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International Journal of Molecular... May 2023The downstream regulatory element antagonist modulator (DREAM) is a multifunctional Ca-sensitive protein exerting a dual mechanism of action to regulate several... (Review)
Review
The downstream regulatory element antagonist modulator (DREAM) is a multifunctional Ca-sensitive protein exerting a dual mechanism of action to regulate several Ca-dependent processes. Upon sumoylation, DREAM enters in nucleus where it downregulates the expression of several genes provided with a consensus sequence named dream regulatory element (DRE). On the other hand, DREAM could also directly modulate the activity or the localization of several cytosolic and plasma membrane proteins. In this review, we summarize recent advances in the knowledge of DREAM dysregulation and DREAM-dependent epigenetic remodeling as a central mechanism in the progression of several diseases affecting central nervous system, including stroke, Alzheimer's and Huntington's diseases, amyotrophic lateral sclerosis, and neuropathic pain. Interestingly, DREAM seems to exert a common detrimental role in these diseases by inhibiting the transcription of several neuroprotective genes, including the sodium/calcium exchanger isoform 3 (NCX3), brain-derived neurotrophic factor (BDNF), pro-dynorphin, and c-fos. These findings lead to the concept that DREAM might represent a pharmacological target to ameliorate symptoms and reduce neurodegenerative processes in several pathological conditions affecting central nervous system.
Topics: Kv Channel-Interacting Proteins; Repressor Proteins; Brain; Dynorphins; Cell Nucleus
PubMed: 37298129
DOI: 10.3390/ijms24119177 -
Protein & Cell Jun 2023
Topics: Humans; Dynorphins; Receptors, Opioid, kappa; Cryoelectron Microscopy
PubMed: 37285260
DOI: 10.1093/procel/pwac033 -
Pharmaceuticals (Basel, Switzerland) May 2023This study provides a narrative review of diterpenoid alkaloids (DAs), a family of extremely important natural products found predominantly in some species of and... (Review)
Review
This study provides a narrative review of diterpenoid alkaloids (DAs), a family of extremely important natural products found predominantly in some species of and (Ranunculaceae). DAs have long been a focus of research attention due to their numerous intricate structures and diverse biological activities, especially in the central nervous system (CNS). These alkaloids originate through the amination reaction of tetra or pentacyclic diterpenoids, which are classified into three categories and 46 types based on the number of carbon atoms in the backbone structure and structural differences. The main chemical characteristics of DAs are their heterocyclic systems containing β-aminoethanol, methylamine, or ethylamine functionality. Although the role of tertiary nitrogen in ring A and the polycyclic complex structure are of great importance in drug-receptor affinity, in silico studies have emphasized the role of certain sidechains in C13, C14, and C8. DAs showed antiepileptic effects in preclinical studies mostly through Na channels. Aconitine () and 3-acetyl aconitine () can desensitize Na channels after persistent activation. Lappaconitine (), N-deacetyllapaconitine (), 6-benzoylheteratisine (), and 1-benzoylnapelline () deactivate these channels. Methyllycaconitine (), mainly found in species, possesses an extreme affinity for the binding sites of α7 nicotinic acetylcholine receptors (nAChR) and contributes to a wide range of neurologic functions and the release of neurotransmitters. Several DAs such as bulleyaconitine A (), (), and mesaconitine () from species have a drastic analgesic effect. Among them, compound has been used in China for decades. Their effect is explained by increasing the release of dynorphin A, activating the inhibitory noradrenergic neurons in the β-adrenergic system, and preventing the transmission of pain messages by inactivating the Na channels that have been stressed. Acetylcholinesterase inhibitory, neuroprotective, antidepressant, and anxiolytic activities are other CNS effects that have been investigated for certain DAs. However, despite various CNS effects, recent advances in developing new drugs from DAs were insignificant due to their neurotoxicity.
PubMed: 37242531
DOI: 10.3390/ph16050747 -
Scientific Reports May 2023Numerous studies in animals demonstrate that embryonic exposure to ethanol (EtOH) at low-moderate doses stimulates neurogenesis and increases the number of hypothalamic...
Subpopulations of hypocretin/orexin neurons differ in measures of their cell proliferation, dynorphin co-expression, projections, and response to embryonic ethanol exposure.
Numerous studies in animals demonstrate that embryonic exposure to ethanol (EtOH) at low-moderate doses stimulates neurogenesis and increases the number of hypothalamic neurons expressing the peptide, hypocretin/orexin (Hcrt). A recent study in zebrafish showed that this effect on the Hcrt neurons in the anterior hypothalamus (AH) is area specific, evident in the anterior (aAH) but not posterior (pAH) part of this region. To understand specific factors that may determine the differential sensitivity to EtOH of these Hcrt subpopulations, we performed additional measures in zebrafish of their cell proliferation, co-expression of the opioid dynorphin (Dyn), and neuronal projections. In association with the increase in Hcrt neurons in the aAH but not pAH, EtOH significantly increased only in the aAH the proliferation of Hcrt neurons and their number lacking Dyn co-expression. The projections of these subpopulations differed markedly in their directionality, with those from the pAH primarily descending to the locus coeruleus and those from the aAH ascending to the subpallium, and they were both stimulated by EtOH, which induced specifically the most anterior subpallium-projecting Hcrt neurons to become ectopically expressed beyond the aAH. These differences between the Hcrt subpopulations suggest they are functionally distinct in their regulation of behavior.
Topics: Animals; Orexins; Zebrafish; Dynorphins; Ethanol; Neurons; Cell Proliferation
PubMed: 37231149
DOI: 10.1038/s41598-023-35432-w -
The Journal of Neuroscience : the... Jul 2023Alcohol use disorder is complex and multifaceted, involving the coordination of multiple signaling systems across numerous brain regions. Previous work has indicated...
Alcohol use disorder is complex and multifaceted, involving the coordination of multiple signaling systems across numerous brain regions. Previous work has indicated that both the insular cortex and dynorphin (DYN)/kappa opioid receptor (KOR) systems contribute to excessive alcohol use. More recently, we identified a microcircuit in the medial aspect of the insular cortex that signals through DYN/KOR. Here, we explored the role of insula DYN/KOR circuit components on alcohol intake in a long-term intermittent access (IA) procedure. Using a combination of conditional knock-out strategies and site-directed pharmacology, we discovered distinct and sex-specific roles for insula DYN and KOR in alcohol drinking and related behavior. Our findings show that insula DYN deletion blocked escalated consumption and decreased the overall intake of and preference for alcohol in male and female mice. This effect was specific to alcohol in male mice, as DYN deletion did not impact sucrose intake. Further, insula KOR antagonism reduced alcohol intake and preference during the early phase of IA in male mice only. Alcohol consumption was not affected by insula KOR knockout in either sex. In addition, we found that long-term IA decreased the intrinsic excitability of DYN and deep layer pyramidal neurons (DLPNs) in the insula of male mice. Excitatory synaptic transmission was also impacted by IA, as it drove an increase in excitatory synaptic drive in both DYN neurons and DLPNs. Combined, our findings suggest there is a dynamic interplay between excessive alcohol consumption and insula DYN/KOR microcircuitry. The insular cortex is a complex region that serves as an integratory hub for sensory inputs. In our previous work, we identified a microcircuit in the insula that signals through the kappa opioid receptor (KOR) and its endogenous ligand dynorphin (DYN). Both the insula and DYN/KOR systems have been implicated in excessive alcohol use and alcohol use disorder (AUD). Here, we use converging approaches to determine how insula DYN/KOR microcircuit components contribute to escalated alcohol consumption. Our findings show that insula DYN/KOR systems regulate distinct phases of alcohol consumption in a sex-specific manner, which may contribute to the progression to AUD.
Topics: Female; Mice; Male; Animals; Receptors, Opioid, kappa; Dynorphins; Alcoholism; Insular Cortex; Alcohol Drinking; Ethanol
PubMed: 37217307
DOI: 10.1523/JNEUROSCI.0406-22.2023 -
Proceedings of the National Academy of... May 2023Narcolepsy with cataplexy is a sleep disorder caused by deficiency in the hypothalamic neuropeptide hypocretin/orexin (HCRT), unanimously believed to result from...
Narcolepsy with cataplexy is a sleep disorder caused by deficiency in the hypothalamic neuropeptide hypocretin/orexin (HCRT), unanimously believed to result from autoimmune destruction of hypocretin-producing neurons. HCRT deficiency can also occur in secondary forms of narcolepsy and be only temporary, suggesting it can occur without irreversible neuronal loss. The recent discovery that narcolepsy patients also show loss of hypothalamic (corticotropin-releasing hormone) CRH-producing neurons suggests that other mechanisms than cell-specific autoimmune attack, are involved. Here, we identify the HCRT cell-colocalized neuropeptide QRFP as the best marker of HCRT neurons. We show that if HCRT neurons are ablated in mice, in addition to transcript is also lost in the lateral hypothalamus, while in mice where only the gene is inactivated is unchanged. Similarly, postmortem hypothalamic tissues of narcolepsy patients show preserved expression, suggesting the neurons are present but fail to actively produce HCRT. We show that the promoter of the gene of patients exhibits hypermethylation at a methylation-sensitive and evolutionary-conserved PAX5:ETS1 transcription factor-binding site, suggesting the gene is subject to transcriptional silencing. We show also that in addition to HCRT, and Dynorphin () gene promoters, exhibit hypermethylation in the hypothalamus of patients. Altogether, we propose that , , and are epigenetically silenced by a hypothalamic assault (inflammation) in narcolepsy patients, without concurrent cell death. Since methylation is reversible, our findings open the prospect of reversing or curing narcolepsy.
Topics: Mice; Animals; Orexins; Cataplexy; Intracellular Signaling Peptides and Proteins; Neuropeptides; Narcolepsy; Hypothalamus; Epigenesis, Genetic; Corticotropin-Releasing Hormone
PubMed: 37126681
DOI: 10.1073/pnas.2220911120 -
Nefrologia 2023Pruritus associated with chronic kidney disease is defined as the sensation of itching, in people with chronic kidney disease, in a one area or all over the body that...
INTRODUCTION
Pruritus associated with chronic kidney disease is defined as the sensation of itching, in people with chronic kidney disease, in a one area or all over the body that causes the need to scratch, after having ruled out other dermatological or systemic causes. It is an old and known problem whose prevalence has been able to decrease with the improvement of dialytic techniques but which still persists and is underdiagnosed.
OBJECTIVES
The objective of this study was to analyse the current perception of nephrologists about this problem that influences the quality of life of people with chronic kidney disease through a survey.
RESULTS
135 nephrologists, most of them engaged in haemodialysis, participated. 86% considered that pruritus associated with chronic kidney disease is still a problem today that affects the quality of life. Most nephrologists believe that the main pathophysiological cause is uremic toxins (60%) and only 16% believe that it is due to the dysregulation of the opioid system/endorphins-dynorphins. Only 16% comment that the prevalence of pruritus in their centre is greater than 20%. 40% believe that the diagnosis is made because it is manifested by the patient and only 27% because it is asked by the doctor. Moreover, it is not usual to use scales to measure it or the codification in the medical records. The main treatment used is antihistamines (96%), followed by moisturizers/anaesthetics (93%) and modification of the dialysis regimen (70%).
CONCLUSIONS
Pruritus associated with chronic kidney disease is still a current problem, it is underdiagnosed, not codified and with a lack of indicated, effective and safe treatments. Nephrologists do not know its real prevalence and the different pathophysiological mechanisms involved in its development. Many therapeutic options are used with very variable results, ignoring their efficacy and applicability at the present time. The new emerging kappa-opioid-receptor agonist agents offer us an opportunity to reevaluate this age-old problem and improve the quality of life for our patients with chronic kidney disease.
Topics: Humans; Nephrologists; Quality of Life; Analgesics, Opioid; Renal Insufficiency, Chronic; Pruritus; Perception
PubMed: 37069038
DOI: 10.1016/j.nefroe.2023.03.012 -
Journal of Internal Medicine May 2023Alcohol use is a major cause of disability and death globally. These negative consequences disproportionately affect people who develop alcohol addiction, a chronic... (Review)
Review
Alcohol use is a major cause of disability and death globally. These negative consequences disproportionately affect people who develop alcohol addiction, a chronic relapsing condition characterized by increased motivation to use alcohol, choice of alcohol over healthy, natural rewards, and continued use despite negative consequences. Available pharmacotherapies for alcohol addiction are few, have effect sizes in need of improvement, and remain infrequently prescribed. Research aimed at developing novel therapeutics has in large part focused on attenuating pleasurable or "rewarding" properties of alcohol, but this targets processes that primarily play a role as initiation factors. As clinical alcohol addiction develops, long-term changes in brain function result in a shift of affective homeostasis, and rewarding alcohol effects become progressively reduced. Instead, increased stress sensitivity and negative affective states emerge in the absence of alcohol and create powerful incentives for relapse and continued use through negative reinforcement, or "relief." Based on research in animal models, several neuropeptide systems have been proposed to play an important role in this shift, suggesting that these systems could be targeted by novel medications. Two mechanisms in this category, antagonism at corticotropin-releasing factor type 1, and neurokinin 1/substance P receptors, have been subject to initial evaluation in humans. A third, kappa-opioid receptor antagonism, has been evaluated in nicotine addiction and could soon be tested for alcohol. This paper discusses findings with these mechanisms to date, and their prospects as future targets for novel medications.
Topics: Animals; Humans; Alcoholism; Neuropeptides; Brain; Corticotropin-Releasing Hormone; Alcohol Drinking; Ethanol
PubMed: 37052145
DOI: 10.1111/joim.13636 -
Journal of Clinical Medicine Mar 2023Chronic pruritus is one of the most common symptoms of dermatological diseases. It may occur in the course of other disorders, such as kidney disease. Chronic kidney...
Chronic pruritus is one of the most common symptoms of dermatological diseases. It may occur in the course of other disorders, such as kidney disease. Chronic kidney disease-associated pruritus (CKD-aP) most often affects people with end-stage renal disease. The etiology of this condition is still not fully understood, but researchers are currently focusing on a thorough analysis of the association between disturbed opioid balance and increased neuronal signaling leading to pruritus. The aim of this study is to assess the concentration of endogenous opioids in dialysis patients with and without pruritus and in the control group, and to determine the correlation between the concentration of these substances and the occurrence and severity of itching. The study involved 126 dialysis patients and 50 healthy controls. Patients were divided into groups with pruritus (n = 62) and without pruritus (n = 64). The severity of pruritus was assessed using the NRS scale. The concentration of endogenous opioids was determined using the ELISA. The concentration of met-enkephalin was higher in the group of patients with pruritus compared to the control group. Moreover, significantly lower levels of β-endorphin and dynorphin A were observed in the group of dialysis patients compared to the control group. In addition, a statistically significant difference was seen between the β-endorphin concentration in the group of dialysis patients with pruritus compared to the group without pruritus. The ratio of β-endorphin/dynorphin A concentrations was significantly lower in the group of patients with pruritus compared to patients without pruritus and the control group. No correlations were found between serum level of studied opioids and the severity of pruritus. The concentrations of the studied opioids did not correlate with the severity of pruritus. Observed opioid imbalance may affect the occurrence of CKD-aP in dialysis patients, but a thorough understanding of the mechanism of action of these substances in the sensation of pruritus is necessary to assess the possibility of finding a new therapeutic target.
PubMed: 37048558
DOI: 10.3390/jcm12072474