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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 -
Biomedicines Jul 2023Caring for patients with Crohn's disease (CD) is a serious challenge in modern medicine. The increasing incidence of CD among adolescents and the severe course of the...
Caring for patients with Crohn's disease (CD) is a serious challenge in modern medicine. The increasing incidence of CD among adolescents and the severe course of the disease create the need for new methods of diagnosis and therapy. Endogenous opioids are a group of low molecular weight chemical compounds with analgesic and anti-inflammatory properties. Endorphins, enkephalins, and dynorphins may have potentially beneficial effects on the course of CD. Previous research data on this topic are inconsistent. Some authors have reported an increase in the concentration of leukocytes during the course of inflammatory bowel disease (IBD) while others have described a downward trend, explained by DPP-IV enzyme activity. Even fewer data are available on plasma endo-opioid level. There is also a lack of comprehensive studies that have assessed the endo-opioid system in patients with IBD. Therefore, the objective of this study was to measure the serum concentrations of human β-endorphin, human proenkephalin (A), and human big dynorphin in CD patients in the acute phase of the disease, during hospital treatment, and in the remission state. All determinations were performed using ELISA kits. The results of our study showed that the concentrations of all the tested endo-opioids, especially β-endorphin and proenkephalin (A), were reduced in adolescents with CD compared to those in the healthy control group, during the acute phase of the disease, and in the remission state. Modulation of the endogenous opioid system and the use of selective nonnarcotic agonists of opioid receptors seems to be promising goals in the future treatment of CD.
PubMed: 37509676
DOI: 10.3390/biomedicines11072037 -
Future Medicinal Chemistry May 2023It is well established that endogenously produced dynorphin 1-17 (DYN 1-17) is susceptible to enzymatic degradation, producing a variety of unique fragments in different... (Review)
Review
It is well established that endogenously produced dynorphin 1-17 (DYN 1-17) is susceptible to enzymatic degradation, producing a variety of unique fragments in different tissue matrices and disease pathologies. DYN 1-17 and its major biotransformation fragments have significant roles in neurological and inflammatory disorders upon interacting with opioid and non-opioid receptors at both central and peripheral levels, thus highlighting their potential as drug candidates. Nevertheless, their development as promising therapeutics is challenged by several issues. This review aims to provide the latest and comprehensive updates on DYN 1-17 biotransformed peptides, including their pharmacological roles, pharmacokinetic studies and relevant clinical trials. Challenges in their development as potential therapeutics and proposed solutions to overcome these limitations are also discussed.
Topics: Dynorphins; Peptides; Analgesics, Opioid; Biotransformation; Peptide Fragments
PubMed: 37227702
DOI: 10.4155/fmc-2023-0016 -
Pharmacology & Therapeutics Feb 2022The discovery of the essential requirement for kisspeptin and subsequently neurokinin B signalling for human reproductive function has sparked renewed interest in the... (Review)
Review
The discovery of the essential requirement for kisspeptin and subsequently neurokinin B signalling for human reproductive function has sparked renewed interest in the neuroendocrinology of reproduction. A key discovery has been a population of cells co-expressing both these neuropeptides and dynorphin in the hypothalamus, directly regulating gonadotropin hormone releasing hormone (GnRH) secretion and thus pituitary secretion of gonadotropins. These neurons also project to the vasomotor centre, and their overactivity in estrogen deficiency results in the common and debilitating hot flushes of the menopause. Several antagonists to the neurokinin 3 receptor, for which neurokinin B is the endogenous ligand, have been developed, and are entering clinical studies in human reproductive function and clinical trials. Even single doses can elicit marked declines in testosterone levels in men, and their use has elicited evidence of the regulation of ovarian follicle growth in women. The most advanced indication is the treatment of menopausal vasomotor symptoms, where these drugs show remarkable results in both the degree and speed of symptom control. A range of other reproductive indications are starting to be explored, notably in polycystic ovary syndrome, the most common endocrinopathy in women.
Topics: Dynorphins; Female; Gonadotropin-Releasing Hormone; Humans; Hypothalamus; Kisspeptins; Male; Neurokinin B; Reproductive Medicine
PubMed: 34273412
DOI: 10.1016/j.pharmthera.2021.107960 -
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 -
Behavioural Brain Research Feb 2024About 280 million people suffer from depression as the most common neurological disorder and the most common cause of death worldwide. Exercise with serotonin released... (Review)
Review
About 280 million people suffer from depression as the most common neurological disorder and the most common cause of death worldwide. Exercise with serotonin released in the brain by the 5-HT3-IGF-1 mechanism can lead to antidepressant effects. Swimming exercise has antidepressant effects by increasing the sensitivity of serotonin 5-HT2 receptors and postsynaptic 5-HT1A receptors, increasing 5-HT and 5HIAA levels, increasing TPH and serotonin, and decreasing inflammatory levels of IFN-γ and TNF-α. Anaerobic and aerobic exercises increase beta-endorphin, enkephalin, and dynorphin and have antidepressant effects. Exercise by increasing dopamine, D1R, and D2R leads to the expression of BDNF and activation of TrkB and has antidepressant behavior. Exercise leads to a significant increase in GABAAR (γ2 and α2 subunits) and reduces neurodegenerative disorders caused by GABA imbalance through anti-inflammatory pathways. By increasing glutamate and PGC1α and reducing glutamatergic neurotoxicity, exercise enhances neurogenesis and synaptogenesis and prevents neurodegeneration and the onset of depression. Irisin release during exercise shows an important role in depression by increasing dopamine, BDNF, NGF, and IGF-1 and decreasing inflammatory mediators such as IL-6 and IL-1β. In addition, exercise-induced orexin and NPY can increase hippocampal neurogenesis and relieve depression. After exercise, the tryptophan to large neutral amino acids (TRP/LNAA) ratio and the tryptophan to branched-chain amino acids (BCAA) ratio increase, which may have antidepressant effects. The expression of M5 receptor and nAChR α7 increases after exercise and significantly increases dopamine and acetylcholine and ameliorates depression. It appears that during exercise, muscarinic receptors can reduce depression through dopamine in the absence of acetylcholine. Therefore, exercise can be used to reduce depression by affecting neurotransmitters, neuromodulators, cytokines, and/or neurotrophins.
Topics: Humans; Depression; Tryptophan; Insulin-Like Growth Factor I; Serotonin; Dopamine; Brain-Derived Neurotrophic Factor; Acetylcholine; Antidepressive Agents; Swimming; Neurotransmitter Agents; Exercise Therapy
PubMed: 38048912
DOI: 10.1016/j.bbr.2023.114791 -
Cell Reports Mar 2022This review highlights recent findings of different amplitude ranges, roles, and modulations of A-type K currents (I) in excitatory (GAD67-GFP) and inhibitory... (Review)
Review
This review highlights recent findings of different amplitude ranges, roles, and modulations of A-type K currents (I) in excitatory (GAD67-GFP) and inhibitory (GAD67-GFP) interneurons in mouse spinal cord pain pathways. Endogenous neuropeptides, such as TAFA4, oxytocin, and dynorphin in particular, have been reported to modulate I in these pain pathways, but only TAFA4 has been shown to fully reverse the opposing modulations that occur selectively in LIIo GAD67-GFP and LIIi GAD67-GFP interneurons following both neuropathic and inflammatory pain. If, as hypothesized here, Kv4 subunits underlie I in both GAD67-GFP and GAD67-GFP interneurons, then I diversity in spinal cord pain pathways may depend on the interneuron-subtype-selective expression of Kv4 auxiliary subunits with functionally different N-terminal variants. Thus, I emerges as a good candidate for explaining the mechanisms underlying injury-induced mechanical hypersensitivity.
Topics: Animals; Cytokines; Green Fluorescent Proteins; Interneurons; Mice; Pain; Spinal Cord
PubMed: 35354022
DOI: 10.1016/j.celrep.2022.110588 -
ELife Jul 2023Somatosensory information is processed by a complex network of interneurons in the spinal dorsal horn. It has been reported that inhibitory interneurons that express...
Somatosensory information is processed by a complex network of interneurons in the spinal dorsal horn. It has been reported that inhibitory interneurons that express neuropeptide Y (NPY), either permanently or during development, suppress mechanical itch, with no effect on pain. Here, we investigate the role of interneurons that continue to express NPY (NPY-INs) in the adult mouse spinal cord. We find that chemogenetic activation of NPY-INs reduces behaviours associated with acute pain and pruritogen-evoked itch, whereas silencing them causes exaggerated itch responses that depend on cells expressing the gastrin-releasing peptide receptor. As predicted by our previous studies, silencing of another population of inhibitory interneurons (those expressing dynorphin) also increases itch, but to a lesser extent. Importantly, NPY-IN activation also reduces behavioural signs of inflammatory and neuropathic pain. These results demonstrate that NPY-INs gate pain and itch transmission at the spinal level, and therefore represent a potential treatment target for pathological pain and itch.
Topics: Mice; Animals; Neuropeptide Y; Spinal Cord Dorsal Horn; Pruritus; Interneurons; Neuralgia; Spinal Cord
PubMed: 37490401
DOI: 10.7554/eLife.86633 -
Brain : a Journal of Neurology Mar 2023Increased vigilance in settings of potential threats or in states of vulnerability related to pain is important for survival. Pain disrupts sleep and conversely, sleep...
Increased vigilance in settings of potential threats or in states of vulnerability related to pain is important for survival. Pain disrupts sleep and conversely, sleep disruption enhances pain, but the underlying mechanisms remain unknown. Chronic pain engages brain stress circuits and increases secretion of dynorphin, an endogenous ligand of the kappa opioid receptor (KOR). We therefore hypothesized that hypothalamic dynorphin/KOR signalling may be a previously unknown mechanism that is recruited in pathological conditions requiring increased vigilance. We investigated the role of KOR in wakefulness, non-rapid eye movement (NREM) sleep and rapid eye movement (REM) sleep in freely moving naïve mice and in mice with neuropathic pain induced by partial sciatic nerve ligation using EEG/EMG recordings. Systemic continuous administration of U69,593, a KOR agonist, over 5 days through an osmotic minipump decreased the amount of NREM and REM sleep and increased sleep fragmentation in naïve mice throughout the light-dark sleep cycle. We used KORcre mice to selectively express a Gi-coupled designer receptor activated by designer drugs (Gi-DREADD) in KORcre neurons of the hypothalamic paraventricular nucleus, a key node of the hypothalamic-pituitary-adrenal stress response. Sustained activation of Gi-DREADD with clozapine-N-oxide delivered in drinking water over 4 days, disrupted sleep in these mice in a similar way as systemic U69,593. Mice with chronic neuropathic pain also showed disrupted NREM and total sleep that was normalized by systemic administration of two structurally different KOR antagonists, norbinaltorphimine and NMRA-140, currently in phase II clinical development, or by CRISPR/Cas9 editing of paraventricular nucleus KOR, consistent with endogenous KOR activation disrupting sleep in chronic pain. Unexpectedly, REM sleep was diminished by either systemic KOR antagonist or by CRISPR/Cas9 editing of paraventricular nucleus KOR in sham-operated mice. Our findings reveal previously unknown physiological and pathophysiological roles of dynorphin/KOR in eliciting arousal. Physiologically, dynorphin/KOR signalling affects transitions between sleep stages that promote REM sleep. Furthermore, while KOR antagonists do not promote somnolence in the absence of pain, they normalized disrupted sleep in chronic pain, revealing a pathophysiological role of KOR signalling that is selectively recruited to promote vigilance, increasing chances of survival. Notably, while this mechanism is likely beneficial in the short-term, disruption of the homeostatic need for sleep over longer periods may become maladaptive resulting in sustained pain chronicity. A novel approach for treatment of chronic pain may thus result from normalization of chronic pain-related sleep disruption by KOR antagonism.
Topics: Mice; Animals; Receptors, Opioid, kappa; Dynorphins; Chronic Pain; Wakefulness; Narcotic Antagonists; Neuralgia
PubMed: 35485490
DOI: 10.1093/brain/awac153 -
Journal of Neurochemistry Dec 2020Regulation of axonal dopamine release by local microcircuitry is at the hub of several biological processes that govern the timing and magnitude of signaling events in... (Review)
Review
Regulation of axonal dopamine release by local microcircuitry is at the hub of several biological processes that govern the timing and magnitude of signaling events in reward-related brain regions. An important characteristic of dopamine release from axon terminals in the striatum is that it is rapidly modulated by local regulatory mechanisms. These processes can occur via homosynaptic mechanisms-such as presynaptic dopamine autoreceptors and dopamine transporters - as well heterosynaptic mechanisms such as retrograde signaling from postsynaptic cholinergic and dynorphin systems, among others. Additionally, modulation of dopamine release via diffusible messengers, such as nitric oxide and hydrogen peroxide, allows for various metabolic factors to quickly and efficiently regulate dopamine release and subsequent signaling. Here we review how these mechanisms work in concert to influence the timing and magnitude of striatal dopamine signaling, independent of action potential activity at the level of dopaminergic cell bodies in the midbrain, thereby providing a parallel pathway by which dopamine can be modulated. Understanding the complexities of local regulation of dopamine signaling is required for building comprehensive frameworks of how activity throughout the dopamine system is integrated to drive signaling and control behavior.
Topics: Action Potentials; Animals; Corpus Striatum; Dopamine; Dopamine Plasma Membrane Transport Proteins; Humans; Nerve Net; Presynaptic Terminals
PubMed: 32356315
DOI: 10.1111/jnc.15034