CNS & Neurological Disorders - Drug Targets (Formerly Current Drug Targets - CNS & Neurological Disorders) - Volume 13, Issue 5, 2014

Evolution rarely ‘designs’ important molecular devices only for one purpose. In fact, the same device is often used in different biological processes. The roles of Wnt signaling clearly illustrate this notion. Although, Wnt signaling has been best known as a master regulator in diverse developmental processes, emerging evidence reveals critical functions of Wnt signaling in the adult nervous system. In this thematic issue of Wnt Signaling in Neurological Disorders, four invited review articles are published. The intention of this collection is to critically assemble and analyze the current knowledge from studies that focus on the roles of Wnt signaling in regulation of the plasticity and function of the adult nervous system, especially in the context of various neurological disorders. The secretion of Wnt protein from neurons is intimately controlled by synaptic activity. This, somewhat, unexpected observation immediately suggests a biological function of Wnt signaling in the adult nervous system. What would secreted Wnt protein do in response to synaptic activation? Evidence for the role of Wnt signaling in synaptic plasticity and glial biology was reviewed by Tang. Some neurological conditions are known to associate with the maladaptive neuronal activity. Given the fact of the regulation of Wnt signaling by synaptic activity, it is natural to expect that Wnt signaling contributes to the pathogenesis of disorders associated with abnormal neuronal activity. As a case in point, Tang also summarized the recent work on the involvement of Wnt signaling in pathological pain, a condition of the hyper-excitation of the pain neural circuitry. Consistent with its role in synaptic plasticity, emerging evidence indicates a regulatory function of Wnt signaling in learning and memory. Abnormalities of the Wnt/β-catenin pathway are associated with the pathology of memory dysfunction in Alzheimer’s Disease (AD). De Ferrari et al. reviewed the recent development in this field, with the focus on the mechanistic implications of aberrant Wnt signaling in different aspects of AD pathologies. In addition to the regulation of memory formation, recent findings suggest an association between Wnt signaling and psychiatric disorders. Peng et al. reviewed the studies on the involvement of Wnt signaling in schizophrenia, while Zhang et al. reviewed work on the contribution of Wnt signaling to autism. Research reviewed in this thematic issue indicates that Wnt signaling is an important regulator of various neurological disorders. Targeting this signaling pathway may lead to the development of novel drugs to treat the disorders.

Wnt signaling pathways play important roles in various developmental and oncogenic processes. In the nervous system, Wnt signaling regulates neuronal morphogenesis and synaptic differentiation. Disturbance of Wnt signaling is implicated in the pathogenesis of neurological diseases. Recent studies indicate that Wnt signaling in neurons is closely coupled to synaptic activation, and that the activity-regulated Wnt signaling is critical for the expression of synaptic plasticity and the formation of memory. Dysregulation of the activity-regulated Wnt signaling may have a significant impact on the function of the nervous system. In this article, we will review the identified mechanisms by which synaptic activity controls Wnt signaling in neurons and the neurological functions of the activity-regulated Wnt signaling under normal and specific disease conditions. In particular, we will discuss the role of Wnt signaling in the pathogenesis of chronic pain.

Alzheimer’s disease is a neurodegenerative disorder that causes a progressive decline of mental and cognitive processes such as memory, judgment and reasoning. We proposed earlier that a sustained loss of function of Wnt/β- catenin signaling components underlies the onset and progression of the disease. Here, we discuss recent data on the involvement of Wnt/b-catenin signaling on amyloid precursor protein (APP) processing, Aβ peptide neurotoxicity, τ phosphorylation, and modulation of Apolipoprotein E function in the brain. We conclude that several components of the cascade are actively engaged in the events leading to AD neuropathology and propose that compounds that mimic activation of this signaling cascade, such as lithium, should be considered for therapeutic intervention in Alzheimer's patients. In summary, data accumulated during the past decade confirm some important predictions of our hypothesis where components of this signaling cascade are actively engaged in the events leading to AD neuropathology and that compounds that mimic activation of this signaling cascade, such as lithium, should be considered for therapeutic intervention in Alzheimer's patients.

The Wnt signaling pathway is one of the crucial signaling pathways that regulate many aspects of central nervous system. In this review, we tempt to depict an overall picture of the Wnt signaling with its multitude of roles in schizophrenia. If the Wnt signaling pathway plays a crucial role in the pathogenesis of schizophrenia as we suggest, a better understanding of the Wnt pathway might contribute to developing new and more effective tools for diagnosis and treatment of schizophrenia.

Mounting attention is being focused on the canonical Wnt signaling pathway which has been implicated in the pathogenesis of autism in some our and other recent studies. The canonical Wnt pathway is involved in cell proliferation, differentiation and migration, especially during nervous system development. Given its various functions, dysfunction of the canonical Wnt pathway may exert adverse effects on neurodevelopment and therefore leads to the pathogenesis of autism. Here, we review human and animal studies that implicate the canonical Wnt signal transduction pathway in the pathogenesis of autism. We also describe the crosstalk between the canonical Wnt pathway and the Notch signaling pathway in several types of autism spectrum disorders, including Asperger syndrome and Fragile X. Further research on the crosstalk between the canonical Wnt signaling pathway and other signaling cascades in autism may be an efficient avenue to understand the etiology of autism and ultimately lead to alternative medications for autism-like phenotypes.

Binge eating disorder (BED) has limited therapeutic options. Repetitive transcranial magnetic stimulation (rTMS) is a modulation technique of cortical excitability that has shown good results in treating certain psychiatric disorders by correcting dysfunctional cortical regions. We hypothesize that rTMS could be an alternative therapy for BED through potential modulation action on frontostriatal abnormalities and dopaminergic pathways noted by neuroimaging. We report the case of a young woman presenting refractory BED and comorbid depression treated with 20 sessions of rTMS for 30 minutes over the left dorsolateral prefrontal cortex at 10 Hz for about a month (2400 stimuli per day). She answered two self-report questionnaires, the Binge Eating Scale (BES) and the Beck Depression Inventory (BDI). Before rTMS treatment, the BES score was 38, and the BDI score was 42. Three days after rTMS treatment, the BES score was 27 and the BDI score was 23, and the patient referred to no binge eating episodes for that week. Therefore, rTMS could offer a new option of treatment for BED and comorbid depression.

The etiology of migraine, a neurological disorder, has still not been clearly established, although it may be categorized as a headache disorder with specific characteristics such as focal neurological symptoms preceding or accompanying the headache. Many researchers have suggested genetic predisposition as one of the underlying causes of migraine. An insight into the various pathophysiological mechanisms such as the role of cortical spreading depression, abnormal brain stem activity, trigeminal nerves, calcitonin gene related peptide, nitric oxide and serotonin receptors in the development of migraine, has been conferred in the present article. The accurate diagnosis of migraine and identification of its type is a prerequisite for appropriate therapy. Ample opportunity still exists for the improvement in the safety, efficacy and tolerance capacity of the currently available antimigraine medications, through the design and development of targeted drug delivery system. In the present review, an attempt has been made to highlight all the underlying pathophysiological mechanisms of migraine, its diagnosis, treatment and therapeutic area to be explored including mitigation of biochemical pathways and gene therapy.

Microglia, the brain’s resident macrophages, contribute to immune surveillance and the response to disease and injury. These immune cells play a dual role in the nervous system, having both neurotoxic and neuroprotective effects. Activation of microglia results in the production of inflammatory molecules and neurotoxic factors that often cause or contribute to neurodegenerative diseases. Inhibition of neurotoxic microglia activation and consequent inflammatory processes may represent an important therapeutic target. Phosphatidylserine (PS), an aminophospholipid of plasma membranes, and curcumin, the yellow pigment isolated from the rhizome of the turmeric plant, have both been reported to suppress microglial activation by reducing pro-inflammatory mediator production and release. In this study we analyzed the effects of PS, curcumin, and their association on microglial activation induced by the bacterial toxin lipopolysaccharide. Primary rat cortical microglial cells were treated with increasing concentrations of PS-liposomes and curcumin, alone or in combination, and their effects on pro-inflammatory cytokine release from unstimulated and lipopolysaccharide-stimulated microglia were evaluated by enzyme-linked immunosorbent assay. Isobolographic analysis was performed to investigate the effect of PS-liposomes and curcumin combination. PS and curcumin inhibited the release of interleukin (IL)-1β, IL-6, and tumor necrosis factor-α induced by lipopolysaccharide. Furthermore, PS and curcumin in combination exerted a synergistic effect in down-regulating IL-1β release. These results suggest that the association of PS with curcumin could be of potential therapeutic utility against diseases associated with microglial activation.

Stroke-induced immunosuppression (SIIS) leads to severe complications in stroke patients, including an increased risk of infections. However, functional alterations of T lymphocytes during SIIS are poorly described in acute ischemic stroke (AIS). We aimed to characterize Ca2+ influx kinetics in major lymphocyte subsets (CD4, Th1, Th2, CD8) in AIS patients without infection 6 hours and one week after the CNS insult. We also assessed the sensitivity of the above subsets to specific inhibition of the Kv1.3 and IKCa1 lymphocyte K+ channels. We took peripheral blood samples from 12 non-stroke individuals and 12 AIS patients. We used an innovative flow cytometry approach to determine Ca2+ influx kinetics and the surface expression of Kv1.3 channels. Our results indicate that Ca2+ influx kinetics is altered in the Th2 and CD8 subsets in AIS which may play a role in the development of SIIS. Specific inhibition of Kv1.3 channels selectively decreased Ca2+ influx in the CD8 and Th2 subsets of AIS patients. The surface expression of Kv1.3 channels is also altered compared to non-stroke individuals. Kv1.3 channel inhibition might have beneficial therapeutic consequences in AIS, selectively targeting two distinct T cell subsets at two different time points following the CNS insult. Within hours after the insult, it might prevent excessive tissue injury through the inhibition of CD8 cells, while at one week after the insult, it may improve the inflammatory response through the inhibition of Th2 cells, thus reducing the unwanted clinical consequences of SIIS.

The post-traumatic stress disorder (PTSD) is defined as a severe anxiety disorder that develops after exposure to an event with actual, threatened, or perceived death or serious injury, or a threat to the physical integrity of oneself or others that results in significant psychological trauma. Moreover, the ability of people to handle acute severe stress experiences varies among individuals. Depending on the underlying personality and resiliency, therefore, PTSD can occur in individuals exposed to exceedingly stressful incidences or those who have encountered seemingly less overwhelming stressors. In addition to severe stressful exposure, multiple other factors including genetic susceptibility; past experiences; cultural, spiritual, and personal beliefs; bullying and harassments; and lack of support at the workplace, social, and home environement may contribute to the development of PTSD. Author investigated multiple potential mechanisms for the development and sustenance of PTSD based on the recent literature and his own experiences and insight. Based on this search, author indicates that among other pathological and biochemical abnormalities, hormonal aberrations are most likely key mechanisms initiating and the maintenance of the PTSD. These pathophysiological neuro-hormonal changes instigate maladaptive learning processes caused by sustained high levels of anxiety and fear, through a hypo-responsive hypothalamic-pituitary axis and hyper-responsive catecholamine system (persistently elevated blood norepinephrine levels and lower than appropriate glucocorticoid levels). In addition to having inappropriately low serum cortisol levels and high epinephrine and norepinephrine levels, patients with PTSD also have mitochondrial dysfunctions and other hormonal abnormalities. Based on these data, author concluded that these pathological, biochemical and sustained neurohormonal abnormalities are likely to influence the structural brain changes, particularly in the amygdala and hippocampus, which are characteristics of patients with PTSD. Considering these abnormalities, neuroendocrine system needs to be considered as a key target for new drug development for prevention and treatment of PTSD.

In many psychiatric, neurodegenerative and systemic inflammatory disorders circadian melatonin is decreased whilst melatonin enzymes and melatonin receptors are genetic susceptibility factors. Treatment with melatonin is useful in a diverse range of medical conditions, including bipolar disorder, Alzheimer’s disease, depression and fibromyalgia. Decreased melatonin effects are classically attributed to lost pineal production. However, melatonin, along with its immediate precursor N-acetylserotonin (NAS), is produced by many, if not all, mitochondrial containing cells, including immune cells and central glia. Here we review the data on local melatonin and NAS production and propose that astrocyte melatonin and NAS efflux is crucial to local central inflammation regulation at the glia-neuronal interface. Melatonin and NAS provide antioxidant and anti-inflammatory effects, as well as increasing mitochondrial oxidative phosphorylation and functioning. Consequently, their decreased production at sites of local inflammation is proposed to underlie melatonin’s genetic association with a diverse range of medical conditions. Similarly the benefits of serotonin boosting medications, including antidepressants, across a wide range of conditions are partly mediated by increasing serotonin availability for astrocytic local NAS and melatonin production. Such a conceptualization incorporates a plethora of data across different disorders, especially the commonalities in oxidative and nitrosative stress, anti-oxidants, tryptophan catabolites and mitochondrial dysregulation evident in a diverse array of medical conditions. Glia melatonin and NAS regulation are important treatment targets in psychiatric disorders, neurodegenerative disorders and glioma.

Migraine is a neurovascular disease that has classically been attributed to multifactorial aetiologies, with genetic components and environmental interactions considered the main influence. Genes such as flavoenzyme 5, 10- methylenetetrahydrofolate reductase (MTHFR), especially the C677T variant, have been associated with elevated plasma homocysteine levels. This elevation in homocysteine results in an array of metabolic disorders and increased risk of complex diseases, including migraine. Catalysation of homocysteine requires the presence of vitamins B6, B12 and folate. Deficiencies in these cofactor vitamins result in hypomethylation, which triggers migraine. Because migraine predominantly affects females, it is hypothesised that fluctuating oestrogen levels, which are governed by oestrogen receptor 1 polymorphisms, are important. Another important factor is homocysteine, the production of which is dependent upon MTHFR and B vitamins. Gene expression is modulated through epigenetic mechanisms, which involve methionine. Additionally, folate plays a major role in DNA synthesis. We propose that vitamin B intake, coupled with MTHFR and oestrogen receptor 1 polymorphisms, causes differential DNA methylation and gene expression that may contribute to the occurrence of migraine.

Twenty years ago the alpha7 nicotinic acetylcholine receptor (nAChR) was thought to be vestigial with little biological relevance, but in recent years it has emerged as a functional target with ubiquitous localization and biological roles. In the last decade more than two thousand manuscripts have been published unraveling the multi-dimensional complexity of this target, the heterogeneity of its genetic variants, the spectrum of transducing signals, and the critical roles it plays in pivotal biological functions in the protection and maturation of neurons and stems cells, immune and inflammatory responses, sensory gating, mnemonic and attentional processes. In addition research and development of novel drugs has also promoted an intense debate on the role of activation, desensitization, β -amyloid oligomers, glutamate, and alpha7 nAChR, in cognition, neuronal survival, and neurodegeneration. The initial alpha7 nAChRs transducing enzyme, aptly named after Janus the two-faced roman deity for crossroads and gateways, reflects the dichotomy of reports on alpha7 nAChRs in promoting neuronal survival and cognitive processes, or as the target of β- amyloid oligomers to destabilize neuronal homeostasis leading to an irreversible neurochemical demise and dementia. It is therefore important to understand the functional neural bases of alpha7 nAChRs-mediated improvement of biological functions. The promise of alpha7 nAChR-directed drugs has already recently translated into proof-of-concept in controlled clinical trials but the full promise of this target(s) will be fully unraveled when its impact on neuronal health and survival is tested in controlled long-term clinical trials of disease progression.

Neuropathic pain is a chronic disability associated with a dysfunction of the nervous system, initiated by a primary lesion or disease. Even after resolution of the initiating pathology, neuropathic pain often persists, leading to a significantly diminished quality of life. A vast literature has documented alterations in the expression and distribution of various pain-related proteins in the peripheral nervous system following injury or disease. The current review examines pain-related molecules in the pathogenesis of peripheral nerve injury-induced pain and discusses potentially useful therapeutic targets on the basis of preclinical findings in rodent neuropathic pain models. There are indeed a number of cellular processes that are involved in maintaining the neuropathic pain state, but the current review will focus on transmembrane proteins, particularly the voltage-gated and ligand-gated ion channels, which modulate peripheral nerve function. Given the complexity of the process involved in peripheral nerves, clinical efficacy could be greatly enhanced if several of these targets are engaged at once. A key advantage of therapy directed peripherally is that penetration of the therapeutic into the CNS is not entirely necessary, thereby reducing the risk of adverse psychomotor effects. While a number of fascinating targets have been identified in preclinical rodent models, there is a need to confirm that they are in fact relevant to clinical neuropathic pain. Thus, the current review will also discuss the extent to which clinical data confirms the findings of preclinical studies.

Total bakkenolides is the major component of the rhizome of Petasites trichinous Franch.. In this study, we investigated its neuroprotective effects in a rat transient focal cerebral ischemia-reperfusion model, and in an in vitro cerebral ischemia model, oxygen-glucose deprivation of cultured nerve cells. Oral administration of total bakkenolides immediately after reperfusion at doses of 5, 10 and 20 mg/kg markedly reduced brain infarct volume and neurological deficits. Total bakkenolides significantly attenuated cell death and apoptosis in primarily cultured neurons subject to 1-h hypoxia followed by 24-h reoxygenation. Morphologic observations directly confirmed its protective effect on neurons. We also demonstrated that total bakkenolides could inhibit nuclear factor-κB (NF-κB) activation by blocking the classic activation pathway through suppression of phosphorylation of IκB-kinase complex, NF-κB/p65 and inhibitor protein IκB, inducing nuclear translocation of NF-κB/p65 and degradation of IκB. Further, total bakkenolides inhibited the activation of Akt and the extracellular signal-regulated kinase 1/2, two important upstream activators of NF-κB. In conclusion, our results provide a strong pharmacological basis for further understanding the potential therapeutic role of total bakkenolides in cerebral ischemic disease and shed new light on its neuroprotective mechanism.

The accumulation and aggregation of misfolded proteins can be highly cytotoxic and may underlie several human degenerative diseases characterized by neuronal inclusions such as Alzheimer's, Parkinson's, prion-like and polyglutamine repeat diseases. In this context small heat shock proteins, molecular chaperones known to be induced by cell stress, play a fundamental role by facilitating folding of nascent polypeptides, preventing aggregation of misfolded proteins and enhancing their degradation. A recently identified member of the small heat shock protein family, HspB8, is of particular interest in the field of neurological diseases since mutations in its sequence correlate with development of distal hereditary motor neuropathy and Charcot-Marie-Tooth disease. HspB8 expression has been detected in neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, Huntington disease and spinocerebellar ataxia type 3. In the latter, HspB8 appears to be involved in protecting the cell from accumulation of insoluble aggregates either by preventing aggregation or by promoting degradation of improperly folded proteins. These data propose that HspB8 may be a major player in the neuroprotective response and a promising target for the development of therapeutic strategies.

The prion protein (PrP) is currently one of the most studied molecules in the neurosciences. It is the main cause of a group of neurological diseases collectively called transmissible spongiform encephalopathies that severely affect both humans and a variety of mammals. Much effort has been directed to understanding the molecular basis of PrP activity, both in physiological and pathological terms. In this context, identification of neuronally-relevant interactors of PrP may play a crucial role. We recently discovered a specific, high-affinity (nanomolar KD) interaction with tyrosine hydroxylase (TH), a enzyme catalyzing the rate-limiting step in the synthesis of the neurotransmitter dopamine. Using molecular biological, biochemical and biophysical techniques we identified the C-terminal structured domain of PrP and the Nterminal regulatory domain of TH as interacting domains between these two proteins. This interaction does not affect TH activity in vitro, although co-expression experiments in HeLa and Chinese hamster ovary cells revealed that PrP is able to internalize TH. Moreover, TH modulated the level of expression of PrP and its localization at the plasma membrane. This novel interaction between two proteins of central importance in nervous system function may shed new light on our understanding of PrP in neurological diseases.

Alzheimer’s disease (AD) is a neurodegenerative disease associated with the development of dementia. It has been established that the pathological hallmarks of neurofibrillary tau protein tangles and senile β-amyloid protein plaques lead to degeneration of neurons via inflammatory pathways. The progressive death of neurons, primarily cholinergic, results in a gradual and fatal decline of cognitive abilities and memory. By targeting these pathological hallmarks and their associated pathways, AD drug therapy can potentially attenuate the disease state. In this review article, we focus on newly proposed and experimental AD drug treatment. We discuss three characteristic areas of AD treatment: prevention of neurotoxic β-amyloid protein plaque formation, stability of neuronal tau proteins, and increase in neuronal growth and function. The primary drug therapy methods and patents discussed include the use of neurotrophic factors and targeting of the amyloid precursor protein cleavage pathway as prevention of β-amyloid formation and tau aggregation.