. Adult hippocampal neurogenesis is modulated by drugs used for treating AD and depression, particularly galantamine, memantine and fluoxetine. This reveals that adult neurogenesis and newly generated neuronal cells of the adult hippocampus are involved in neurological diseases and disorders and that adult neurogenesis and neural stem cells (NSCs) of the adult hippocampus are the target of drugs used for treating AD and depression. Hence, adult neurogenesis and NSCs open new opportunities for our understanding of the pathology of the nervous system and new avenues to discover and develop novel drugs for treating neurogical diseases and disorders; drugs that would target specifically the NSCs of the neurogenic regions in the adult brain, or neurogenic drugs, and that would reverse or compensate deficits and impairments associated with neurological diseases and disorders, particularly those associated with the hippocampus. Adult NSCs represent a model to discover and develop novel drugs for treating neurological diseases and disorders. These drugs may also have potential for regenerative medicine and the treatment of brain tumors.