1,721,096 research outputs found
The Evolving Challenge of New Psychoactive Substances: Understanding the Risks and Behavioral Effects of Novel Analogs of Dissociative Anesthetics
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Anti-IL5 Drugs in COVID-19 Patients: Role of Eosinophils in SARS-CoV-2-Induced Immunopathology
Full text linkSARS-CoV-2 infection stimulates a complex activation of the immune system. Eosinophils belong to the host’s defense equipment against respiratory viruses. In the first phase of the infection, eosinophils contribution is probably appropriate and beneficial, as they facilitate the suppression of the viral replication. However, in severe COVID-19 patients, during the second and third phases of the disease, eosinophils may participate in a maladaptive immune response and directly contribute to immunopathology. In fact, in severe patients, the immune response is prevalently T helper 1 type, but T helper 2 is also present. Eosinophils’ expansion and activation are stimulated by Type 2 cytokines, especially IL-5. Moreover, bronchial asthma, in which eosinophils play a central role, seems not to be a major risk factor for severe COVID-19. Among possible explanations, asthmatic patients are often treated with corticosteroids, which have been demonstrated to reduce the progression to critical COVID-19 in hospitalized patients. In addition to steroids, severe asthmatic patients are currently treated with biological drugs that target Type 2 immune response. Because IL-5 is necessary for the growth, survival, and activation of eosinophils, IL-5 inhibitors, such as mepolizumab, decrease the peripheral blood count of eosinophils, but do not influence eosinophils activation in the airway. In severe COVID-19 patients, the blockade of eosinophils’ activation might contrast harmful immunity
Endocannabinoid signalling in midbrain dopamine neurons: more than physiology?
No full textDifferent classes of neurons in the CNS utilize endogenous cannabinoids as retrograde messengers to shape afferent activity in a short- and long-lasting fashion. Transient suppression of excitation and inhibition as well as long-term depression or potentiation in many brain regions require endocannabinoids to be released by the postsynaptic neurons and activate presynaptic CB1 receptors. Memory consolidation and/or extinction and habit forming have been suggested as the potential behavioral consequences of endocannabinoid-mediated synaptic modulation. However, endocannabinoids have a dual role: beyond a physiological modulation of synaptic functions, they have been demonstrated to participate in the mechanisms of neuronal protection under circumstances involving excessive excitatory drive, glutamate excitotoxicity, hypoxia-ischemia, which are key features of several neurodegenerative disorders. In this framework, the recent discovery that the endocannabinoid 2-arachidonoyl-glycerol is released by midbrain dopaminergic neurons, under both physiological synaptic activity to modulate afferent inputs and pathological conditions such as ischemia, is particularly interesting for the possible implication of these molecules in brain functions and dysfunctions. Since dopamine dysfunctions underlie diverse neuropsychiatric disorders including schizophrenia, psychoses, and drug addiction, the importance of better understanding the correlation between an unbalanced endocannabinoid signal and the dopamine system is even greater. Additionally, we will review the evidence of the involvement of the endocannabinoid system in the pathogenesis of Parkinson's disease, where neuroprotective actions of cannabinoid-acting compounds may prove beneficial. The modulation of the endocannabinoid system by pharmacological agents is a valuable target in protection of dopamine neurons against functional abnormalities as well as against their neurodegeneration
From surface to nuclear receptors: the endocannabinoid family extends its assets
No full textPeroxisome proliferator-activated receptors (PPARs) have long been known as mediators of several physiological functions, among which the best characterized are lipid metabolism, energy balance and anti-inflammation. Their rather large and promiscuous ligand binding site has been recently discovered to accommodate, among a plethora of lipid molecules and metabolic intermediates, endocannabinoids and their cognate compounds, specifically belonging to the N-acylethanolamine group. In fact, oleoylethanolamide, palmitoylethanolamide and probably anandamide bind with relatively high affinity to PPARs and have now been included among their endogenous ligands. Through activation of PPARs these molecules exert a variety of physiological processes. Particularly, both long-term effects via genomic mechanisms and rapid non-genomic actions have been described, which in several instances are opposite to those evoked by activation of "classical" surface cannabinoid receptors.
In this review, we describe how these effects are relevant under diverse physiological and pathophysiological circumstances, such as lipid metabolism and feeding behaviour, neuroprotection and epilepsy, circadian rhythms, addiction and cognition. A picture is emerging where nuclear receptors are involved in anorexiant, anti-inflammatory, neuroprotective, anti-epileptic, wakefulness-and cognitive-enhancing, and anti-addicting properties of endocannabinoid-like molecules. Further studies are necessary to fully understand cellular mechanisms underlying the interactions between endocannabinoids and PPARs, but also between their surface and nuclear receptors, and to exploit their potential therapeutic applications
Maternal Immune Activation and Endocannabinoid System: Focus on Two-Hit Models of Schizophrenia
Full text linkThe devastating effects of the COVID-19 pandemic have underscored the significant threat infectious diseases pose to our society. Pregnancy represents a particularly vulnerable period for infections, which can compromise maternal health and increase the risk of neurodevelopmental disorders in offspring. Preclinical and clinical investigations suggest a potential association between maternal immune activation (MIA), triggered by viral or bacterial infections, and the increased risk for neurodevelopmental disorders such as autism and schizophrenia. Genetic and environmental factors might contribute to the overall risk. Hence, the two-hit hypothesis of schizophrenia suggests that MIA could act as a first trigger, with subsequent factors, such as stress or drug abuse, exacerbating latent abnormalities. A growing body of research focuses on the interaction between MIA and cannabis use during adolescence, considering the role of the endocannabinoid system in neurodevelopment and in neurodevelopmental disorders. The endocannabinoid system, crucial for fetal brain development, may be disrupted by MIA, leading to adverse outcomes in adulthood. Recent research indicates the endocannabinoid system's significant role in the pathophysiology of neurodevelopmental disorders in preclinical models. However, findings on adolescent cannabinoid exposure in MIA-exposed animals reveal unexpected complexities, with several studies failing to support the exacerbation of MIA-related abnormalities. This review delves into the functional implications of the endocannabinoid system in MIA models, emphasizing 2-arachidonoylglycerol (2-AG) signaling's role in synaptic plasticity and neuroinflammation, and its relevance to the two-hit model of schizophrenia
Anandamide and 2-arachidonoylglycerol: pharmacological properties, functional features and emerging specificities of the two major endocannabinoids
No full textSince the discovery of endocannabinoids and their receptors, two major members of the endocannabinoid family, anandamide and 2-arachidonoylglycerol (2-AG), have been regarded almost as twin brothers. Pharmacological properties were initially considered to be similar, as these molecules were believed mutually exchangeable and almost indistinguishable in the regulation of synaptic functions, such as long- and short-term synaptic plasticity, and in behavioral aspects, such as learning and memory, reward and addiction, antinociception and anxiety. In recent years, however, endocannabinoid signaling specificity began to emerge, in particular due to the production of genetically engineered mice lacking key enzymes in endocannabinoid synthesis or degradation, together with the development of selective inhibitors of anandamide or 2-AG catabolic enzymes. Evidence now suggests that anandamide and 2-AG possess specific pharmacological properties, are engaged in different forms of synaptic plasticity and take part in different behavioral functions. In this review, we provide an overview on similarities and specificities of the two endocannabinoids in the CNS and on the unresolved questions concerning their role in synaptic signalin
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