CNS & Neurological Disorders - Drug Targets (Formerly Current Drug Targets - CNS & Neurological Disorders) - Volume 13, Issue 7, 2014

The International Summer School of Neurology provides a forum for a selected group of medical students and postgraduates specializing in neurology to interact with an internationally recognized faculty in the neurological sciences. Credit for having the vision to create the School goes to its founders and program coordinators, Dafin F. Mureşanu (Professor of Neurology and Chairman of the Department of Clinical Neurosciences, University of Medicine and Pharmacy "IuIiu Haţieganu", Cluj-Napoca, Romania) and Natan M. Bornstein (Professor of Neurology, Tel-Aviv University Sackler School of Medicine, Israel). This year’s edition of the School, its ninth, continued the tradition of integrating classes covering the latest developments in the neurological sciences with a tranquil setting on the shores of the Black Sea. Long-term support from academic organizations such as The Society for the Study of Neuroprotection and Neuroplasticity, Tel Aviv University, Uppsala Universitet, the Romanian Society of Neurology and World Federation for NeuroRehabilitation (among others) has been an important factor in sustaining the School over the years. This year’s program began on Sunday afternoon (July 6) with a series of basic research talks on advances in brain protection and recovery, including nanowired drug delivery for the treatment of traumatic and concussive brain injuries, the peripheral nerve microenvironment in chronic pain, and practical pharmacology in neurorehabilitation. It is of paramount important that physicians have a grasp of the basic science underlying clinical medicine. The first full day of the course, Monday July 7, was divided into morning and afternoon sessions covering the topics of neurorehabilitation and peripheral neuropathies, repectively. The high prevalence of back pain and its bearing on an individual’s quality of life, together with associated health care costs is a matter of common knowledge. The two principal factors in treatment of lower back pain are: to operate or not and how to alleviate pain. An interdisciplinary approach is recommended, which encompasses both morphological and functional findings. A clear diagnosis is of paramount importance in protecting the patient from unnecessary surgery and the fear of failed back surgery. Symptoms of peripheral neuropathy are common neurologic complaints. Peripheral neuropathy has an overall prevalence of 2 - 3% in the general population, which can reach 8% or more in those over 55 years of age. Understanding the cause(s) of peripheral neuropathy is important, as it may inform on treatment to prevent progression to disability and poor quality of life. Diabetic neuropathy is perhaps the most common peripheral neuropathy. A key clinical issue in the management of diabetic neuropathy is pain. Treatment options available for diabetic neuropathy should target both metabolic and vascular disturbances along with the clinical manifestations such as neuropathic pain and dysautonomic manifestations, and the role of advanced glycation end-products (AGEs), whose accumulation may be exacerbated by hyperglycemia. Non-steroidal anti-inflammatory drugs remain in the frontline of analgesic drugs prescribed for nociceptive pain, which is surprising given that clinical and experimental evidence shows that neuropathic pain syndromes in general respond poorly to the former or opioid analgesics. Thiamine (vitamin B1) is efficacious as an adjuvant medicine to treat neuropathic disorders, with its lipid-soluble form (benfotiamine) having much higher bioavailability compared to thiamine. At the preclinical level benfotiamine demonstrated lower toxicity in comparison to water-soluble vitamin B1. In clinical studies, benfotiamine restored nerve function in diabetic neuropathy, improved nerve conduction velocity, prevented diabetic retinal damage and halted the development of diabetic nephropathy without affecting blood glucose levels. It is believed that benfotiamine prevents progression of diabetic complications by increasing tissue levels of thiamine diphosphate. The resulted enhancement of transketolase activity can direct precursors of AGEs to the pentose phosphate pathway, thereby reducing tissue levels of AGEs. In addition, Alpha-lipoic acid, a water- and fat-soluble cell-penetrant antioxidant which scavenges mitochondrial reactive oxygen species blocks alternative pathways of glucose metabolism. Because beneficial effects of alpha-lipoic acid can be achieved at low micromolar concentrations, one cannot exclude that its therapeutic benefits are independent of its antioxidant status. This module concluded in the evening with a basic course in neurologic clinical examination. The course’s second day (July 8) focused on stroke. Lectures included a presentation on the updated and new recommendations of the 2014 American Stroke Guidelines, secondary stroke prevention, and advances in brain protection and recovery in acute and long-term stroke treatment. Patients with transient ischemic attacks (TIA) have a 43% chance of stroke within the next 7 days. In terms of early TIA management, there is an 80% risk reduction at 3 months when the patient is seen within the first 24 hours. In patients with TIA or ischemic stroke of non-cardiac origin anti-platelet drugs decrease stroke riskby 11-15%, myocardial ischemia and vascular death by 15-22%. Aspirin is the most widely used drug, given its affordability and effectiveness. Aspirin in combination with slow release dipyridamole surpasses aspirin alone in preventing stroke, with a 20-24% relative risk reduction of stroke and death. Clopidgrel (Plavix) is superior to aspirin (around 8.7%) in patients at high risk of recurrence. Dual anti-platelet therapy (aspirin + plavix) is not more effective than plavix alone for long-term secondary stroke prevention and has a higher risk of bleeding. These antiplatelet agents do not significantly reduce mortality. This was followed by highly informative lecture on atrial fibrillation (AF) and stroke prevention. Twenty to twenty-five percent of ischemic strokes are cardioembolic. Atrial fibrillation (AF), the most frequently found arrhythmia occurs in 0.4 – 0.7% of the general population. Its prevalence rises to approximately 6% in those over 65 years of age, and up to 10% in individuals older than 75 years. AF related-stroke accounts for something like 45% of all cardioembolic strokes. AF is a well-established independent risk factor for stroke, increasing the risk of stroke 5.6-fold. AF patients without antithrombotic treatment have a 12% risk per year of recurrent stroke. Non-anticoagulated AF patients run a 35% risk of an ischemic stroke occurring during their lifetime. Indeed, underuse of warfarin is greatest in elderly patients who are at the highest risk of stroke. Class I evidence tells us that adjusted-dose warfarin reduces stroke risk in AF patients by ~70% but aspirin by only 20%. A target INR of 2.5 (range 2.0-3.0) is recommended for warfain treatment. The novel anticoagulants (NOACs) dabigatran etexilate, rivaroxaban, apixaban, now approved in a number of countries for stroke prevention in AF are: associated with the same or lower rates of stroke, bleeding (intracranially, in particular) and death compared with warfarin; can be administered in fixed doses without routine coagulation monitoring – in contrast to warfarin. In comparing the effects of NOACs with warfarin, results are consistent in almost all populations and patients subgroups studied. In terms of statistical significance only dabigatran (150 mg/2 times a day) was superior to warfarin. Lack of NOAC antidotes in patients who experience major bleeding has not yet been linked to worse outcome among patients treated with NOACs compared with warfarin in secondary analysis. Multiple guidelines for AF management recommend NOACs for stroke prevention in AF patients at risk for stroke, along with periodic renal function assessment. Identifying the best therapeutic approach for brain protection and recovery in stroke remains difficult. Endogenous neurobiological processes than span neurotrophism, neuroprotection, neuroplasticity and neurogenesis are key to protection and recovery and form the core of endogenous defense activity. The pathological cascades of stroke comprise a limited number of pathophysiological processes: excitotoxicity, oxidative stress, inflammation and apoptotic-like processes. Identification of therapeutic modalities to limit brain damage and enhance recovery of motor function through neuroprotective and neurorestorative mechanisms, even with delayed initiation, is a critical goal. We may define neurorecovery as: positive outcome to yield clinically relevant results with both early functional and later structural effects; linked to adaptative plasticity of undamaged nervous tissue; depends on the non-affected elements of a functional network. The initial size and location of injury are key factors in determining the extent of brain recovery. Neurotrophic factors, produced by distinct brain cell types act in a pleotropic way against pathological cascades. The same molecules initially induce a endogenous neuroprotective effect, followed by neuroplasticity and neurogenesis actions, as well. One can thus say that they confer multimodal pleotropic activity. Neuroprotection, neuroplasticity and neurogenesis, although apparently independent, are actually sequences of the same endogenous defense activity, regulated by endogenous molecules. Today’s research continues to view drug activity in terms of single mechanisms and focus, which can ‘mask’ one’s vision of paradigms with greater explanatory power - thereby inhibiting development of more effective treatment strategies. From a pharmacological perspective, the best approach to achieve neurorecovery is to focus on molecules that mimic the endogenous molecules with multimodal and pleiotropic neuroprotective effects. Biological agents such as neurotrophic factors, with their modulating and multimodal effects are superior agents for brain protection and recovery, given an inherent pleiotropic neuroprotective effect. In other words, they pharmacologically ‘span’ the gap between acute neuroprotective processes and long-term recovery processes. As such, a change of concept is in order in terms of pharmacological brain protection and recovery stroke therapy. A fuller comprehension of the mechanisms underlying neuroplasticity will be needed to achieve a more efficient and comprehensive treatment. The presentation concluded by highlighting current and future needs in stroke therapy, including an integrated pharmacological approach which focuses on biological entities having multimodal activity and pleiotropic neuroprotective effects, rather than single mechanism drugs. The next presentation gave an overview on early and late neurorehabilitation in stroke therapy. Rehabilitation is a process through which each disabled person achieves his/her maximum physical, functional, cognitive and psychosocial recovery that are possible within the limits of one’s disability. As mentioned above, endogenous defense activity of the nervous system is acontinuum operating at the levels of neurotrophism, neuroprotection, neuroplasticity and neurogenesis. Neuroregeneration (neurorepair) is the morphological result of interactions between these basic neurobiological processes. Neurorecovery is the outcome that generates clinically relevant results. Restitution is a intrinsic process acting on biochemically and geneticallyinduced events, such as reduction of edema and restoration of axonal transport. Substitution depends on external stimuli that, through learning, drive activity-dependant plasticity. Compensation is intended to improve the mismatch between a patient’s impaired skills and his/her demand on the environment. The take-home message is that all basic biological processes can be activated endogenously or exogenously. This day’s module concluded in the evening with selected case presentations on stroke. The third day of the course (July 9) covered Parkinson disease (PD), the most common neurodegenerative movement disorder. PD is a complex and heterogeneous pathology whose lack of reliable biological markers complicates diagnostic criteria. It is now generally accepted that what we call PD is the result of phenotypic convergence. For example, molecular genetic analysis has been used to identify over 500 distinct DNA variants in five disease genes associated with familial PD. Knowledge dealing with the functions of the genes’ protein products has revealed pathways of neurodegeneration that may have features in common between inherited and sporadic PD. The main primary genetic lesions lead to abnormalities in the ubiquitinproteasome system function, or to mitochondrial respiratory chain abnormalities or to abnormalities in the mitochondrial life cycle. Studies from genetic association indicate that genetic variation in such genes may be susceptibility factors in sporadic PD, the most common form of parkinsonism. Environmental factors may have also an important role in PD etiopathogenesis. Exposure to pesticides may is increase the risk of developing PD. Chronic exposure to neurotoxic chemicals appears associated with epigenetic changes, protein aggregation and autophagy, which are important cellular and molecular correlates of neurodegenerative diseases. Dopaminergic neuron degeneration in PD is widely believed to result from a combination of multiple converging signaling pathways rather than a single unifying mechanism. Since the clinical manifestations of PD can be the result of quite divergent mechanisms, it is unlikely that an intervention can be developed which will is able to influence the disease development in all PD patients. Such disease-modifying therapy should be based not on clinical but rather on understanding the underling pathogenetic processes which differ among cases. Individualized therapy to interrupt, or at least slow, disease progression must be based on elucidation of the metabolic processes. It is becoming increasingly evident that non-motor symptoms (NMS) in PD are important and impact quality-of-life; these may be reported some years before PD is diagnosed. Unfortunately, NMS are not well-recognized in PD patients in the clinic and are often not reported spontaneously by the patient. The spectrum of NMS includes: neuropsychiatric symptoms, sleep disorders, gastrointestinal, sensory symptoms, autonomic dysfunction, sexual dysfunction, as well as fatigue, diplopia, and weight loss. Since the discovery of levodopa as the mainstay of pharmacotherapy in the early 1960s, the pharmacological treatment of PD has been continuously debated and adapted. Several treatment options for switching from intermittent to continuous dopaminergic stimulation (CDS) therapy were discussed. Duodenal infusion of levodopa (LCIG) or apomorphine (a nonselective dopamine agonist) infusions offer significant benefits to counteract the ‘off’ symptomatology and end-of-dose biphasic dyskinesia for selected patients. This can be considered an option prior to surgery (Deep Brain Stimulation). Notable improvements in motor and non-motor functioning can be achieved with CDS therapy, although limitations and unanswered questions remain (such as how early CDS therapies should be initiated). The final day of the course (July 10) began with a presentation by Ioana Ispas, the European Affairs Advisor for Bioethics, Genomics and Health International Cooperation, Department Ministry of National Education, Bucharest, Romania. She discussed European funding opportunities in the neurosciences in relation to Horizon 2020 – the European Union Framework Programme Horizon 2020. In addition, In addition, the rules and procedures for applying for research funding opportunities offered in a coordinated way by Member States through Joint Programming Initiative in the area of neurodegenerative diseases and joint programming initiatives was described. The remainder of the morning was dedicated to multiple sclerosis (MS), including: management of disease symptoms; cognition, fatigue and MS, and their significance and use as broader clinical indicators of treatment success; current treatments and new perspectives for MS therapy. MS is the most common non-traumatic cause of disability in young adults. In addition to the so-called 'classical' immunomodulators, oral disease-modifying therapies (teriflunomide, fingolimod, laquinimod, dimethyl fumarate) have been developed; there is also the possibility of regenerative or reparative therapies. Inflammation and oxidative stress are believed to be key features in the pathophysiology of MS and are associated with damage to the blood-brain barrier, myelin and axons.Cognitive impairment, fatigue, and depression often interact in a complex way in MS. MS-related fatigue is related to disturbances in cognitive function, leading to a perception of impaired overall health, mental state, and quality of life. Assessment of cognition and fatigue can be used as additional measures to evaluate treatment efficacy in the individual patient. For all patients with MS, particularly those developing cognitive issues, it is important to evaluate the depression and to treat accordingly. One of the most disruptive functional impairments in MS relates to mobility, which is influenced by other disese-associated deficits and symptoms. MS patients are most concerned by walking impairments, followed in importance by visual function and thinking/memory. Walking impairment hinders the patient’s ability to perform daily activities, decreases employment prospects and reduces health-related quality of life. As mobility is one of the most important aspects related to MS, the combination of a proper medication, the patients’ active attitude and exercise programs may improve significantly the profile of their disability and therefore quality of life. The students (some 200 in all, representing Romania, Ukraine, Uzbekistan, Vietnam, Russia, Chile, Egypt) received their course certificates of completion during the evening’s farewell dinner.

Neurodegenerative disorders encompass a spectrum of illnesses, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and even schizophrenia, autism and potential mood disorders [1]. In parallel with this, a number of metabolic disorders – largely brought together under the term, metabolic syndrome (a conglomerate of several conditions, such as glucose intolerance/insulin resistance, hypertension, obesity, and dyslipidemia that, as a collection, elevate the risk of developing type 2 diabetes and cardiovascular diseases) - can negatively impact human health and life span dramatically. Type 2 diabetes, like cardiovascular and neurodegenerative diseases, tends to progressively affect people as they age, particularly those with genetic and epigenetic pre-dispositions. Furthermore, like a number of other conditions, type 2 diabetes is clearly associated with over-nutrition and physical inactivity [2]. Affected individuals can be distinguished by a defect in insulin secretion together with a reduced response to insulin-stimulated glucose uptake in target tissues, including liver and adipose tissues - a disorder termed insulin resistance. With insulin secretion no longer able to compensate for rising peripheral insulin demand, the prediabetic state advances to diabetes and, although multiple mechanisms clearly underlie defective insulin secretion and resistance (for example, glucotoxicity, oxidative stress, lipotoxicity, endoplasmic reticulum stress, changes in gut microbiota, and others) [2], the contributions of each remain largely unknown and these same mechanisms can impact and induce dysfunction in other body systems – including the brain. It is widely accepted that neurodegenerative disorders, type 2 diabetes and cardiovascular diseases are debilitating disorders impacting over one hundred million persons across the globe, regardless of continuous new discoveries in science and technology [3]. It is becoming increasingly clear that all of these disorders - and the aberrant biochemical cascades occurring in each - have the potential to promote the other disorders; and hence special attention is required by medical scientists to understand and develop strategies to remedy this. More and more links are being found almost daily between environmental factors, obesity, oxidative stress, inflammation, systemic maladies and central nervous system disorders like Alzheimer's disease, Parkinson's disease, Huntington's and even some cancers [4-8] (Fig. 1). With this at the forefront, the current thematic issue of CNS & Neurological Disorders - Drug Targets was developed, and contributing authors were requested to shed light on important features deemed critical - like abnormalities in the level of key enzymes, hormones, peptides, inflammatory modulators, microbiota, bacterial/viral infections and the insulin signaling system in their articles (whether a review, original research, case report or letter). In this way, this special issue of CNS & Neurological Disorders - Drug Targets will hopefully move towards a greater understanding of the linkage between neurodegenerative conditions and other disorders with respect to cellular, molecular neurobiology, genetics, drug development and clinical aspects to promote progress towards effective management strategies for neurodegenerative disorders.On a personal level, I wish to end this editorial by thanking Stephen D. Skaper, the Editor in Chief, as well as Hina Wahaj, the Managing Editor, and all the contributing authors who have passionately responded to my request to provide interesting articles (Table 1). I additionally extend my thanks to all peer reviewers for their time and expertise in revising individual contributions to a consistently high level of excellence. Finally, I am grateful to Nigel H. Greig (Drug Design & Development Section, Intramural Research Program, National Institute on Aging, National Institute Health, USA) for kindly editing this ‘editorial article’ and for his continuous support in relation to my own research journey in Alzheimer's disease and type 2 diabetes.

Class B G-protein coupled receptors are involved in a wide variety of diseases and are a major focus in drug design. Migraines are a common problem, and one of their major causative agents is the class B G-protein coupled receptor, Calcitonin gene-related peptide (CGRP) receptor, a target for competitive drug discovery. The calcitonin receptor-like receptor generates complexes with a receptor activity-modifying protein, which determines the type of receptor protein formed. The CGRP receptor comprises a complex formed from the calcitonin receptor-like receptor and receptor activity-modifying protein 1. In this study, an in silico docking approach was used to target the calcitonin receptor-like receptor in the bound form with receptor activity-modifying protein 1 (CGRP receptor), as well as in the unbound form. In both cases, the resulting inhibitors bound to the same cavity of the calcitonin receptor-like receptor. The twelve evaluated compounds were competitive inhibitors and showed efficient inhibitory activity against the CGRP receptor and Calcitonin receptor-like receptor. The two studied quinoline derivatives demonstrated potentially ideal inhibitory activity in terms of binding interactions and low range nano-molar inhibition constants. These compounds could prove helpful in designing drugs for the effective treatment of migraines. We propose that quinoline derivatives possess inhibitory activity by disturbing CGRP binding in the trigeminovascular system and may be considered for further preclinical appraisal for the treatment of migraines.

Alzheimer's disease (AD) is a degenerative disease of brain that is associated with dementia, brain atrophy, accumulation of hyperphosphorylated tau protein and amyloid-beta peptide in hippocampus and cortex region of the brain. The development of AD is a multifactorial process that may also involve infection with bacterial pathogens. Recent studies suggest that bacteria including spirochetes have the potential to initiate cascade of events, leading to inflammatory condition of the central nervous system. Bacteria and spirochetes are activators of proinflammatory cytokines, generate free radicals, nitric oxide and further induction of apoptosis. Infection with these microbes may be considered as a risk factor for pathophysiology of AD or to cognitive changes. Recent studies have revealed that exposure to these microorganisms induces Aβ accumulation and tau protein phosphorylation, and chronic infections with these pathogenic bacteria can possibly contribute to progression of AD. In this article, we update and review the role of bacteria in the pathogenesis of AD resulting from initiation of cascade events in chronic inflammations and amyloidogenesis. Controlling these chronic infections with antibacterial or anti-inflammatory drugs will allow preventing inflammation, a risk factor for AD.

γ-aminobutyric acid type A receptors (GABAARs) are key players in the mediation of synaptic inhibition in the mammalian brain. Several proteins have a significant role in the complex trafficking mechanisms of GABAARs to and from the neuronal surface. Proper trafficking maintain number and localization of GABAAR at the neuronal surface which is necessary for inhibitory neuronal transmission. Among many other proteins, recently identified molecular motor protein KIF5A is also involved in the GABAAR trafficking by interacting with GABARP protein. Deletion in the KIF5A can impair transportation mechanism of GABAAR, while an inappropriate inhibitory GABAAR mediated neuronal transmission leads to epilepsy. In this article, we discussed the dynamic regulation of GABAAR, role of different proteins in GABAAR trafficking, clustering and endocytosis by direct interaction with GABAAR or interaction through adaptor proteins linked with microtubules and also the dysregulation of GABAAR trafficking in epilepsy. It is concluded that various proteins are involved in the GABAAR trafficking; mutation or any other change in the interacting proteins can reduce the GABAAR trafficking and also reduces their cell surface expression which may lead to epilepsy.

Dementia is the leading cause of disability worldwide among chronic diseases in the elderly and is a major contributor to mortality. Importantly, dementia that develops as a comorbid condition significantly compounds the burden of disease on the person, their caregivers and the health care system. Dementia is a frequent comorbidity of Parkinson’s disease (PD) and about 80% of people with PD will develop dementia during the course of the disease. Incidence of dementia in PD ranges from 54.7 to 107.14 per 1000 person-years while point prevalence estimates range from 19.7 to 35.3%. The range in incidence and point prevalence can be attributed to varying diagnostic criteria, sample biases, and sample size. Nosologically, there is still disagreement on the origins of dementia in PD. Dementia development may be most often caused by the progression of PD-type pathology; however, the occurrence of Alzheimer’s disease (AD)-type pathology suggests that an interplay exists between the genes and proteins associated with PD and AD. Furthermore, these genes and proteins may increase the risk and severity of dementia development in people with PD. Understanding the mechanisms of neurodegeneration in PD and AD may, therefore, improve efforts to manage and treat PD dementia. Given this, it is important to adequately define the frequency of PD dementia for informed decision making, particularly in the areas of aged-care and government health policy.

Neurodegenerative diseases that afflict nervous system are characterized by progressive nervous system dysfunction and associated with the one-set of many diseases like Segawa’s syndrome (recessive form), autosomal recessive L-dopa-responsive dystonia, L-dopa non-responsive dystonia or progressive early-onset encephalopathy and recessive L-dopa-responsive parkinsonism. It has been reported that a number of mutations in coding regions, splice sites and promoter regions of tyrosine hydroxylase (TH) are associated with many such diseases. TH is responsible for catalyzing the conversion of L-tyrosine to L-3,4-dihydroxyphenylalanine. This reaction is considered as rate-limiting step in the biosynthesis of catecholamines, dopamine, norepinephrine and epinephrine, which has made TH an important target for drug development. In our previous study using comparative molecular docking approach, it was concluded that [4- (Propan-2-yl) Phenyl]Carbamic acid (PPCA) may serve as a potential inhibitor. By further extending, our focus is to determine the binding affinities of PPCA and mutated TH. 3D structures of mutated TH were predicted and subjected to molecular docking studies. PPCA was found to bind in the deep narrow groove lined with polar and aromatic amino acids in 14 out of 17 mutants under study (R202H, L205P, H215Y, G216S, T245P, F278P, T283M, R297W, R306H, C328F, A345V, L356M, T368M, Q381K, P461L, T463M and D467G). Our results corroborate efficient binding of PPCA with normal and mutated TH, indicating that PPCA might be a strong therapeutic candidate for the management of Parkinson’s disease and other related disorders. It may be a valuable target for evaluation in preclinical models.

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder, characterized by deposition of amyloid beta, neurofibrillary tangles, astrogliosis and microgliosis, leading to neuronal dysfunction and loss in the brain. Bio- and histochemical evidence suggests a pivotal role of central and peripheral inflammation in its aetiopathology, linked to the production of free radicals. Numerous epidemiological studies support that the long-term use of non-steroidal antiinflammatory drugs is preventive against AD, but these medications do not slow down the progression of the disease in already diagnosed patients. There are a number of studies focusing on traditional herbal medicines and small molecules (usually plant secondary metabolites) as potential anti-inflammatory drugs, particulary in respect to cytokine suppression. For instance, ω-3 polyunsaturated fatty acids and a number of polyphenolic phytochemicals have been shown to be effective against inflammation in animal and cell models. Some of these plant secondary metabolites have also been shown to possess antioxidant, anti-inflammatory, anti-amyloidogenic, neuroprotective, and cognition-enhancing effects. This review will provide an overview the effects of catechins/proanthocyanidins from green tea, curcumin from turmeric, extracts enriched in bacosides from Brahmi (Bacopa monnieri), flavone glycosides from Ginkgo biloba, and ω-3 polyunsaturated fatty acids. They do not only counteract one pathophysiological aspect of AD in numerous in vitro and in vivo studies of models of AD, but also ameliorate several of the above mentioned pathologies. The evidence suggests that increased consumption of these compounds might lead to a safe strategy to delay the onset of AD. The continuing investigation of the potential of these substances is necessary as they are promising to yield a possible remedy for this pervasive disease.

The emerging data suggest that type 2 diabetes mellitus (T2DM) can contribute significantly to the onset or progression of Alzheimer’s disease (AD) either directly or as a cofactor. Various in vitro and in vivo animal and human clinical studies have provided evidence that T2DM is a major risk factor in the pathology of AD and the two diseases share common biological mechanisms at the molecular level. The biological mechanisms that are common in the pathology of both T2DM and AD include insulin resistance, impaired glucose metabolism, β-amyloid formation, oxidative stress, and the presence of advanced glycation end products. With better understanding of the degree of association between AD and T2DM and the underlying molecular mechanisms explaining this relationship, it is hoped that researchers will be able to develop effective therapeutic interventions to treat or control T2DM and, as a consequence, delay the onset or progression of AD.

Alzheimer’s disease (AD) is a common neurodegenerative disorder primarily affecting memory and thinking ability; caused by progressive degeneration and death of nerve cells. In this study, we integrated multiple dataset retrieved from the National Center for Biotechnology Information's Gene Expression Omnibus database, and took a systemsbiology approach to compare and distinguish the molecular network based synaptic dysregulation associated with AD in particular and neurodegenerative diseases in general. We first identified 832 differentially expressed genes using cut off P value <0.5 and fold change > 2, followed by gene ontology study to identify genes associated with synapse (n=95) [membrane associated guanylate kinase, 2, amyloid beta precursor protein, neurotrophic tyrosine kinase, receptor, type 2], synapse part [γ-aminobutyric acid A receptor, γ1], synaptic vesicle [glutamate receptor, ionotropic, α-amino-3-hydroxy-5- methyl-4-isoxazole propionic acid receptor 2, synaptoporin], pre- and post-synaptic density [neuronal calcium sensor 1, glutamate receptor, metabotropic 3]. We integrated these data with known pathways using Ingenuity Pathway Analysis tool and found following synapse associated pathways to be most affected; γ-aminobutyric acid receptor signaling, synaptic long term potentiation/depression, nuclear factor-erythroid 2-related factor 2-mediated oxidative stress response, huntington's disease signaling and Reelin signaling in neurons. In conclusion, synaptic dysfunction is tightly associated with the development and progression of neurodegenerative diseases like AD.

Neurodegenerative and neurobehavioral diseases may be caused by chronic and neuropathic viral infections and may result in a loss of neurons and axons in the central nervous system that increases with age. To date, there is evidence of systemic viral infections that occur with some neurodegenerative conditions such as Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, multiple sclerosis, autism spectrum disorders, and HIV-associated neurocognitive disorders. With increasing lifespan, the incidence of neurodegenerative diseases increases consistently. Neurodegenerative diseases affect approximately 37 million people worldwide and are an important cause of mortality. In addition to established non-viral-induced reasons for neurodegenerative diseases, neuropathic infections and viruses associated with neurodegenerative diseases have been proposed. Neuronal degeneration can be either directly or indirectly affected by viral infection. Viruses that attack the human immune system can also affect the nervous system and interfere with classical pathways of neurodegenerative diseases. Viruses can enter the central nervous system, but the exact mechanism cannot be understood well. Various studies have supported viral- and non-viral-mediated neurodegeneration at the cellular, molecular, genomic and proteomic levels. The main focus of this review is to illustrate the association between viral infections and both neurodegenerative and neurobehavioral diseases, so that the possible mechanism and pathway of neurodegenerative diseases can be better explained. This information will strengthen new concepts and ideas for neurodegenerative and neurobehavioral disease treatment.

Amyloid β (Aβ) polypeptide plays a key role in determining the state of protein aggregation in Alzheimer’s disease. The hydrophobic C-terminal part of the Aβ peptide is critical in triggering the transformation from α-helical to β- sheet structure. We hypothesized that phospholipase A2 (PLA2) may inhibit the aggregation of Aβ peptide by interacting with the peptide and keeping the two peptide chains apart. In order to examine the nature of interactions between PLA2 and Aβ peptide, we prepared and crystallized complex of Naja naja sagittifera PLA2 with the C-terminal hepta-peptide Val-Gly-Gly-Val-Val-Ile-Ala. The X-ray intensity data were collected to 2.04 A resolution and the structure was determined by molecular replacement and refined to the crystallographic R factor of 0.186. The structural analysis revealed that the peptide binds to PLA2 at the hydrophobic substrate binding cavity forming at least eight hydrogen bonds and approximately a two dozen Van der Waals interactions. The number and nature of interactions indicate that the affinity between PLA2 and the hepta-peptide is greater than the affinity between two Aβ peptide chains. Therefore, PLA2 is proposed as a probable ligand to prevent the aggregation of Aβ peptides.

During recent years, numerous lines of research including proteomics and molecular biology have highlighted multiple targets and signaling pathways involved in metabolic abnormalities and neurodegeneration. However, correlation studies of individual neurodegenerative disorders (ND) including Alzheimer, Parkinson, Huntington and Amyotrophic lateral sclerosis in association with Diabetes type 2 Mellitus (D2M) are demanding tasks. Here, we report a comprehensive mechanistic overview of major contributors involved in process-based co-regulation of D2M and NDs. D2M is linked with Alzheimer’s disease through deregulation of calcium ions thereby leading to metabolic fluctuations of glucose and insulin. Parkinson-associated proteins disturb insulin level through ATP-sensitive potassium ion channels and extracellular signal-regulated kinases to enhance glucose level. Similarly, proteins which perturb carbohydrate metabolism for disturbing glucose homeostasis link Huntington, Amyotrophic lateral sclerosis and D2M. Other misleading processes which interconnect D2M and NDs include oxidative stress, mitochondrial dysfunctions and microRNAs (miRNA29a/b and miRNA-9). Overall, the collective listing of pathway-specific targets would help in establishing novel connections between NDs and D2M to explore better therapeutic interventions.

Alpha-Synuclein (αSyn) is a 14 kDa pre-synaptic protein predominantly expressed in various regions of brain comprising neocortex, hippocampus, striatum, thalamus and cerebellum. αSyn aggregates have special neuropathologic relevance for comprehending Parkinson’s disease (PD) and other synucleopathies due to the presence of αSyn aggregates in brain of patients suffering from these diseases. Direct relationship between PD and various single nuclear polymorphisms of αSyn further displays an inherent significance of mutated αSyn in increasing the risk for developing PD. So far, various theories have been emerged to explain αSyn mediated neuronal cell toxicity seen in patients with PD, including interaction of αSyn aggregates with biomolecules, vesicle dystrafficking, augmented oxidative stress, mitochondrial dysfunction, and disruption of synaptic function. Despite the advances in understanding of PD pathophysiology, current available treatments are still aiming at giving symptomatic relief. Lately, PD vaccines against αSyn aggregates are also being considered. However, various other avenues for e.g. post-translational and conformational modifications of αSyn, effect of cellular small molecules such as polyamines and osmolytes on αSyn aggregation, still remain unexplored and we believe that therapeutics directed at these ignored targets will surface as a successful combinational therapy for PD. Additionally, understanding mechanisms behind the interplay between PD and other health conditions, such as Gaucher’s disease, Cardiovascular disorders, Hypertension, Homocystinuria, Type-II Diabetes, and Cancer are also speculated to provide great insight for novel therapeutic interventions. In the current review, we have precisely discussed all these ignored avenues with their possible clinical implications. Link between PD and other associated diseases has also been extensively reviewed.

Neurodegenerative disorders are increasingly identified as one of the major causes of epilepsy. The relationship of epileptic activity to Alzheimer’s disease (AD) is of clinical importance. Voltage-gated sodium channel (VSC) is one of the best targets in the treatment of epilepsy while β-secretase (BACE) has long been observed as a curative target for AD. To explore a possible link between the treatment of AD and epilepsy, the molecular interactions of recently Food and Drug Administration approved antiepileptic drug Aptiom (Eslicarbazepine acetate) with BACE and VSC were studied. Docking study was performed using ‘Autodock4.2’. Hydrophobic and pi-pi interactions play critical role in the correct positioning of Eslicarbazepine acetate within the catalytic site of VSC and BACE enzyme to permit docking. Free energy of binding (ΔG) of ‘Eslicarbazepine acetate-VSC’ interaction and ‘Eslicarbazepine acetate-CAS domain of BACE’ interaction was found to be -5.97 and -7.19 kcal/mol, respectively. Hence, Eslicarbazepine acetate might act as a potent dual inhibitor of BACE and VSC. However, scope still remains in the determination of the three-dimensional structure of BACE- Eslicarbazepine acetate and VSC-Eslicarbazepine acetate complexes by X-ray crystallography to validate the described data. Further, Aptiom (Eslicarbazepine acetate) could be expected to form the basis of future dual therapy against epilepsy associated neurological disorders.

GNE (UDP-N-acetylglucosamine 2-epimerase/ N-acetylmannosamine kinase) is a bifunctional enzyme which catalyzes the conversion of UDP-GlcNAc to ManNAc and ManNAc to ManNAc 6-phosphate, key steps in the sialic acid biosynthesis. Mutations in GNE lead to a neuromuscular disorder, Hereditary Inclusion Body Myopathy (HIBM). A major limitation in understanding the function of GNE is lack of recombinant full length GNE (rGNE) protein for detailed biophysical and structural characterization. In the present study, we have used Dictyostelium discoideum (Dd) as an alternate host for successful expression and secretion of functionally active form of GNE and its mutant proteins. We have generated Dd-AX3 stable cell lines harboring wtGNE or its mutants with Dd specific secretory signal sequence, PsA (prespore antigen). Upon starvation, rGNE was secreted in the medium from secretory vesicles. The rGNE was functionally active with epimerase activity (54±5.2 mU/mg) and kinase activity (66.45±3.48 mU/mg), while both epimerase and kinase activities of mutant GNE were drastically reduced. These activities were found to be statistically significant at p value < 0.05. Our study clearly demonstrates that Dd can be used as an expression host for the production of recombinant and functionally active form of GNE and its mutant proteins that can be used for biophysical characterization and structural determination of GNE to understand the pathomechanism of HIBM.

Parkinson’s disease is a common neurodegenerative disease diagnosed by well established clinical motor symptoms. However, the disease also encompasses many nonmotor issues that can impact a myriad of processes such as cardiovascular status, gastrointestinal function, autonomic function, mood and sleep. These issues can be more debilitating and impactful on health status in part because of a lack of effective treatments. The pathophysiology of the disease process is under active investigation with postulated mechanisms involving both the central nervous system and the periphery. More in depth examination of the many nonmotor symptoms may aid in the discovery of the overarching pathological origin and progression of Parkinson’s disease. Examining the disease process from the perspective of nonmotor symptoms may also provide additional target pathways and potential drug development options not considered previously.

In general, proteins can only execute their various biological functions when they are appropriately folded. Their amino acid sequence encodes the relevant information required for correct three-dimensional folding, with or without the assistance of chaperones. The challenge associated with understanding protein folding is currently one of the most important aspects of the biological sciences. Misfolded protein intermediates form large polymers of unwanted aggregates and are involved in the pathogenesis of many human diseases, including Alzheimer’s disease (AD) and Type 2 diabetes mellitus (T2DM). AD is one of the most prevalent neurological disorders and has worldwide impact; whereas T2DM is considered a metabolic disease that detrementally influences numerous organs, afflicts some 8% of the adult population, and shares many risk factors with AD. Research data indicates that there is a widespread conformational change in the proteins involved in AD and T2DM that form β-sheet like motifs. Although conformation of these β-sheets is common to many functional proteins, the transition from α-helix to β-sheet is a typical characteristic of amyloid deposits. Any abnormality in this transition results in protein aggregation and generation of insoluble fibrils. The abnormal and toxic proteins can interact with other native proteins and consequently catalyze their transition into the toxic state. Both AD and T2DM are prevalent in the aged population. AD is characterized by the accumulation of amyloid-β (Aβ) in brain, while T2DM is characterized by the deposition of islet amyloid polypeptide (IAPP, also known as amylin) within beta-cells of the pancreas. T2DM increases pathological angiogenesis and immature vascularisation. This also leads to chronic cerebral hypoperfusion, which results in dysfunction and degeneration of neuroglial cells. With an abundance of common mechanisms underpinning both disorders, a significant question that can be posed is whether T2DM leads to AD in aged individuals and the associations between other protein misfolding diseases.

Acetylcholine (ACh) has been the first molecule to be identified as neurotransmitter. The cholinergic and cholinoceptive areas, both in central and peripheral nervous system, have been well documented. Acetylcholine has been described to control, during embryogenesis, cell proliferation as well as neuron and glial cell survival and differentiation. In the adult, acetylcholine and its receptors are distributed in many tissues other than in the nervous system. More recently, new physiological roles in neuronal and non-neuronal tissues have been proposed for ACh as well as its possible involvement in different pathologies. Altered levels of ACh or modified receptors expression and function, in selected areas of the nervous system, have been described in several neurodegenerative diseases such as Alzheimer’s, Parkinson’s and Huntington as well as in psychiatric disorders such as schizophrenia. Frequently own cognitive, behavioral and motor disabilities that characterize these pathologies are correlated to cholinergic circuit dysfunction. Moreover the involvement of ACh as modulator of the inflammation, in and out of the nervous system, has suggested that its altered functions might represent an additional pathogenetic mechanism negatively influencing the disease outcome as recently suggested in multiple sclerosis. The present review will focus on identifying the cause/effect relationship that may explain the cholinergic dysfunction in several nervous system disorders. Moreover the possible therapeutic novelties including cholinesterase inhibitors, muscarinic agonists and antagonists, and genetic therapy will be discussed.