Current Neuropharmacology

Cerebrovascular diseases are one of the leading causes of death and adult disability worldwide and most common types of this diseases are ischemic stroke and hemorrhagic stroke. Blood-brain barrier (BBB) plays a vital role in regulating the trafficking of fluid, solutes and cells at the blood-brain interface and maintaining the homeostatic microenvironment of the central nervous system. Disruption of BBB has been proved closely related to the development of brain edema and neuronal cell death in cerebrovascular diseases. Recently, major efforts have been made to investigate the pathological mechanisms of BBB dysfunction, and develop pharmacological agents which would be able maintain BBB function after pathological events. In this Special Issue on BBB dysfunction in Current Neuropharmacology, the authors provide the latest review on cellular and molecular basis of BBB dysfunction, bring new insights into BBB protection, and point toward potential translation of preclinical studies to improve the treatment of cerebrovascular diseases. In this special issue, Okada and colleagues presented a panoramic view of current studies on BBB dysfunctions after cerebrovascular diseases, including structure and function of BBB, techniques utilized to study BBB breakdown, biomarkers and imaging techniques in clinical settings, as well as pathological mechanisms and therapeutic targets [1]. They illustrated that phenotypic transformation of myeloid cells such as macrophages and microglia regulates the initiation, evolution, and resolution of inflammation, which compromise the integrity of BBB. Another group, Kang et al presented an in-depth discussion on the diversity of microglia phenotypic polarizations and the communication between microglia and endothelial cells after stroke. They concluded that the time pattern of microglia polarization may determine the therapeutic effect of pharmacological agents [2]. The crosstalk between inflammation and BBB dysfunction was eloquently elucidated by Ziping Han’s team [3]. They reviewed how the dynamic and bidirectional crosstalk between inflammation and BBB during stroke occurs, and proposed personalized medicine for the treatment of stroke. The contribution from Shen and Ma represent an important advance in the role of miRNAs in the modulation of BBB functions after ischemic stroke and highlight the role of several miRNAs which are implicated in the pathogenesis of neonatal hypoxic-ischemic brain injury [4]. As there is a significant physiological difference between the developing and mature brain, more studies are needed to further determine the protective effect of miRNAs in hypoxic-ischemic brain injury in neonates. In subarachnoid hemorrhage (SAH) patients, BBB disruption is a critical contributor to the development of early brain injury [5]. The disruption is highly associated with increased mortality and poor prognosis. Li and colleagues summarized the molecular mechanisms of BBB disruption after SAH, and stated that the apoptosis of endothelial cells and loss of tight junction proteins are the two major causes responsible for BBB broken after SAH [6]. They suggested, therefore, therapeutic strategies against these two factors should be further explored in the future. Furthermore, Chen et al. addressed the recent clinical trials on neuroprotection of SAH patients, including pharmacological and non- pharmacological approaches [7]. The authors indicated that intraventricular nimodipine shows the exciting result to achieve better clinical efficacy and fewer side effects. They also considered that imaging techniques are promising tools to detect the abnormality of BBB and to predict the outcome in clinical setting. Angiogenesis is an important defense mechanism for the restoration of blood supply and re-organization of the neuronal circuit following ischemic stroke [8]. However, there is compelling concern that the therapeutic angiogenesis in vascular remodeling after stroke accompanied with abnormally increased BBB permeability. Yang and Torbey presented an elegant work in which they demonstrated that the abnormally high BBB permeability in peri-infarct areas is caused by a lack of major tight junction proteins in endothelial cells in newly build vessels, and pericytes play a key role in tight junction formation during angiogenesis [9]. They recommended defining and optimizing restorative therapies by characterizing the cellular and molecular mechanisms to facilitate functional BBB restoration without exacerbating brain edema and inflammation during treatment of ischemic stroke. Given the prosperity of stem cell therapy in recent years, Gao et al. extensively illustrated the effects and underlying mechanisms of cell therapy on the BBB permeability in ischemic stroke [10]. There is still a great gap between preclinical and clinical applications of stem cells, and some teething problems such as safety and ethical concerns need to be ironed out. Collectively, this Special Issue highlights several issues that are at the forefront of the BBB dysfunction in cerebral diseases. A better understanding of these mechanisms will contribute to the identification of therapeutic targets and promote the translational research of BBB protection.

Obsessive-compulsive (OC) spectrum disorders are a group of psychiatric disorders new to the DSM. They are mainly characterized by repetitive thoughts, anxiety, emotional distress, and compulsive behaviours. The specific types of obsessions, anxiety symptoms, and compulsive behaviours vary according to each disorder. The DSM-5 distinguishes five main OC spectrum disorders: obsessive-compulsive disorder (OCD); body dysmorphic disorder (BDD); hoarding disorder; hair-pulling disorder (trichotillomania); and skinpicking disorder (excoriation). Although these disorders have some similarities regarding characteristics of patients, symptom presentation, neurobiological correlates, and treatment response, they are clearly distinct from one another. This special issue aims to explore the rationale and the clinical practice of current pharmacological strategies as related to the specific neurobiology of each OC spectrum disorder.

Addiction Medicine: What's new in this area?

The decline in both antioxidants and aging per se are associated with an increased risk of cognitive impairment, chronic brain damage, the outcome of which can manifest as neurodegeneration. Based on recent reports, neurodegenerative diseases affect more than 100 million people worldwide and cause significant economical and personal stress, and require long-term cost effective care. The main motives and the key driving force in the field of neurodegenerative research, are the desire for solutions to the ravages of CNS diseases especially, Alzheimer’s, Parkinson’s (respectively AD and PD), and others. An important topic to address is the use of neuropharmacological-driven approaches that could attenuate neuroinflammatory processes in the diseased brain, and improve the outcome. In this special issue of Current Neuropharmacology, contributors discuss a variety of experimental and clinical approaches including the development and delivery of novel central nervous system agents, gene therapies, and drug- and cell-based strategies, as well as micro RNA therapeutics. All of the treatments target CNS cellular compartment mechanisms and/or the mediators leading to neurodegenerative diseases in vivo and/or cytotoxicity in vitro as well. These downstream mechanisms include the activation of pro and/or anti-inflammatory signaling cascades, production of oxygen, nitric oxide (including nitric oxide oxidation products such as nitrite and nitrate contain reactive species), excitatory mediators and amino acids, and downregulation of growth factors that may lead to the development of neuronal injuries. Thus, this special issue focuses on up-to-date research, targeting these pathways and mediators upon CNS damage and potential drug targets. Pouran Makhdoumi and coworkers report the molecular mechanism of aniline induced spleen and neuronal toxicity in experimental rat exposure. It has been reported that the aniline exposure leads to neuron and spleen toxicity specifically, and results in diverse neurological effects and sarcoma that are defined by splenomegaly, hyperplasia, and fibrosis and tumors’ formation at the end. However, the molecular mechanism(s) of aniline-induced spleen toxicity is not fully understood, and previous studies have represented that aniline exposure results in iron overload and initiation of oxidative/nitrosative disorder stress and oxidative damage to proteins, lipids and DNA, and subsequently, in the spleen. Elevated expression of cyclins, cyclin- dependent kinases (CDKs) and phosphorylation of pRB protein along with increases in A, B and CDK1 as cell cycle regulatory proteins cyclins, and reduction in CDK inhibitors (p21 and p27) could be critical in cell cycle regulation, which contribute to tumorigenic response after aniline exposure. Critical analysis of the literature has shown that the aniline-induced splenic toxicity is correlated to oxidative DNA damage and initiation of DNA glycosylases expression (OGG1, NEIL1/2, NTH1, APE1 and PNK) for removal of oxidative DNA lesions in the rat. Oxidative stress causes transcriptional up-regulation of fibrogenic/ inflammatory factors (cytokines, IL-1, IL-6 and TNF-α) via induction of nuclear factor-kappa B, AP-1 and redoxsensitive transcription factors, in aniline treated-rats. The upstream signaling events as phosphorylation of IκB kinases (IKKα and IKKβ) and mitogen-activated protein kinases (MAPKs) could potentially be the causes of activation of NF-κB and AP-1. All of these events could initiate a fibrogenic and/or tumorigenic response in the spleen. Based on the authors’ interpretation, most likely, the spleen toxicity of aniline has been studied more, and the different mechanisms are suggested. This review summarizes those events following aniline exposure that induces spleen toxicity and neurotoxicity. Muneeb U Rehman and coworkers report recent literature evidence regarding the implication of natural products as neuroprotective strategies for neurological disorders. It has been well documented and reported that natural products can have a significant role in the prevention of diseases and in boosting the health of humans and animals. These natural products have been experimentally documented to possess various biological properties such as antioxidant, anti-inflammatory and antiapoptotic activities. In vitro and in vivo studies have further established the usefulness of natural products in various preclinical models of neurodegenerative disorders. Natural products include phytoconstituents, like polyphenolic antioxidants, found in herbs, fruits, nuts, vegetables and also in marine and fresh water flora. These phytoconstituents may potentially suppress neurodegeneration and improve memory as well as cognitive functions of the brain. Also, they are known to play a pivotal role in the prevention and cure of different neurodegenerative diseases, such as AD, epilepsy, PD etc. The large scale neuropharmacological activities of natural products have been documented which are due to the result of either inhibition of inflammatory processes, and/or the up-regulation of various cell survival proteins and/or combination of both. Due to the scarcity of human studies on neuroprotective effects of natural products, this review focuses on the various established activities of natural products in in vitro and in vivo preclinical models, and their potential neurotherapeutic applications using the available knowledge in the literature. Studies by Faheem Hyder Pottoo and coworkers discussed the mechanisms of estrogen and serotonin: the complexity of interactions and potential implications for epileptic seizures and epileptogenesis. Based on this report, burgeoning literature documents the confluence of ovarian steroids and central serotonergic systems in the injunction of epileptic seizures and epileptogenesis. In addition, estrogen administration in animals reduces neuronal death from seizures by up-regulation of the prosurvival molecule i.e. Bcl-2, anti-oxidant potential and protection of NPY interneurons. Serotonin modulates epileptiform activity in either direction i.e. by administration of 5-HT agonists or by reuptake of inhibitors that leads to the activation of 5-HT3 and 5-HT1A receptors tending to impede focal and generalized seizures, while depletion of brain 5-HT along with the destruction of serotonergic terminals leads to expanded neuronal excitability hence abatement of seizure threshold in experimental animal models. Serotonergic neurotransmission is influenced by the organizational activity of steroid hormones in the growing brain and the actuation effects of steroids which appear in adulthood. It is further established that ovarian steroids bring induction of dendritic spine proliferation on serotonin neurons thus thawing a profound effect on serotonergic transmission. This review features 5-HT1A and 5-HT3 receptors as potential targets for ameliorating seizure-induced neurodegeneration and recurrent hypersynchronous neuronal activity. Indeed 5-HT3 receptors mediate a cross-talk between estrogenic and serotonergic pathways, and could well be exploited for combinatorial drug therapy against epileptogenesis. Ylia A. Sidorova and coworkers report the pathophysiology of PD and potential implication of small molecules as a new treatment option for PD. PD is the second most common neurodegenerative disorder worldwide, the lifetime risk of developing this disease is 1.5%. Motor diagnostic symptoms of PD are caused by degeneration of nigrostriatal dopamine neurons. Unfortunately, there is no effective long-term treatment for PD and current therapy is limited to supportive care that partially alleviates disease signs and symptoms. As diagnostic symptoms of PD result from progressive degeneration of dopaminergic neurons, drugs restoring these neurons may significantly improve the treatment of PD. A literature search performed by Ylia A. Sidorova et al., using the PubMed, Web of Science and Scopus databases discussed the progress achieved in the development of neurodegenerative agents for PD. Based on this study, there are several groups of potential agents capable of protecting and restoring dopamine neurons in vitro cell cultures as well as animal models that mimic PD including neurotrophic factors and small molecular weight compounds. Based on the very careful analysis, authors’ conclusion is that in the promising results of in vitro and in vivo experiments, none of the found agents have yet shown conclusive neurorestorative properties in PD patients. Meanwhile, a few promising biological and small molecules have been identified. Their further clinical development could eventually give rise to disease-modifying drugs for PD. Dr. Iván Carrera and Professor Ramon Cacabelos present a report which demonstrates the current drugs and potential future neuroprotective compounds in the context of PD. Unfortunately, the progress made so far in understanding the etiology and pathogenesis of PD has only achieved the development of some clinical approaches intended to treat cognitive and behavioral symptoms such as memory and perception disorders. Despite the major advances in different genetic causes and risk factors for PD, which share common pathways to cell dysfunction and death, there is no complete model of PD that can be used to accurately predict the effect of drugs on disease progression. In addition, clinical trials are also important to test any novel neuroprotective agent, and recently, there have been great advances in the use of anti-inflammatory drugs and plant flavonoid antioxidants to protect against specific neuronal degeneration and interference with lipid and cholesterol metabolism. The increasing knowledge of the molecular events underlying the degenerative process of PD has stimulated research to identify natural compounds capable of halting or slowing down the progress of neural deterioration. Polyphenols and flavonoids, which play a neuroprotective role in a wide array of in vitro and in vivo models of neurological disorders, emerged from the multi-target bioagents found mainly in plants and microorganisms. This review presents a detailed overview of the multimodal activities of neuroprotective bio-agents tested so far, emphasizing their neurorescue/neuroregenerative activity. The brain-penetrating property of bio-agents may make these compounds an important class of natural drugs for the treatment of neurodegenerative diseases. Although there are numerous studies demonstrating beneficial effects in the laboratory by identifying critical molecular targets, the clinical efficacy of these neuroprotective treatments remains to be proven accurately. Mahmood Ahmad Khan and co-authors analyzed the current progress of peroxisome proliferator-activated receptor gamma agonist as an emerging therapeutic approach for the treatment of AD. Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors known to play an important role in the regulation of glucose absorption, homeostasis of lipid metabolism and are further involved in repressing the expression of genes related to inflammation. Thus, agonists of this receptor represent an attractive therapeutic target for AD. In recent, both clinical and preclinical studies show that using Peroxisome proliferator-activated receptor gamma (PPARγ) agonist improves both learning and memory along with other AD-related pathologies. Thus , PPARγ signifies a significant new therapeutic target in treating AD. This review has shed some light on the recent progress of how PPARγ agonist selectively modulates different cellular targets in AD and its potential in the future treatment of AD. Professor Gjumrakch Aliev’s research team critically analyzed the potential implication of dendrimer-based therapy for AD. AD is characterized by the loss of neurons in different brain regions. It is the most common cause of dementia in the elderly population accompanied by pathological degeneration of the neurons and formation of neurofibrillary tangles (NFT). Senile plaques are formed with amyloid-beta (Aβ), hyperphosphorylated tau protein, apolipoprotein E and presenilin associated with protease activity [Aβ, gamma-secretase (γS)]. The molecular mechanisms of neurodegeneration most likely include but are not limited to apoptosis, oxidative stress (free radical generation that follows the cellular and subcellular damage), inflammation, immune activation etc. The lack of effective treatments for AD stems mainly from the incomplete understanding of the causes of AD. Currently, there are several hypotheses explaining the early mechanisms of AD pathogenesis. Recent years witnessed an unprecedented research growth in the area of nanotechnology, which uses atomic, molecular and macromolecular methods to create products in microscale (nanoscale) dimensions. This review article has discussed the role of nanotechnology in the development and improvement of techniques for early diagnosis and effective treatment of AD. Moreover, since AD pathology is practically irreversible, applications of disease-modifying treatments could be successful only if early diagnosis of AD is available. This review first time highlights various possibilities for the early diagnosis and therapy of AD, and investigates potential adaptation of nanoparticles-dendrimers, a class of well-defined branched polymers, chemically synthesized with a well-defined shape, size and nanoscopic physicochemical properties reminiscent of the proteins for the treatment of neurodegenerative diseases including AD, PD and many others. I am confident that review articles which are included in this special issue provide not only novel ideas to the pathophysiological hallmarks of the different cellular compartments of the brain in the course of neurodegeneration, but also provide new research directions regarding the treatment of CNS disorders in general.

Major advances in our understanding of the neurology/pathology, anatomy/physiology, and molecular biology of the cerebellum have opened a new door for cerebellar ataxias (CAs). We have now entered in the ‘era of therapies’. Cures are knocking at the door. We discuss the hot topics in the therapeutic protocols available for CAs, including aminopyridines, noninvasive cerebellar stimulation, anti-oxidant drugs and therapies for immune-mediated cerbellar ataxias (IMCAs), topics emphasized in this issue. The history of the cerebellum is a typical example of the importance of apparently divergent and multi-disciplinary approaches.

Programmed cell death (PCD), referring to apoptosis, autophagy and programmed necrosis (necroptosis and pyroptosis), plays crucial roles in the pathophysiology of stroke and has always been the potential therapeutic target. Deciphering PCD signaling pathways helps to understanding the molecular mechanisms of the brain disorders and promotes discovery of novel therapeutic targets for stroke treatment. The aims of this thematic issue are to review the progress of PCD signaling pathways in stroke, and update the new advance of novel pharmacological and molecular treatment strategies targeting PCD in the basic science research of stroke, translation and neurobiology of clinical treatment.

Eating disorders (anorexia nervosa, bulimia nervosa, binge eating disorder, and related syndromes) are highly distinctive psychiatric disorders. The peak age of onset is 15–25 years, a developmentally sensitive time. The average illness duration is about 6 years. Young women make up the majority of people with anorexia and bulimia nervosa, with binge eating disorder nearly equally common in both sexes. The prevalence of eating disorder behaviours is rising in high-income countries, especially in combination with obesity. One in every six or seven young women has an eating disorder and anorexia nervosa is one of the most common chronic disorders in adolescence. Mortality rates are almost twice as high for people with eating disorders as in the general population, and nearly six times higher for people with anorexia nervosa. To date there is a lack in basic, neurobiologically informed research in eating disorders. Alongside genetic research, brain imaging might help to elucidate mechanisms related to brain pathophysiology that drive eating disorder behaviours. There are also various endocrine alterations in eating disorders, and especially when patients are underweight. However, such endocrine alterations frequently normalize with weight restoration, and whether they specifically affect the brains and behaviours of patients with an eating disorder is uncertain. Thus far pharmacotherapy has a secondary role in the treatment of eating disorders and should not be considered as a sole or primary intervention With this special issue on “Psychobiology of eating disorders” leading experts in the field of eating disorders aim to provide current and up-to-date knowledge with focused and cutting edge reviews of hot topics in eating disorders research to close the gap of bench to bedside and facilitate a more individualized and precision medicine therapy approach in the treatment of eating disorders for the future.

This hot topic issue reviews the most up to date literature dealing with pathophysiology mechanisms underlying RGC death with the scope to propose new venues for the discovery of better therapeutics on a rational basis.

Neurodegenerative diseases include Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), and Huntington's disease. These diseases involve different aspects of reward processing (primary rewards, secondary rewards, reward-based learning, and reward-based decisionmaking). About 70% of the population with 65 years or more are affected by these progressive neurodegenerative disorders of the central nervous system and characterized by gradual loss of cognitive function, progressive memory loss, disorientation, language impairment, abnormal behavior, personality changes, etc Theoretical studies using in silico methods have aided in the process of drug discovery. Technological advances in the areas of structural characterization, computational science, and molecular biology have contributed to faster planning of new feasible molecules. Chemoinformatic studies show that a large fraction of compoundss are “drug-like” or at least, “lead-like” having structural and physicochemical properties that render them as potential drugs or leads. This thematic issue will bring together theoretical studies of different methodologies, such as QSAR, docking, chemometric tools, artificial intelligence and other applied in order to optimize the search for new drugs for the cure and treatment of neurodegenerative diseases.

Traditionally, neuroscientists regarded glial functions as simply providing physical support and maintenance for neurons. Thus, in this limited role glia had been long ignored. Recently, glial functions have been gradually investigated, and increasing evidence has suggested that glial cells perform important roles in various brain functions. Digging up the glial functions and further understanding of these crucial cells, and the interaction between neurons and glia may shed new light on clarifying many unknown aspects including the mind-brain gap, and conscious-unconscious relationships. It is well known that CNS inflammation and immune activation play a major role in the pathophysiology of neurodegenerative diseases. Although the blood-brain barrier is able to protect the CNS from immune activation, it becomes more permeable during inflammation, which renders the brain vulnerable to infections. A better understanding of the interaction between inflammatory mediators, such as cytokines, and the activated immune response, including astrocytes and microglia, is critical for the development of new therapeutic strategies for neurodegenerative diseases. The goal of this SI is to review the relationship of neuron-glia and cytokines in the pathophysiology of neuropsychiatric disorders and the mechanisms of action of drugs used for their treatment. The SI provides evidences for the role of the inflammation induced toxic metabolites from the tryptophan pathway in neuropsychiatric disorders such as depression, schizophrenia, and Alzheimer's disease and so on. A better understanding of the interaction between cytokines, glia and neurons provide new strategies for the development of novel therapeutic targets for neuropsychiatric disorders.

This themed issue aims to bring together recent findings in basic and clinical sciences with a translational perspective that will cover the involvement of the nicotinic cholinergic system not only in physiological functions but also in disease states, including but not limited to tobacco addiction, as well as drug development.   

No Text Found

No Text Found

No Text Found

No Text Found

No Text Found

No Text Found

No Text Found