SciCombinator

Discover the most talked about and latest scientific content & concepts.

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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Ayahuasca, a traditional Amazonian decoction with psychoactive properties, is made from bark of the Banisteriopsis caapi vine (contains beta-carboline alkaloids) and leaves of the Psychotria viridis bush (supply the hallucinogen N,N-dimethyltryptamine (DMT)). Originally used by indigenous shamans for the purposes of spirit communication, magical experiences, healing, and religious rituals, across several South American countries ayahuasca has been incorporated into folk medicine and spiritual healing, and several Brazilian churches use it routinely to foster spiritual experience. More recently it is being used in Europe and North America, not only for religious or healing reasons, but also for recreation.

Concepts: North America, South America, Americas, Dimethyltryptamine, Ayahuasca, Psychotria viridis, Banisteriopsis caapi, Santo Daime

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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

1

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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Temozolomide (TMZ), an oral alkylating prodrug which delivers a methyl group to purine bases of DNA (O6- guanine; N7-guanine and N3-adenine), is frequently used together with radiotherapy as part of the first-line treatment of high-grade gliomas. The main advantages are its high oral bioavailability (almost 100% although the concentration found in the cerebrospinal fluid was approximately 20% of the plasma concentration of TMZ), its lipophilic properties, and small size that confer the ability to cross the blood-brain barrier. Furthermore, this agent has demonstrated activity not only in brain tumors but also in a variety of solid tumors. However, conventional therapy using surgery, radiation, and TMZ in glioblastoma results in a median patient survival of 14.6 months. Treatment failure has been associated with the tumor drug resistance. This phenomenon has been linked to the expression of O6-methylguanine-DNA methyltransferase, but the mismatch repair system and the presence of cancer stem-like cells in tumors have also been related to TMZ resistance. The understanding of these mechanisms is essential for the development of new therapeutic strategies in the clinical use of TMZ, including the use of nanomaterial delivery systems and the association with other chemotherapy agents. The aim of this review is to summarize the resistance mechanisms of TMZ and the current advances to improve its clinical use.

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Alzheimer’s disease (AD), recognized as the most common neurodegenerative disorder, is clinically characterized by the presence of extracellular beta amyloid (A╬▓) plaques and by intracellular neurofibrillary tau tangles, accompanied by glial activation and neuroinflammation. Increasing evidence suggests that self-misfolded proteins stimulate an immune response mediated by glial cells, inducing release of inflammatory mediators and the recruitment of peripheral macrophages into the brain, which in turn aggravate AD pathology. Aim of the present review is to update the current knowledge on the role of autoimmunity and neuroinflammation in the pathogenesis of the disease, indicating new target for therapeutic intervention. We mainly focused on the NLRP3 microglial inflammasome as a critical factor in stimulating innate immune responses, thus sustaining chronic inflammation. Additionally, we discussed the involvement of the NLRP3 inflammasome in the gut-brain axis. Direct targeting the NLRP3 inflammasome and the associated receptors could be a potential pharmacological strategy, since its inhibition would selectively reduce AD neuroinflammation.

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The blood-brain barrier (BBB), which is located at the interface between the central nervous system (CNS) and the circulatory system, is instrumental in establishing and maintaining the microenvironmental homeostasis of the CNS. BBB disruption following stroke promotes inflammation by enabling leukocytes, T cells and other immune cells to migrate via both the paracellular and transcellular routes across the BBB and to infiltrate the CNS parenchyma. Leukocytes promote the removal of necrotic tissues and neuronal recovery, but they also aggravate BBB injury and exacerbate stroke outcomes, especially after late reperfusion. Moreover, the swelling of astrocyte endfeet is thought to contribute to the ‘no-reflow’ phenomenon observed after cerebral ischemia, that is, blood flow cannot return to capillaries after recanalization of large blood vessels. Pericyte recruitment and subsequent coverage of endothelial cells (ECs) alleviates BBB disruption, which causes the transmigration of inflammatory cells across the BBB to be a dynamic process. Furthermore, interneurons and perivascular microglia also make contacts with ECs, astrocytes and pericytes to establish the neurovascular unit. BBB-derived factors after cerebral ischemia triggered microglial activation. During the later stage of injury, microglia remain associated with brain ECs and contribute to repair mechanisms, including postinjury angiogenesis, by acquiring a protective phenotype, which possibly occurs through the release of microglia-derived soluble factors. Taken together, we reviewed how dynamic and bidirectional crosstalk between inflammation and the BBB during stroke and revealed targeted interventions based on crosstalk between inflammation and the BBB, which will provide novel insights for developing new therapeutic strategies.

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Dementia is a collection of symptoms affecting a person’s cognition. Dementia is debilitating, and therefore, finding an effective treatment is of the utmost importance. Resveratrol, which exhibits neuroprotective effects, has low bioavailability. However, it’s glucoside polydatin is more bioavailable. Here, the evidence that supports the protective role of polydatin against dementia-related diseases such as Alzheimer’s disease, vascular dementia, alcohol-related dementia, and Lewy body dementias is presented. The beneficial effects of polydatin from a mechanistic perspective are specifically emphasized in this review. Future directions in this area of research are also discussed.

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Nur77 belongs to the NR4A subgroup of the nuclear receptor superfamily. Unlike other nuclear receptors, a natural ligand for Nur77 has not been identified yet. However, a few small molecules can interact with this receptor and induce a conformational change to mediate its activity. The expression and activation of Nur77 can be rapidly increased using various physiological and pathological stimuli. In vivo and in vitro studies have demonstrated its regulatory role in tissues and cells of multiple systems by means of participation in cell differentiation, apoptosis, metabolism, mitochondrial homeostasis, and other processes. Although research on Nur77 in the pathophysiology of the central nervous system (CNS) is currently limited, the present data support the fact that Nur77 is involved in many neurological disorders such as stroke, multiple sclerosis, Parkinson’s disease. This indicates that activation of Nur77 has considerable potential in treating these diseases. This review summarizes the regulatory mechanisms of Nur77 in CNS diseases and presents available evidence for its potential as a targeted therapy, especially for cerebrovascular and inflammation-related CNS diseases.