CNS & Neurological Disorders - Drug Targets - Volume 16, Issue 3, 2017

Neuroplasticity is not only shaped by learning and memory but is also a mediator of responses to neuron attrition and injury (compensatory plasticity). As an ongoing process it reacts to neuronal cell activity and injury, death, and genesis, which encompasses the modulation of structural and functional processes of axons, dendrites, and synapses. The range of structural elements that comprise plasticity includes long-term potentiation (a cellular correlate of learning and memory), synaptic efficacy and remodelling, synaptogenesis, axonal sprouting and dendritic remodelling, and neurogenesis and recruitment. Degenerative diseases of the human brain continue to pose one of biomedicine’s most intractable problems. Research on human neurodegeneration is now moving from descriptive to mechanistic analyses. At the same time, it is increasing apparently that morphological lesions traditionally used by neuropathologists to confirm post-mortem clinical diagnosis might furnish us with an experimentally tractable handle to understand causative pathways. Consider the aging-dependent neurodegenerative disorder Alzheimer’s disease (AD) which is characterised at the neuropathological level by deposits of insoluble amyloid β-peptide (Aβ) in extracellular plaques and aggregated tau protein, which is found largely in the intracellular neurofibrillary tangles. We now appreciate that mild cognitive impairment in early AD may be due to synaptic dysfunction caused by accumulation of non-fibrillar, oligomeric Aβ, occurring well in advance of evident widespread synaptic loss and neurodegeneration. Soluble Aβ oligomers can adversely affect synaptic structure and plasticity at extremely low concentrations, although the molecular substrates by which synaptic memory mechanisms are disrupted remain to be fully elucidated. The dendritic spine constitutes a primary locus of excitatory synaptic transmission in the mammalian central nervous system. These structures protruding from dendritic shafts undergo dynamic changes in number, size and shape in response to variations in hormonal status, developmental stage, and changes in afferent input. It is perhaps not unexpected that loss of spine density may be linked to cognitive and memory impairment in AD, although the underlying mechanism(s) remain uncertain. This article aims to present a critical overview of current knowledge on the bases of synaptic dysfunction in neurodegenerative diseases, with a focus on AD, and will cover amyloid- and nonamyloid- driven mechanisms. We will consider also emerging data dealing with potential therapeutic approaches for ameliorating the cognitive and memory deficits associated with these disorders.

Parkinson’s disease (PD) is a progressive neurodegenerative disorder with prominent motor and non-motor symptoms. Psychosis develops in over 40% of PD patients and it is one of the most distressing symptoms for patients and caregivers alike. Until recently, atypical antipsychotics, clozapine and quetiapine were used to treat psychotic symptoms, but treatment was associated with substantial concerns for side-effects of clozapine and unfounded efficacy for quetiapine. Extensive research has shown that the antipsychotic effect of these drugs could be attributed to serotonin 2a receptor (5-HT2A) triggered mechanisms. A selective 5-HT2A inverse agonist, pimavanserin, has been developed, investigated and has gained approval in April 2016 in the US for the treatment of hallucinations and delusions in PD. In this review we primarily focus on psychosis in PD, the current treatment possibilities and the new, emerging therapy, pimavanserin, a selective 5-HT2A inverse agonist. All articles were reviewed in this topic and indexed in PubMed with keywords: Parkinson’s disease psychosis, serotonin 2a receptor inverse agonist, clozapine, quetiapine, pimavanserin.

Heat shock proteins (HSPs) are families of molecular chaperones that play important homeostatic functions in the central nervous system (CNS) by preventing protein misfolding, promoting degradation of improperly folded proteins, and protecting against apoptosis and inflammatory damage especially during hyperthermia, hypoxia, or oxidative stress. Under stress conditions, HSPs are upregulated to protect cells from damage that accumulates during ageing as well as pathological conditions. An important, yet frequently overlooked function of some HSPs is their ability to function as extracellular messengers (also termed chaperokines) that modulate immune responses within the CNS. Given the strong association between protein aggregation, innate immune cell activation and neurodegeneration, the expression and roles of HSPs in the CNS is attracting attention in many neurodegenerative disorders including inflammatory diseases such as multiple sclerosis, protein folding diseases such as Alzheimer’s disease and amyotrophic lateral sclerosis, and genetic white matter diseases. This is especially so since several studies show that HSPs act therapeutically by modulating innate immune activation and may thus serve as neuroprotective agents. Here we review the evidence linking HSPs with neurodegenerative disorders in humans and the experimental animal models of these disorders. We discuss the mechanisms by which HSPs protect cells, and how the knowledge of their endogenous functions can be exploited to treat disorders of the CNS.

Purinergic signalling, i.e. ATP as an extracellular signalling molecule and cotransmitter in both peripheral and central neurons, is involved in the physiology of neurotransmission and neuromodulation. Receptors for purines have been cloned and characterised, including 4 subtypes of the P1(adenosine) receptor family, 7 subtypes of the P2X ion channel nucleotide receptor family and 8 subtypes of the P2Y G protein-coupled nucleotide receptor family. The roles of purinergic signalling in diseases of the central nervous system and the potential use of purinergic compounds for their treatment are attracting increasing attention. In this review, the focus is on the findings reported in recent papers and reviews to update knowledge in this field about the involvement of purinergic signalling in Alzheimer’s, Parkinson’s and Huntington’s diseases, multiple sclerosis, amyotrophic lateral sclerosis, degeneration and regeneration after brain injury, stroke, ischaemia, inflammation, migraine, epilepsy, psychiatric disorders, schizophrenia, bipolar disorder, autism, addiction, sleep disorders and brain tumours. The use in particular of P2X7 receptor antagonists for the treatment of neurodegenerative diseases, cancer, depression, stroke and ischaemia, A2A receptor antagonists for Parkinson’s disease and agonists for brain injury and depression and P2X3 receptor antagonists for migraine and seizures has been recommended. P2Y receptors have also been claimed to be involved in some central nervous disorders.

In this article the emerging biological overlaps of CNS disorders and psychiatric conditions are reviewed. Recent work has highlighted how immune-inflammatory processes and their interactions with oxidative and nitrosative stress, couple to drive changes in neuroregulatory tryptophan catabolites, with consequences for serotonin availability, including as a precursor for the melatonergic pathways. Subsequent alterations in the regulation of local melatonin synthesis are likely to have direct impacts on the reactivity of immune cells, both centrally and systemically. These inflammatory processes also lead to the activation of wider immune processes. Such wider processes can include the production of immunoglobulin (Ig)A and IgM antibody responses, including to tryptophan catabolites, emphasizing the importance of immune responses, and their interactions with inflammatory processes, in the etiology and course of an array of medical conditions, including CNS disorders and psychiatric conditions. Such work poses questions as to the validity and utility of current, non-biologically based classification systems for psychiatric and CNS disorders. In this article, the biological underpinnings of CNS disorders and psychiatric conditions are reviewed in the context of how recent data, in reconceptualizing key processes in these classically-conceived brain-associated disorders, provides scope for novel, and hopefully more clinically useful, treatments. These processes are looked at in detail in Alzheimer's disease and major depressive disorder. One important treatment target is the gut. Alterations in the gut, including gut permeability and the composition of the microbiome, have now become an important target for treatment across an array of medical conditions, emphasizing the importance of targeting regulators of the immune system in developing novel treatments that are based on a more comprehensive and 'wholistic' understanding of currently poorly managed medical conditions, particularly psychiatric and CNS disorders.

The blood brain barrier (BBB) is a continuous, non-fenestrated vessel system that tightly regulates the movement of molecules, ions, and cells between the blood and the central nervous system. Endothelial cells are the major constituents of the BBB and these cells are linked to each other through intercellular contact points composed of tight junctions, adherent junctions and gap junctions. These three types of junctions are connected to the intracellular actin cytoskeleton via various adaptor proteins. Thus, the actin cytoskeleton plays a crucial role in regulating the stability of endothelial cell contacts and vascular permeability. Shear stress, growth factors, and Wnt/β-catenin pathway modulators contribute to maintaining endothelial cell integrity by controlling actin dynamics under homeostatic conditions. Interestingly, the downstream signaling of the aforementioned factors converges at Rac1, which mediates cortical actin stabilization, stress fiber destabilization and junctional complex stabilization by controlling subcellular cofilin dynamics. However, Rac1 is not the only modulator of cofilin activity; many other agents activated during inflammatory, ischemic, and excitotoxic conditions can disturb homeostatic cofilin dynamics and induce BBB disruption. Therefore, in this review, we discuss organization of the actin cytoskeleton in BBB endothelial cells and how interactions between the actin cytoskeleton and junctional complexes are maintained during homeostatic conditions. Furthermore, we discuss how an imbalance in subcellular cofilin dynamics can contribute to BBB disruption and highlight Rac1 as a potential target that can be exploited to preserve BBB stability.

Effective non-genetic disease modifying treatments for Huntington’s disease (HD) will necessarily target multiple diverse neurodegenerative processes triggered by mutant huntingtin. Neurotrophin receptors are well-positioned for this task as they regulate signaling pathways that largely overlap with signaling networks contributing to HD-related synaptic dysfunction, glial activation, excitotoxicity, and other degenerative processes. This review will discuss the contributions of disrupted neurotrophin receptor-related signaling to primary HD neuropathologies, and prospects for harnessing this signaling to develop therapeutics to counteract HD degenerative mechanisms. Application of the native protein ligands has been challenging pharmacologically, but progress has been made with the advent of small molecule compounds that can selectively bind to and activate specific Trk receptors or p75NTR to promote trophic and/or inhibit degenerative signaling in cell populations preferentially affected in HD.

Neuropathic pain is a chronic neurological disorder affecting millions of people around the world. The currently available pharmacologic agents for the treatment of neuropathic pain have limited efficacy and are associated with dose related unwanted adverse effects. Due to the limited access of drug molecules across blood-brain barrier, a small percentage of drug that is administered systematically, reaches the central nervous system in active form. These therapeutic agents also require daily treatment regimen that is inconvenient and potentially impact patient compliance. Application of nanoparticulate drugs for enhanced delivery system has been explored extensively in the last decades. Pulmonary delivery of nanomedicines for the management of various diseases has become an emerging treatment strategy that ensures the targeted delivery of drugs both for systemic and local effects with low dose and limited adverse effects. To the best of our knowledge, there are no inhaled drug products available on market for the treatment of neuropathic pain. The advantages of delivering therapeutics into deep lungs include non-invasive drug delivery, higher bioavailability with low dose, lower systemic toxicity, and potentially greater blood-brain barrier penetration. This review discusses and highlights the important issues on the application of emerging nanoparticulate lung delivery of drugs for the effective treatment of neuropathic pain.

It is currently known that erythrocytes are the major source of sphingosine 1-phosphate (S1P) in the body. S1P acts both extracellularly as a cellular mediator and intracellularly as an important second messenger molecule. Its effects are mediated by interaction with five specific types of G proteincoupled S1P receptor. Fingolimod, is a recognized modulator of S1P receptors, and is the first orally active disease-modifying therapy that has been approved for the treatment of multiple sclerosis. Magnetic resonance imaging data suggest that fingolimod may be effective in multiple sclerosis by preventing blood-brain barrier disruption and brain atrophy. Fingolimod might also possess S1P receptorindependent effects and exerts both anti-inflammatory and neuroprotective effects. In the therapeutic management of epilepsy, there are a great number of antiepileptic drugs, but there is still a need for others that are more effective and safer. S1P and its receptors might represent a suitable novel target also in light of their involvement in neuroinflammation, a well-known process underlying seizures and epileptogenesis. The objective of this manuscript is to review the biological role of S1P and its receptors, focusing on their expression, effects and possible involvement in epilepsy; furthermore, we summarize the possible anti-seizure properties of fingolimod and discuss its possible usefulness in epilepsy treatment. We conclude that fingolimod, being already commercially available, might be easily tested for its possible therapeutic effectiveness in epileptic patients, both after a more comprehensive evaluation of the real potential of this drug and following a clear evaluation of the potential role of its main targets, including the S1P signaling pathway in epilepsy.

Central nervous system diseases are major health issues and are often associated with disability or death. Most central nervous system disorders are characterized by high levels of oxidative stress. Nuclear factor erythroid 2 related factor (Nrf2) is known for its ability to regulate the expression of a series of enzymes with antioxidative, prosurvival, and detoxification effects. Under basal conditions, Nrf2 forms a complex with Kelch-like ECH associated protein 1, leading to Nrf2 inactivation via ubiquitination and degradation. However, following exposure of Keap1 to oxidative stress, Nrf2 is released from Keap1, activated, and translocated into the nucleus. Upon nuclear entry, Nrf2 binds to antioxidant response elements (ARE), thereby inducing the expression of genes such as glutathione s-transferase, heme oxygenase 1, and NADPH quinine oxidoreductase 1. Many dietary phytochemicals have been reported to activate the protective Nrf2/ARE pathway. Here, we review the preventive and protective effects of dietary Nrf2 activators against CNS diseases, including stroke, traumatic brain injury, Alzheimer’s disease, and Parkinson’s disease.

Background: Cerebrospinal-fluid (CSF) Alzheimer’s Disease (AD) biomarkers have been extensively studied in Parkinson’s Disease (PD). Although reduced CSF beta-amyloid1-42 (Aβ42) levels have been associated with cognitive decline in PD, the alteration of CSF tau proteins remains controversial. In addition, the impairment of the blood-brain barrier (BBB) has been previously demonstrated along the PD progression. Objective: The aim of the present study was to assess CSF AD biomarkers and BBB integrity in a natural cohort of cognitive intact PD patients compared to matched controls. Method: We measured and correlated CSF AD biomarkers and CSF/serum albumin ratio (expression of BBB integrity) in 124 PD patients and 46 controls. We distributed PD patients in three subgroups based on the Hoehn and Yahr (H) staging: mild PD (1-1.5, n=40); moderate PD (2-2.5, n=58); advanced PD (3-5, n=26). PD patients were also distinguished as tremor dominant (TD, n=44) and non-tremor dominant (NTD, n=80). Results: PD patients showed lower CSF Aβ42 levels and higher CSF/serum albumin ratio compared to controls. CSF total tau (t-tau) concentrations as well as the CSF/serum albumin ratio gradually increased among H stages. Conversely, we did not find differences between TD and NTD patients. Significantly, we documented the positive correlation between CSF t-tau levels and both CSF/serum albumin ratio and motor impairment in PD patients. Conclusion: This study performed in cognitive intact PD patients confirms the progressive increase of CSF tau proteins levels and BBB impairment along with the evolution of PD pathology. Since the BBB ensures the clearance of tau proteins from brain, we hypothesize that the dysfunction of the BBB throughout the disease progression may possibly cause the concurrent increase of CSF tau proteins levels in PD, which could be irrespective of cognitive decline.

Purpose: To investigate the effect of curcumin on tumor growth and angiogenesis of human gliomas and identify the underlying molecular mechanisms. Methods: A mouse xenograft glioma model was established by subcutaneously inoculating tumor cell aggregates derived from the U87 cell line. Mice were treated with 0.01ml/g body weight of curcumin or saline. Tumor volume was measured. Microvessel density was assessed by CD34 immunostaining, and angiogenesis by immunohistochemical staining of vascular endothelial growth factor (VEGF), angiopoietin-2 (Ang-2) and thrombospondin 1 (TSP-1). Results: At 28 days after treatment, tumor weights in the curcumin-treated group were much smaller than in the control group (0.23±0.11g vs 0.44±0.15g#140;p#156;0.05), resulting in a 45.8% inhibition of tumor growth. Curcumin also markedly inhibited microvessel density. Expression of VEGF and Ang-2 was inhibited by curcumin, whereas TSP-1 expression was up-regulated. Conclusion: This study shows that curcumin inhibits tumor growth by inhibiting VEGF/Ang-2/TSP-1- mediated angiogenesis in a xenograft glioma mouse model.

Background: Oxidative stress and amyloid deposition are tightly interconnected pathological features of Alzheimer disease. In this respect, both amyloid production and aggregation may be stimulated by oxidative stress and also the increase of pathogenic β-amyloid and its aggregated form lead to oxidative stress progression. Therefore, the search for potential drugs with both antioxidant and antiaggregation properties are of great interest. Methods: In this study, we described the stereospecific synthesis of alkaloid securinine aminoderivatives. Results: We showed that the newly synthesized compounds possess antioxidant and metal-chelating properties. Indeed, we report that one compound has inhibitory effects towards μ-amyloid aggregation. Conclusion: Based on these results, aminoderivatives of securinine scaffold are promising compounds for development of new drugs for the treatment of neurodegenerative diseases.

Background: Motoneurons with naturally elevated calcium binding protein content, such as parvalbumin, are more resistant against injury. Furthermore, increase of intracellular calcium, which plays a pivotal role in injury of neurons, could be moderated by elevating their calcium binding proteins. Objective: To test whether by elevating parvalbumin content of motoneurons, activation of neighboring microglial cells, a robust component of the inflammatory reaction after injury, could be influenced. Methods: Mice overexpressing neuronal parvalbumin were derived and the spinal motoneurons were challenged by cutting the sciatic nerve. At postoperative days 1, 4, 7, 14 and 21 the change of the chemokine ligand 2 immunostaining in the motoneurons and the activation of microglial cells, measured as alterations in CD11b immunostaining were determined. Calcium level of motoneurons was tested electron microscopically at postoperative day 7. Results: After axotomy, increased level of chemokine ligand 2 was detected in the lumbar motoneurons. The staining intensity reached its maximum at day 7 and decayed faster in transgenic mice compared to controls. Microglial activation around motoneurons attenuated faster in parvalbumin overexpressing mice, too, but the decrease of microglial activation was delayed compared to the decline of the chemokine ligand 2 signal. At the time when the microglial reaction peaked, no intracellular calcium increase was detected in the motoneurons of transgenic mice, in contrast to the twofold increase in wild type animals. Conclusion: Increased calcium buffering capacity, which augments resistance of motoneurons against calcium-mediated injury, leads to earlier termination of motoneuronal emission of CCL2 followed by a reduction of neighboring microglial activation after axotomy.