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Journal: Current neuropharmacology

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Chronic prescription of antipsychotics seems to lose its therapeutic benefits in the prevention of recurring psychotic symptoms. In many instances, the occurrence of relapse from initial remission is followed by an increase in dose of the prescribed antipsychotic. The current understanding of why this occurs is still in its infancy, but a controversial idea that has regained attention recently is the notion of iatrogenic dopamine supersensitivity. Studies on cell cultures and animal models have shown that long-term antipsychotic use is linked to both an upregulation of dopamine D2-receptors in the striatum and the emergence of enhanced receptor affinity to endogenous dopamine. These findings have been hypothesized to contribute to the phenomenon known as dopamine supersensitivity psychosis (DSP), which has been clinically typified as the foundation of rebound psychosis, drug tolerance, and tardive dyskinesia. The focus of this review is the update of evidence behind the classification of antipsychotic induced DSP and an investigation of its relationship to treatment resistance. Since antipsychotics are the foundation of illness management, a greater understanding of DSP and its prevention may greatly affect patient outcomes.

Concepts: Tardive dyskinesia, Antipsychotic, Schizophrenia, Psychosis, Bipolar disorder, Dopamine, Benzodiazepine, Tardive dysphrenia

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Background: Currently, there is great interest in the potential medical use of cannabidiol (CBD), a non-intoxicating cannabinoid. Productive pharmacological research on CBD occurred in the 1970s and intensified recently with many discoveries about the endocannabinoid system. Multiple preclinical and clinical studies led to FDA-approval of Epidiolex┬«, a purified CBD medicine formulated for oral administration for treatment of infantile refractory epileptic syndromes, by the US Food and Drug Administration in 2018. The World Health Organization is considering rescheduling cannabis and cannabinoids. CBD use around the world is expanding for diseases that lack scientific evidence of the drug’s efficacy. Preclinical and clinical studies also report adverse effects (AEs) and toxicity following CBD intake.

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The relevance of tyrosine kinase inhibitors (TKIs) in the treatment of malignancies has been already defined. Aberrant activation of tyrosine kinase signaling pathways has been causally linked not only to cancers but also to other non-oncological diseases. This review concentrates on the novel plausible usage of this group of drugs in neurological disorders, such as ischemic brain stroke, subarachnoid hemorrhage, Alzheimer’s disease, multiple sclerosis. The drugs considered here are representatives of both receptor and non-receptor TKIs. Among them imatinib and masitinib have the broadest spectrum of therapeutic usage. Both drugs are effective in ischemic brain stroke and multiple sclerosis, but only imatinib produces a therapeutic effect in subarachnoid hemorrhage. Masitinib and dasatinib reduce the symptoms of Alzheimer’s disease. In the case of multiple sclerosis several TKIs are useful, including apart from imatinib and masitinib, also sunitinib, sorafenib, lestaurtinib. Furthermore, the possible molecular targets for the drugs are described in connection with the underlying pathophysiological mechanisms in the diseases in question. The most frequent target for the TKIs is PDGFR which plays a pivotal role particularly in ischemic brain stroke and subarachnoid hemorrhage. The collected data indicates that TKIs are very promising candidates for new therapeutic interventions in neurological diseases.

Concepts: Medicine, Cancer, Signal transduction, Stroke, Neurology, Dementia, Subarachnoid hemorrhage, Neurological disorder

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Myalgic Encephalomyelitis (ME) continues to cause significant morbiditiy worldwide with an estimated one million cases in the United States. Hurdles to establishing consensus to achieve accurate evaluation of patients with ME continue, fueled by poor agreement about case definitions, slow progress in development of standardized diagnostic approaches, and issues surrounding research priorities. Because there are other medical problems, such as early MS and Parkinson’s Disease, which have some similar clinical presentations, it is critical to accurately diagnose ME to make a differential diagnosis. In this article, we explore and summarize advances in the physiological and neurological approaches to understanding, diagnosing, and treating ME. We identify key areas and approaches to eludicate the core and secondary symptom clusters in ME so as to provide some practical suggestions in evaluation of ME for clinicians and researchers.This review, therefore, represents a synthesis of key discussions in the literature, andhas important implications for a better understanding of ME, its biological markers, and diagnostic criteria. There is a clear need for more longitudinal studies in this area with larger data sets, which correct for multiple testing.

Concepts: Medical terms, Diagnosis, Greek loanwords

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Atherosclerosis is a chronic inflammatory condition that affects different arteries in the human body and often leads to severe neurological complications, such as stroke and its sequelae. Affected blood vessels develop atherosclerotic lesions in the form of focal thickening of the intimal layer, so called atherosclerotic plaques.

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Over 100 people die daily from opioid overdose and $78.5B per year is spent toward treatment efforts, however the real societal cost is multifold greater. Alternative strategies to eradicate/manage drug misuse and addiction need consideration. The perception of opioid addiction as a social/criminal problem has evolved to evidence-based considerations of them as clinical disorders with a genetic basis. We present evaluations of the genetics of addiction with ancestry-specific risk profiles for consideration.

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Epileptogenesis refers to the process in which a normal brain becomes epileptic, and is characterized by hypersynchronous spontaneous recurrent seizures involving a complex epileptogenic network. Current available pharmacological treatment of epilepsy is generally symptomatic in controlling seizures but is not disease-modifying in epileptogenesis. Cumulative evidence suggests that adult neurogenesis, specifically in the subgranular zone of the hippocampal dentate gyrus, is crucial in epileptogenesis. In this review, we describe the pathological changes that occur in adult neurogenesis in the epileptic brain and how adult neurogenesis is involved in epileptogenesis through different interventions. This is followed by a discussion of some of the molecular signaling pathways involved in regulating adult neurogenesis, which could be potential druggable targets for epileptogenesis. Finally, we provide perspectives on some possible research directions for future studies.

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Until recently, it was thought that there were no lymphatic vessels in the central nervous system (CNS). Therefore, all metabolic processes were assumed to take place only in the circulation of the cerebrospinal fluid (CSF) and through the blood-brain barrier’s (BBB), which regulate ion transport and ensure the functioning of the CNS. However, recent findings yield a new perspective: There is an exchange of CSF with interstitial fluid (ISF), which is drained to the paravenous space and reaches lymphatic nodes at the end. This circulation is known as the glymphatic system. The glymphatic system is an extensive network of meningeal lymphatic vessels (MLV) in the basal area of the skull that provides another path for waste products from CNS to reach the bloodstream. MLV develop postnatally, initially appearing around the foramina in the basal part of the skull and the spinal cord, thereafter sprouting along the skull’s blood vessels and spinal nerves in various areas of the meninges. VEGF-C protein (vascular endothelial growth factor), expressed mainly by vascular smooth cells, plays an important role in the development of the MLV. The regenerative potential and plasticity of MLV and the novel discoveries related to CNS drainage offer potential for the treatment of neurodegenerative diseases such as dementia, hydrocephalus, stroke, multiple sclerosis, and Alzheimer disease (AD). Herein, we present an overview of the structure and function of the glymphatic system and MLV, and their potential involvement in the pathology and progression of neurodegenerative diseases.

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The acronym TBI refers to traumatic brain injury, an alteration of brain function, or an evidence of brain pathology, that is caused by an external force. TBI is estimated to become the third leading cause of permanent disability and mortality worldwide. TBI-related injuries can be classified in many ways, according to the degree of severity or to the pathophysiology of brain injury (primary and secondary damage). Numerous cellular pathways act in secondary brain damage: excitotoxicity (mediated by excitatory neurotransmitters); free radical generation (due to mitochondrial impairment); neuroinflammatory response (due to central nervous system and immunoactivation); apoptosis. In this scenario, microRNAs are implicated in the regulation of almost all genes at the post-transcriptional level. Several microRNAs have been demonstrated to be specifically expressed in particular cerebral areas; moreover, physiological changes in microRNA expression during normal cerebral development upon the establishment of neural networks have been characterized. More importantly, microRNAs show profound alteration in expression in response to brain pathological states, both traumatic or not. This review summarizes the most important molecular networks involved in TBI and examines the most recent and important findings on TBI-related microRNAs, both in animal and clinical studies. The importance of microRNA research holds promise to find biomarkers able to unearth primary and secondary molecular patterns altered upon TBI, to ultimately identify key points of regulation, as valuable support in forensic pathology and potential therapeutic targets for clinical treatment.

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The bidirectional communication between neurons and microglia is fundamental for the proper functioning of the central nervous system (CNS). Chemokines and clusters of differentiation (CD) along with their receptors represent ligand - receptor signalling that is uniquely important for neuron - microglia communication. Among these molecules, CX3CL1 (fractalkine) and CD200 (OX-2 membrane glycoprotein) come to the fore because of their cell-type-specific localization. They are principally expressed by neurons when their receptors, CX3CR1 and CD200R, respectively, are predominantly present on microglia, resulting in the specific axis that maintains the CNS homeostasis. Disruptions to this balance are suggested as the contributors or even the basis for many neurological diseases. In this review, we discuss the roles of CX3CL1, CD200 and their receptors in both physiological and pathological processes within the CNS. We want to underline the critical involvement of these molecules in the controlling of neuron - microglia communication, noting that dysfunctions in their interactions constitute a key factor in severe neurological diseases, such as schizophrenia, depression and neurodegeneration-based conditions.